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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 9 Pathophysiologic and Life-Stage Considerations BODY WEIGHT Data on body weight are routinely collected as part of captive-animal management. The mean body weights of individual animals are often used as summary measures of body size and in the assessment of health status (Terranova and Coffman, 1997). These data can be used to monitor relationships among environment (including diet), genetics, and such diverse biologic issues as metabolic rate, growth, reproduction, and longevity (Lundrigan, 1996). The opportunity to collect systematic, repeated measurements on the same animal is rarely available in work with free-ranging specimens. However, such measures can be used to help identify health problems, evaluate the effect of changes in management practices, and establish standards for normal growth and development of captive primates (Lundrigan, 1996; Terranova and Coffman, 1997). The effects of captivity on body weight should be considered in direct comparisons of captive and noncaptive animals (Lundrigan, 1996; Leigh, 1994; Terranova and Coffman, 1997). Within anthropoid primate species, correlations between wild and captive weights are high (r = 0.95) (Leigh, 1994). However, captive lemurs (Eulemur, Hapalemur, and Varecia) were found to be, on the average, heavier than noncaptive conspecifics (Terranova and Coffman, 1997). The data on adult body weight in Table 9-1 are derived largely from studies of captive animals. For inclusion in this table, the data were required to meet the following criteria: actual weights only, no estimates; animal’s age and sex were known; weighed animals were alive, non-gravid, and physiologically normal (that is, no evidence of clinical disease); and animals were in good body condition (not emaciated or obviously obese). For comparisons with free-ranging primates, users might wish to refer to Silva and Downing (1995). In comparison with many other mammals, primates typically grow slowly (Oftedal, 1991), and rates of growth within a species or subspecies can be influenced by birth weight, rearing method (maternal vs hand-rearing), and sex (Ausman et al., 1985). Squirrel monkeys attained the body weights (± SD) of their dams and sires by the age of 3 years, 665 ± 122 and 990 ± 212 g, respectively (Ausman et al., 1985). Weight data on five model species for specific age categories from birth to adulthood are presented in Table 9-2. Obesity—as a consequence of excessive food intake, limited physical activity, or altered thermogenesis—can influence body weight measures. Adult body weights (± SD) of 14 male and 18 female squirrel monkeys classified as obese were 1,527 ± 246 g and 1,032 ± 229 g, respectively (Ausman et al., 1985). Chimpanzees were described as obese when mean adult weights were 68 kg in males and 61 kg in females (Smith et al., 1975). Judgments of obesity in captive primates have been made by comparing their body weights with those of noncaptive conspecifics. However, the weights of free-ranging primates might not be ideal, and other measures associated with fat accumulation, such as increased body-mass index, should also be considered. Animals in any species can exhibit obesity; the species seemingly at greater risk in captive surroundings are listed in Table 9-3. NUTRITION FROM BIRTH TO WEANING Growth “Normal” growth of infants is commonly considered a good indicator of adequate nutrition, whereas inadequate nutrition can, but does not always, result in suboptimal growth. Most early researchers, rearing infant nonhuman primates on milk replacers, strived to achieve growth patterns similar to those of infants reared by their mothers. Changes in body weight were commonly used measures of growth, but crown-rump length, limb length, and head circumference have also been used. Observer-to-observer variations in the latter measures tend to be greater, but
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 TABLE 9-1 Body Weight of Captive Adult Primates Taxon Sexa Mean ± SD (kg) Min (kg) Max (kg) n Location Country Reference Lorisidae Perodicticus potto b 1.280 ± 0.170 1.10 1.50 4 Midland, MI US Cowgill et al., 1989 Lemuridae Hapalemur griseus b 0.940 ± 0.145 0.66 1.55 25 Durham, NC US Terranova and Coffman, 1997 Varecia variegata rubra f 4.295 ± 0.494 3.60 5.30 4 San Diego, CA US Edwards, 1995 Varecia variegata variegata f 4.350 ± 0.475 3.80 |5.00 2 San Diego, CA US Edwards, 1995 b 3.524 ± 0.465 2.51 5.62 53 Durham, NC US Terranova and Coffman, 1997 Eulemur coronatus b 1.660 ± 0.238 1.12 2.98 30 Durham, NC US Terranova and Coffman, 1997 Eulemur fulvus rufus b 2.261 ± 0.341 1.59 3.59 41 Durham, NC US Terranova and Coffman, 1997 Eulemur fulvus sanfordi b 2.128 ± 0.205 1.72 2.90 17 Durham, NC US Terranova and Coffman, 1997 Eulemur macaco flavifrons b 2.339 ± 0.185 1.73 3.11 21 Durham, NC US Terranova and Coffman, 1997 Eulemur macaco macaco b 2.473 ± 0.260 1.59 4.00 66 Durham, NC US Terranova and Coffman, 1997 Eulemur mongoz b 0.618 ± 0.222 0.52 0.82 67 Durham, NC US Terranova and Coffman, 1997 Eulemur rubriventer b 2.060 ± 0.178 1.58 2.63 15 Durham, NC US Terranova and Coffman, 1997 Galagonidae Galago senegalensis m 0.235 0.215 0.257 — East Lansing, MI US Holmes et al., 1968 f 0.215 0.177 0.237 — East Lansing, MI US Holmes et al., 1968 Otolemur crassicaudatus m 1.300 — — — Kensington, MD US Valerio et al., 1972 f 1.100 — — — Kensington, MD US Valerio et al., 1972 Tarsiidae Tarsius bancanus m f Callithricidae Callithrix jacchus u 0.355 — — 8 Bethesda, MD US Power and Oftedal, 1996 Cebuella pygmaea u 0.133 — — 3 Washington, DC US Power and Oftedal, 1996 Leontopithecus rosalia u 0.678 — — 7 Washington, DC US Power and Oftedal, 1996 Saguinus fuscicollis u 0.310 — — 7 Oak Ridge, TN US Power and Oftedal, 1996 Saguinus oedipus m 0.490 — — — Bristol England Kirkwood, 1983 f 0.481 — — — Bristol England Kirkwood, 1983 u 0.472 — — 10 Oak Ridge, TN US Power and Oftedal, 1996 Cebidae Alouatta caraya m 10.70 — — 1 Cleveland, OH US Edwards, 1995 f 7.033 ± 2.139 4.72 8.94 3 Cleveland, OH US Edwards, 1995 Alouatta villosa m 6.192 ± 0.653 5.15 6.85 2 San Diego, CA US Edwards, 1995 Alouatta seniculus m 8.140 ± 0.698 7.50 9.15 2 San Diego, CA US Edwards, 1995 Cebus albifrons m 3.252 ± 0.858 — — 24 Boston, MA US Ausman et al, 1981 f 2.130 ± 0.564 — — 43 Boston, MA US Ausman et al, 1981 Cebus apella f 2.35 ± 0.160 — — 11 Athens, GA US Fragaszy and Adams-Curtis, 1998 f 4.40 — — 13 Yemassee, SC US Fragaszy and Bard, 1997 Siamiri sciureus (Leticia) m 0.990 ± 0.212 — — 7 Boston, MA US Rasmussen et al., 1980 f 0.665 ± 0.132 — — 129 Boston, MA US Rasmussen et al., 1980
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 Taxon Sexa Mean ± SD (kg) Min (kg) Max (kg) n Location Country Reference Cercopithecidae Cercocebus galeritus m 10.000 ± 0.361 9.60 10.30 1 San Diego, CA US Edwards, 1995 Colobus guereza m 10.750 ± 0.132 10.65 10.90 1 San Diego, CA US Edwards, 1995 f 11.34 — — 1 San Diego, CA US Edwards, 1995 Macaca mulatta m 8.8 ± 0.3 — — 9 Poolesville, MD US Baer et al., 1998 Mandrillus leucophaeus f 9.700 ± 0.700 8.90 10.20 1 San Diego, CA US Edwards, 1995 Pygathrix nemaeus m 12.083 ± 0.325 11.75 12.40 1 San Diego, CA US Edwards, 1995 Trachypithecus francoisi m 6.734 ± 0.869 5.75 7.78 3 San Diego, CA US Edwards, 1995 f 5.955 ± 0.478 5.67 6.67 2 Cleveland, OH US Edwards, 1995 Hylobatidae Symphalangus syndactylus m 12.8 ± 2.5 6.80 19.40 89 Various Various Orgeldinger, 1994 f 10.5 ± 1.7 6.80 15.70 87 Various Various Orgeldinger, 1994 Pongidae Gorilla gorilla gorilla m 147.05 117.90 174.60 4 Various Various Cousins, 1979 f 67.30 54.90 77.10 5 Various Various Cousins, 1979 Pan troglodytes m 53.20 — — 4 Kumamoto Japan Hamada et al., 1996 f 42.70 — — 4 Kumamoto Japan Hamada et al., 1996 m 53.40 — — — Atlanta, GA US Gavan, 1953 f 47.70 — — — Atlanta, GA US Gavan, 1953 f 55.00 — — — Atlanta, GA US Fragaszy and Bard, 1997 f 47.0 ± 4.9 — — 6 Atlanta, GA US Milton and Demment, 1988 aMale = m, female = f, both sexes = b, sex unreported = u. linear measures involving the skeleton are not as distorted by accumulations of fat as are body weights. MOTHER-REARED INFANTS Growth rates of captive, breast-fed, infant primates have been published in a number of handbooks and research articles (Jacobson and Windl, 1960; Long and Cooper, 1968; Sackett et al., 1979). For some species, there appear to be substantial differences in growth rates among animals raised at different US Regional Primate Research Centers. Growth rates of animals maintained in one of these centers, the Wisconsin Regional Primate Research Center, have been published (Goy and Kemnitz, 1983). The reasons for variation in growth rates of captive primates among centers have not been identified, but differences between colonies in genetic background, maternal nutrition during pregnancy and lactation, early availability of supplemental or weaning foods, and different rearing practices have been suggested. ARTIFICIALLY REARED INFANTS Published data on growth rates of formula-fed infants vary considerably (Blomquist and Harlow, 1961; Fleishman, 1963; Kaye et al., 1966; Vice et al., 1966; Kerr et al., 1969a, 1969b; Buss et al., 1970; King and King, 1970; Ausman et al., 1970, 1972, 1976, 1977, 1986, 1989; Kaplan, 1970, 1979; Samonds et al., 1973; Cicmanec et al., 1979; Moore and Cummins, 1979: Ruppenthal, 1979; Sackett et al., 1979; Golub et al., 1990). In some studies, growth rates of formula-fed infants were lower than those of nursing infants. Limited access to food (less-frequent feeding), low nutrient or caloric density of formulas, and lack of social contacts were offered as explanations for the differences. In other studies, artificially reared primates grew faster than mother-reared infants; in most of these cases, formula was available around the clock or very frequently, allowing on-demand feeding. Some mother-reared infants, particularly as early neonates, had difficulty in obtaining sufficient breast milk because of the low productivity of the mother’s mammary glands. That result is similar to what is sometimes seen in humans when formula-fed infants gain weight much faster than breast-fed infants because milk is more available. Milk Volume and Composition VOLUME Nutrient requirements of infants have been estimated by analyzing mothers’ milk and estimating the volume of milk consumed (Neville, 1986). Amounts of nutrients ingested per unit of infant body weight per day can then be determined. The determinations are sometimes used as minimal nutrient requirements when milk replacers are
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 TABLE 9-2 Body Weight of Captive Primates at Various Stages of Development Taxon Sexa Age BW (kg) Min (kg) Max (kg) n Location Country Reference Galagonidae Otolemur crassicaudatus u 0 d 0.047 ± 0.006 — — 77 Kensington, MD US Valerio et al., 1972 Galago senegalensis zanzibaricus u 1 d 0.015 — — 1 Wroclaw Poland Gucwinska and Gucwinski, 1968 2 d 0.014 ± 0.001 0.013 0.014 2 Wroclaw Poland Gucwinska and Gucwinski, 1968 6 d 0.023 ± 0.001 0.022 0.023 2 Harpenden England Brown, 1979 7 d 0.024 ± 0.003 0.022 0.026 2 Wroclaw Poland Gucwinska and Gucwinski, 1968 12 d 0.025 — — 1 Wroclaw Poland Gucwinska and Gucwinski, 1968 14 d 0.044 ± 0.007 0.039 0.048 2 Wroclaw Poland Gucwinska and Gucwinski, 1968 22 d 0.053 — — 1 Wroclaw Poland Gucwinska and Gucwinski, 1968 28 d 0.046 ± 0.008 0.041 0.052 2 Wroclaw Poland Gucwinska and Gucwinski, 1968 31 d 0.040 ± 0.001 0.035 0.045 2 Wroclaw Poland Gucwinska and Gucwinski, 1968 39 d 0.063 — — 1 Wroclaw Poland Gucwinska and Gucwinski, 1968 Callithricidae Saguinus oedipus oedipus m >2 y 0.490 — — — Bristol England Kirkwood, 1983 f >2 y 0.481 — — — Bristol England Kirkwood, 1983 Cebidae Cebus albifrons m 3080 d 3.252 ± 0.858 — — 24 Boston, MA US Ausman et al., 1981 f 0 d 0.226 ± 0.006 — — 10 Boston, MA US Wilen and Naftolin, 1978 >1245 d 1.617 ± 0.033 — — 10 Boston, MA US Wilen and Naftolin, 1978 2940 d 2.130 ± 0.564 — — 43 Boston, MA US Ausman et al., 1981 Cebus apella b 0 d 0.210 0.170 0.260 7 Athens, GA US Fragaszy and Adams-Curtis, 1998 b 0 d 0.210 ± 0.012 — — 5 Argentina Patiño et al., 1997 b 0 d 0.197 ± 0.020 — — 10 Argentina Patiño et al., 1997 b 28 d 0.317 ± 0.440 — — 5 Argentina Patiño et al., 1997 b 28 d 0.355 ± 0.035 — — 10 Argentina Patiño et al., 1997 b 56 d 0.472 ± 0.082 — — 5 Argentina Patiño et al., 1997 b 56 d 0.460 ± 0.110 — — 10 Argentina Patiño et al., 1997 b 84 d 0.597 ± 0.094 — — 5 Argentina Patiño et al., 1997 b 84 d 0.537 ± 0.097 — — 10 Argentina Patiño et al., 1997 b 112 d 0.678 ± 0.108 — — 5 Argentina Patiño et al., 1997 b 112 d 0.647 ± 0.110 — — 10 Argentina Patiño et al., 1997 b 140 d 0.779 ± 0.131 — — 5 Argentina Patiño et al., 1997 b 140 d 0.772 ± 0.166 — — 10 Argentina Patiño et al., 1997 Siamiri sciureus, Leticia m 0 d 0.116 ± 0.014 — — 37 Boston, MA US Russo et al., 1980 0 d 0.112 0.092 0.129 10 San Diego, CA US Long and Cooper, 1968 1 m 0.200 0.161 0.232 10 San Diego, CA US Long and Cooper, 1968 2 m 0.272 0.234 0.311 10 San Diego, CA US Long and Cooper, 1968 3 m 0.343 0.309 0.391 8 San Diego, CA US Long and Cooper, 1968 4 m 0.398 0.364 0.422 4 San Diego, CA US Long and Cooper, 1968 5 m 0.451 0.445 0.455 3 San Diego, CA US Long and Cooper, 1968 6 m 0.467 0.441 0.496 3 San Diego, CA US Long and Cooper, 1968 7 m 0.502 0.480 0.520 3 San Diego, CA US Long and Cooper, 1968 8 m 0.546 0.528 0.564 3 San Diego, CA US Long and Cooper, 1968 9 m 0.556 0.531 0.582 3 San Diego, CA US Long and Cooper, 1968 10 m 0.600 0.562 0.624 3 San Diego, CA US Long and Cooper, 1968 11 m 0.624 0.588 0.653 3 San Diego, CA US Long and Cooper, 1968 12 m 0.640 0.621 0.662 3 San Diego, CA US Long and Cooper, 1968 13 m 0.654 0.611 0.698 2 San Diego, CA US Long and Cooper, 1968 14 m 0.680 0.663 0.701 3 San Diego, CA US Long and Cooper, 1968 15 m 0.703 0.665 0.770 4 San Diego, CA US Long and Cooper, 1968
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 Taxon Sexa Age BW (kg) Min (kg) Max (kg) n Location Country Reference 16 m 0.709 0.677 0.756 4 San Diego, CA US Long and Cooper, 1968 17 m 0.729 0.694 0.788 4 San Diego, CA US Long and Cooper, 1968 18 m 0.731 0.660 0.797 4 San Diego, CA US Long and Cooper, 1968 19 m 0.751 0.698 0.808 4 San Diego, CA US Long and Cooper, 1968 20 m 0.758 0.713 0.814 4 San Diego, CA US Long and Cooper, 1968 21 m 0.758 0.716 0.829 4 San Diego, CA US Long and Cooper, 1968 22 m 0.779 0.730 0.827 4 San Diego, CA US Long and Cooper, 1968 23 m 0.792 0.760 0.822 4 San Diego, CA US Long and Cooper, 1968 24 m 0.817 0.765 0.868 4 San Diego, CA US Long and Cooper, 1968 25 m 0.853 0.816 0.885 4 San Diego, CA US Long and Cooper, 1968 26 m 0.862 0.843 0.894 4 San Diego, CA US Long and Cooper, 1968 27 m 0.867 0.839 0.895 3 San Diego, CA US Long and Cooper, 1968 28 m 0.905 0.863 0.966 3 San Diego, CA US Long and Cooper, 1968 29 m 0.911 0.866 0.964 3 San Diego, CA US Long and Cooper, 1968 30 m 0.900 0.849 0.965 3 San Diego, CA US Long and Cooper, 1968 31 m 0.906 0.835 0.973 3 San Diego, CA US Long and Cooper, 1968 32 m 0.913 0.837 0.978 3 San Diego, CA US Long and Cooper, 1968 33 m 0.921 0.854 0.985 3 San Diego, CA US Long and Cooper, 1968 34 m 0.916 0.867 0.962 3 San Diego, CA US Long and Cooper, 1968 35 m 0.931 0.907 0.959 3 San Diego, CA US Long and Cooper, 1968 36 m 0.942 0.918 0.962 3 San Diego, CA US Long and Cooper, 1968 >36 m 0.990 ± 0.212 — — — Boston, MA US Rasmussen et al., 1980 f 0 d 0.108 ± 0.014 — — 32 Boston, MA US Russo et al., 1980 0 d 0.106 0.084 0.144 11 San Diego, CA US Long and Cooper, 1968 1 m 0.191 0.156 0.235 10 San Diego, CA US Long and Cooper, 1968 2 m 0.269 0.222 0.324 9 San Diego, CA US Long and Cooper, 1968 3 m 0.316 0.271 0.389 6 San Diego, CA US Long and Cooper, 1968 4 m 0.359 0.307 0.447 6 San Diego, CA US Long and Cooper, 1968 5 m 0.397 0.353 0.465 6 San Diego, CA US Long and Cooper, 1968 6 m 0.425 0.368 0.507 6 San Diego, CA US Long and Cooper, 1968 7 m 0.452 0.389 0.552 6 San Diego, CA US Long and Cooper, 1968 8 m 0.471 0.395 0.563 6 San Diego, CA US Long and Cooper, 1968 9 m 0.487 0.415 0.577 5 San Diego, CA US Long and Cooper, 1968 10 m 0.507 0.427 0.607 5 San Diego, CA US Long and Cooper, 1968 11 m 0.522 0.460 0.610 5 San Diego, CA US Long and Cooper, 1968 12 m 0.548 0.475 0.618 5 San Diego, CA US Long and Cooper, 1968 13 m 0.570 0.503 0.647 3 San Diego, CA US Long and Cooper, 1968 14 m 0.620 0.567 0.673 2 San Diego, CA US Long and Cooper, 1968 >36 m 0.665 ± 0.122 — — — Boston, MA US Rasmussen et al., 1980 Cercopithecidae Macaca fascicularis m 0 d 0.369 ± 0.005 — — 166 Clamart France Dang et al., 1992 f 0 d 0.339 ± 0.005 — — 156 Clamart France Dang et al., 1992 Macaca mulatta m 0 d 0.498 ± 0.066 — — 255 Madison, WS US Kemnitz, 1994 0 d 0.453 — — 16 Bowman and Lee, 1995 336 d 1.880 — — — Bowman and Lee, 1991 f 0 d 0.464 ± 0.063 — — 255 Madison, WS US Kemnitz, 1994 0 d 0.473 — — 16 Bowman and Lee, 1995 336 d 1.805 — — — Bowman and Lee, 1991 Papio cynocephalus m 0 0.910 — — 9 San Antonio, TX US McMahan et al., 1976 f 0 0.820 — — 15 San Antonio, TX US McMahan et al., 1976 Pongidae Pan troglodytes b 0 1.800 42 Atlanta, GA US Gavan, 1953 0 1.820 77 Graham et al., 1985 0 1.770 ± 0.260 18 Kumamoto Japan Udono et al., 1989 0 1.830 ± 0.253 41 Kumamoto Japan Hamada et al., 1996 m 0 2.130 5 Holloman AFB US Smith et al., 1975 f 0 2.100 4 Holloman AFB US Smith et al., 1975 aMale = m, female = f, both sexes = b, sex unreported = u.
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 TABLE 9-3 Primate Species Identified as Potentially at Increased Risk of Obesity in Captive Environments (Leigh, 1994; Terranova and Coffman, 1997) Species Eulemur coronatus Macaca cyclopis Eulemur macaco flavifrons Macaca mulattaa Hapalemur griseus griseus Macaca arctoides Mandrillus leucophaeus Cercopithecus neglectusa Mandrillus sphinx Cercopithecus torquatus atysa aOnly aged adults of these species appear to be at risk. being formulated for artificial rearing. In reality, some nutrients appear to be present in breast milk at concentrations higher than required. Thus, such estimates can provide margins of safety for nutrients that are poorly absorbed from synthetic milk and ensure that milk replacers will be nutritionally complete. Milk volumes ingested by mother-reared infant primates are difficult to measure, and few data have been published (Oftedal, 1984). The commonly used weigh-suckle-weigh method, in which an infant is weighed before and after each nursing bout during a 24-hour (or longer) period, is not particularly applicable to primates, because an infant primate nurses often and might hold the nipple in its mouth when not nursing. As a consequence, it is difficult to determine when nursing starts and stops. Other methods for measuring milk consumption, such as the use of isotope dilution, have been used little with nonhuman primates, although Buss and Voss (1971) used such a technique with baboons (Papio cynocephalus). Formula intakes by artificially reared infants can be determined with reasonable accuracy by measuring volumes consumed over a long period (to modulate diurnal variations). Caution is urged because large holes in artificial nipples and the manipulative skills of young primates often lead to substantial losses of formula and overestimates of intake. If formula spillage is observed and ‘‘nonspillers’’ are selected for study, reliability of intake data can be enhanced. Caloric density of the formula must be taken into account because it will affect volumes of milk ingested. Some early researchers concluded that neonates of several species are incapable of handling nursing bottles and should be hand-fed at frequent intervals up to the age of 30-60 days. Other studies have found that newborn infants adapt quickly to the bottle and will self-feed soon after birth. COMPOSITION OF MOTHER’S MILK There are several reports on the gross nutrient composition of milk of nonhuman primate species (Van Wagenen et al., 1941; Pilson and Cooper, 1967;Buss 1968a, b, 1975; Buss and Cooper, 1970, 1972; Taylor and Tomkinson, 1975; Buss et al., 1976; Nishikawa et al., 1976; Turton et al., 1978; Lonnerdal et al., 1984) (Table 9-4). Many of the reports were published years ago, and some of the analytic methods are different from those of today. In some cases, the method of milk collection was such that samples obtained were not representative of milk consumed during a complete nursing bout; thus, a sampling bias was introduced (Oftedal, 1984). For example, fat concentrations in milk at the beginning of mammary evacuation can be one-third or less of concentrations near the end of mammary evacuation (Erb et al., 1977). Ideally, milk sampling replicates normal suckling behavior. It should include the normal interval for accumulation of milk before suckling and the normal amount of milk removed by suckling. If milk samples represent less than normal expression of the contents of the mammary gland, concentrations of fat and other nutrients can be in error. The stage of lactation also affects milk composition. As lactation progresses and infants are weaned, the volumes of milk produced per nursing bout decrease, and concentrations of fat and protein dramatically increase. Maternal diet can also affect some composition values if nursing mothers have been fed diets that are not nutritionally complete. Finally, excessively vigorous manual milking can result in bleeding that is insufficient to color the milk noticeably but sufficient to affect its composition. Various milking devices have been developed to obtain milk samples without causing trauma to the breast (Buss and Kriewaldt, 1968). Ketamine as a sedative and oxytocin to promote milk ejection have been helpful in the collection of milk samples and appeared to have no effect on milk composition (Buss, 1968b), but nonphysiologic doses and repeated injections of oxytocin might result in spurious values (Oftedal, 1984). There are reports on specific components of nonhuman-primate milk, including individual milk proteins (Davidson and Lonnerdal, 1986; Kunz and Lonnerdal, 1994), amino acids (Hayes et al., 1980; Buss and Cooper, 1970), oligosaccharides, triglycerides (Turton et al., 1978; Myher et al., 1994; Buss et al., 1976), cholesterol (Mott et al., 1982, 1985, 1990, 1993a,b), and minerals (Lonnerdal, 1984; Buss et al., 1976; Turton et al., 1978; Buss and Cooper, 1970). In chapter 5, detailed information about fatty acid composition of milk from different primates, and the effect of fat thereon, is provided. In many cases, the information was sought to explore the applicability of nonhuman primates as models for study of issues in human pediatric nutrition. Nutrient Intakes with Milk Replacers Nutrient intakes by artificially reared infants can be estimated by multiplying the volume of milk replacer ingested by the concentration of nutrients in the formula. Estimates of nutrient intake in commercial products will be more accurate if the milk replacer is analyzed, as opposed to
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 TABLE 9-4 Proximate Composition of Milk from Several Primate Species Species No. of Samples Lactation Stage, Days Dry Matter, % Fat,% Crude Protein,% Carbohydrates, % Ash, % References Lemuridae Brown lemur (Eulemur fulvus) 6 28-74 9.6 0.9 1.3 8.5 0.2 Tilden and Oftedal, 1997 2 90 — 2.75 1.95 6.2 0.295 Buss et al, 1976 Black lemur (Eulemur macaco) 7 30-82 10.1 1.1 1.5 8.4 0.3 Tilden and Oftedal, 1997 2 2-5 h; — 0.8 6.0 5.5 0.60 Buss et al, 1976 184 d 2.6 4.8 5.0 0.59 Lemur (Lemur catta) 3 7-161 — 2.5 3.23 6.43 0.37 Buss et al, 1976 Red-bellied lemur (Eulemur rubriventer) 3 26-57 10.3 0.8 1.1 8.9 0.2 Tilden and Oftedal, 1997 Mongoose lemur (Eulemur mongoz) 4 45-81 9.8 0.7 1.3 7.9 0.2 Tilden and Oftedal, 1997 Ruffed lemur (Varecia variegata) 5 17-48 14.0 3.2 4.2 7.7 0.4 Tilden and Oftedal, 1997 Galagidae Garnett’s bushbaby (Otolemur garnettii) 14 14-73 18.5 7.3 5.2 6.6 0.6 Tilden and Oftedal, 1997 Thick-tailed bushbaby (Otolemur crassicaudatus) 8 19-60 18.6 8.0 4.8 6.4 0.6 Tilden and Oftedal, 1997 Pilson and Cooper, 1967 Lorisidae Slow loris (Nycticebus coucang) 4 18-90 16.3 7.0 3.9 6.6 0.7 Tilden and Oftedal, 1997 Callitrichidae Golden lion tamarin (Leontopithecus rosalia) 1 3 — 5.8 5.7 6.9 0.78 Buss, 1975; 4 10-55 19.4 10.2 3.0 6.8 — Oftedal and Iverson, 1995 Common marmoset (Callathrix jacchus) 4 14-75 — 7.14 3.56 7.5 0.26 Turton et al, 1978 Cotton-top tamarin (Saguinus oedipus) 3 — 13.1 3.1 3.8 5.8 0.4 Jenness and Sloan, 1970 Cebidae Red howler (Alouatta seniculus) 7 30-150 11.3 1.1 1.9 6.6 — Oftedal and Iverson, 1995 Mantled howler (Aloutta palliata) 7 30-150 11.7 1.6 2.2 6.7 — Oftedal and Iverson, 1995 Squirrel monkey (Saimiri sciureus) 13 — — 5.1 3.5 6.3 0.3 Buss and Cooper, 1972 Squirrel monkey (Saimiri sciureus) 2-7 — — 3.3 4.3 0.1 — Hopf, 1970 Squirrel monkey (Saimiri sciureus) 2 — — 1.0 3.0 7.0 0.2 Jenness and Sloan, 1970 Cercopithecidae Talapoin monkey (Cercopithecus talapoin) 5 17-38 12.3 2.9 2.1 7.2 0.28 Buss and Cooper, 1970 Crab-eating macaque (Macaca fascicularis) 8 44-119 12.2 5.2 1.6 — 0.4 Nishikawa et al., 1976 Japanese macaque (Macaca fuscata) 7 35-56 14.0 4.2 1.6 6.2 — Ota et al., 1991 Rhesus macaque (Macaca mulatta) 13-18 16-35 15.6 4.6 2.3 7.9 0.8 Lönnerdal et al., 1984; 45 3.0 2.1 5.9 0.26 Wagenen et al., 1941 Baboons (Papio anubis, Papio cynocephalus, Papio papio) 24 21-63 14.0 4.5 1.5 7.8 0.3 Buss, 1968a; Roberts et al., 1985 Lowland gorilla (Gorilla gorilla) 1 13 . 2.05 3.0 3.60 0.28 Taylor and Tomkinson, 1975 Humans (Homo sapiens) Mature 11.6 3.2 0.89 7.4 0.143 Fomon, 1993 Humans (Homo sapiens) 1160 >10 12.4 4.1 0.8 6.8 0.2 Jenness, 1979 depending upon the product label. To ensure that label claims will be met, manufacturers often incorporate excesses of some nutrients to account for loss during production, storage, and use. Formulas Used for Artificially Rearing Infant Nonhuman Primates Early on, it was found that milk formulas intended for human infants could be used to rear some newborn nonhuman primates (Table 9-5). Originally, human-infant formulas were used to ensure survival of newborn monkeys that had lost their mothers. That was successful, and it was soon recognized that artificially reared (formula-fed) nonhuman primates could be used as animal models for studies of nutrition, growth, and development of human infants (Ausman et al., 1977, 1986, 1989; Samonds and Hegsted, 1973, 1978). For some nonhuman-primate species, however, the proportion of metabolizable energy provided by protein (usually 5-10%) was too low, and protein malnutrition was induced, since those species normally produce milk in which protein accounts for 12-16% of metabolizable energy. Later, higher-protein diets that successfully nourish these infants were developed (Samonds and Hegsted, 1978; Ausman et al, 1989). It is difficult to prepare liquid diets in the laboratory that keep nutrient sources in a homogeneous suspension. Some particles precipitate and others float, causing varia-
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 TABLE 9-5 Composition of Nonhuman-Primate Milk, Human Milk, and Human-Infant Formula Constituent Rhesusa Infant Formulab Human Milk Baboonc Lipids, % 4.6-5.4 3.6 4.6 4.6-5.8 Protein, % 2.3-2.5 1.5 1.3 1.5-1.7 Carbohydrate, % 7.8-8.1 7.2 7.1 7.4-7.7 GE, kcal·L-1 820-910 670 670 770-900 Calcium, mg·L-1 364-420 420 270 Magnesium, mg·L-1 31-33 45 34 Iron, mg·L-1 1.1-1.2 1.5, 12d 0.2-0.6 Zinc, mg·L-1 1.8-2.4 5.4 0.5-3.0 Copper, mg·L-1 0.5-1.2 0.5 0.2-0.4 Sodium, mg·L-1 82-96 150 184 Potassium, mg·L-1 242-276 560 470 aMature milk (Lönnerdal et al., 1984). bSMA® (Wyeth-Ayerst). cBuss (1968b). dUnfortified/iron-fortified formula. tions in caloric and nutrient intake. Thus, if self-fed, a nutritionally dilute formula might be consumed during some hours, and a thick, nutrient-dense diet at others. Other reports indicate that the vitamin D content of some human infant formulas may be too low to support normal bone growth in some nonhuman primates; the use of vitamin D supplement drops would be required. A variety of options for preparation of milk replacers that match the milk composition of many mammal species has been developed by commercial manufacturers. Long-Term Consequences of Different Modes of Infant Feeding Development of feeding regimens that produced satisfactory growth in artificially reared infant nonhuman primates led to studies of the long-term physiologic and metabolic consequences of early nutrition. Examples of long-term, carefully controlled studies include those focusing on effects of dietary taurine on development of visual and brain function (Hayes et al., 1980; Stephan et al., 1981; Sturman et al., 1984, 1988), the relationship of cholesterol intake and plasma lipoproteins, bile acid metabolism, and atherosclerosis (see Chapter 5), and the effect of marginal zinc deficiency on growth, immune function, and behavior (Hendrickx, 1984; Strobel and Sandstead, 1984; Golub et al., 1984, 1985, 1991; Haynes et al., 1985; Keen et al., 1989: Lonnerdal et al., 1990a, b; Liu et al., 1992; Polberger et al., 1996). Not only has important information regarding the specific nutrients being studied been obtained, but the studies provide important lessons for long-term management of nonhuman-primate research facilities and for conduct of primate research. It is important to recognize that the composition of commercial infant formulas is only as good as our current knowledge of human infant nutrition. For example, taurine was not added to infant formulas until the 1980s, although it is a major free amino acid in human milk and has specific metabolic roles. In fact, nonhuman-primate studies were instrumental in gaining approval for taurine supplementation of human-infant formulas in the 1990s. Another important consideration, despite the fact that formula rearing can lead to growth patterns similar to those of mother-reared infants, is that mode of feeding (natural vs formula) can lead to long-term differences in metabolism of nutrients and in health and development (Lucas, 1990). That is illustrated by a series of experiments performed on breast-fed and formula-fed baboons (Mott et al., 1982, 1985, 1990, 1993 a, b; Jackson et al., 1993; Lewis et al., 1988, 1993). Although many metabolic indices were similar in the two groups during infancy, plasma lipoprotein patterns, cholesterol levels and forms, arterial plaque formation, and bile acid conjugation were considerably different in both juvenile and adult baboons. This metabolic “imprinting” suggests that infant nonhuman primates that have been artificially reared might respond to some study conditions quite differently from animals that have been breast-fed. Furthermore, even though growth and development of infant nonhuman primates fed diets marginally deficient in single nutrients appear to be normal, subtle, less apparent impairments can have long-term consequences. For example, the marginally zinc-deficient pregnant rhesus monkey can deliver an infant that is apparently normal but has defects in immune function and in behavior that are not overcome by consumption of a zinc-sufficient diet (Golub et al., 1984; Haynes et al., 1985). The association of such signs with a prenatal or early postnatal nutritional insult is particularly difficult to diagnose because marginal zinc deficiency usually does not affect plasma zinc concentration or other potential indicators of zinc status.
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 Weaning Foods and Strategies Weaning hand-reared infant primates of the usual laboratory species from a bottle to solid food is not particularly difficult. For infants fed semipurified milk replacers, the same ingredients can be formulated into solid diets with gelling agents, such as agar. Sugars, such as lactose or glucose, can be used in place of the starch, dextrins, and dextromaltose that are so commonly used in semipurified diets for adults. Provision of a solid diet simultaneously with the liquid diet allows infants to become accustomed to the novelty of a new food, providing opportunities to smell, touch, taste, and carry it around long before appreciable quantities are consumed. By the age of 2-4 months, infant monkeys still consuming liquid diets with lactose or glucose as a carbohydrate can be converted to solid diets containing ‘‘adult’’ carbohydrates or any of a variety of natural-ingredient-based products. Older monkeys generally prefer to handle and chew their food rather than drink it. NUTRITION AND AGING Dietary Restriction Humans share many age-related phenomena with great apes and Old World monkeys. If biologic aging of nonhuman primates is studied longitudinally, data representing a substantial portion of the human life span can be obtained within relatively few years (Short et al., 1987). Because of their close genomic relationship, the most relevant models of human aging may be chimpanzees (Pan troglodytes) or bonobos (P. paniscus), but the costs of acquisition and care of these species, combined with longevities of more than 5 decades in captivity, renders their use prohibitive. Perhaps rhesus (Macaca mulatta), pigtail (Macaca nemestrina), and celebes (M. nigra) macaques are more practical; all have been used as models for studies of aging (Hansen et al., 1981; Howard, 1983; Kemnitz et al., 1993; Lane et al., 1996). They share aging maladies with humans, including atherosclerotic vascular disease, altered plasma lipid metabolism, signs of Alzheimer’s disease, menopause, diabetes mellitus, rheumatoid arthritis, obesity, and osteoporosis (Brown et al., 1974; Howard, 1983; Kaplan et al., 1985; DeRousseau, 1985a,b; Willcox et al., 1986; Sumner et al., 1989; Hansen, 1992; vom Saal et al., 1994; DeRousseau, 1994; Austad, 1997; Cefalu et al., 1997; Colman and Kemnitz, 1998). Early reviews described age-related changes in old primates (Bowden, 1979; Davis and Leathers, 1985; Short et al., 1987). Many current studies in primate gerontology are focused on age-related disorders that are influenced by nutrition. Undoubtedly, many factors accelerate aging, but alterations in diet composition and limitations in the amount of food consumed have proved to be effective modulators of this process. Diet restriction, in the absence of essential-nutrient deficiencies, plays a positive and fundamental role in increasing survival and in delaying the onset and slowing the development of degenerative aging conditions (McCay et al., 1935; Tannenbaum, 1940; Merry and Holehan, 1979; Bodkin et al., 1995; Lane et al., 1996; Cefalu et al., 1997; Verdery et al., 1997). It is the only intervention consistently shown to extend both median and maximal life span in mammals (Weindruch and Walford, 1988; Weindruch et al., 1995; Roth et al., 1995). Many types of diets work. Both highly purified diets and commercial diets increase maximal life span when fed in reduced amounts, provided that all essential nutrients are present and moderate reductions in caloric intake are achieved (Weindruch, 1995). It is probable that experimentally increasing the maximal age of research animals at death will yield important insights into the systematic processes of aging (Hayflick, 1985). Likewise, increasing the life span of research subjects will assist in the definition of biomarkers of aging, attributes that generally change with age and could help in predicting health and length of life (Ingram et al., 1993). A preliminary aging study with 30 male rhesus macaques (M. mulatta) 0.6-25 years old and 30 male squirrel monkeys (Saimiri sciurius) 1 to more than 10 years old, representing Old World and New World species, respectively, was begun in 1987 for the National Institute on Aging (NIA) at the National Institutes of Health (NIH) Primate Unit of the National Center for Research Resources in Poolesville, MD (Ingram et al., 1990; Lane et al., 1992; Moon and Taylor, 1994; Roth et al., 1995). These species have natural life spans of about 40 and 20 years, respectively. The study was later expanded to include 120 female and male rhesus macaques and 30 male squirrel monkeys of various ages. All except the oldest animals, were caged as pairs (Weindruch et al., 1995). Separate pelleted natural-ingredient diets were fed to each species. The proximate proportions of components of the diets (by weight) for rhesus and squirrel monkeys, respectively, were as follows: 15.4% and 20.3% crude protein; 5.0% and 8.0% crude fat; and 5% and 5% crude fiber. Gross energy (GE) concentrations in the rhesus and squirrel monkey diets were 3.77 kcal·g-1 and 4.03 kcal·g-1, respectively. Each diet was supplemented with vitamins and minerals at concentrations 40% above recommended allowances (Ingram et al., 1990; Weindruch et al., 1995). Diet-restricted primates were fed about 30% less than normally fed controls of each species and were adapted to the lower intakes over a 3-month period. Daily diet allotments during the preliminary study were based on National Research Council (National Research Council, 1978) estimates of GE requirements in kilocalories per kilogram of body weight (BW). Daily GE intakes by juvenile, adult, and old rhesus macaques fed ad libitum were
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 216, 145, and 93 kcal·kg-1 of BW, respectively, and by diet-restricted juvenile, adult, and old rhesus macaques were 153, 102, and 66 kcal·kg-1 of BW. Daily GE intakes by juvenile, adult, and old squirrel monkeys fed ad libitum were 341, 264, and 229 kcal·kg-1of BW, respectively, and for diet-restricted squirrel monkeys 242, 188, and 160 kcal·kg-1 of BW, respectively. Those values were calculated on the basis of measured daily dietary intakes in grams, GE concentrations of the diets, and average BW of the animal groups (Ingram et al., 1990). A second aging primate study, done at the University of Wisconsin Regional Primate Research Center, was initiated concurrently (Kemnitz et al., 1993; Weindruch, 1996; Ramsey et al., 1997, 2000). An original group of 30 adult male rhesus macaques (M. mulatta) 8-14 years old, divided into 15 fed ad libitum and 15 that were diet-restricted to 30% below ad libitum intake, was expanded to include 16 additional male and 30 female rhesus macaques (Moon and Taylor, 1994). The monkeys were individually caged to control access to diet and to allow accurate daily measurement of dietary intake and feed waste. All monkeys were fed a defined, pelleted diet containing (by weight) 15% lactalbumin, 10% corn oil, about 65% carbohydrate, and 5% cellulose (Kemnitz et al., 1993; Ramsey et al., 1997). Ad libitum-fed controls were given free access to this semipurified diet for 6-8 h·d-1 while diet-restricted monkeys were fed the diet at 70% of their baseline intake, predetermined individually. A piece of fresh fruit was provided daily (kind and energy contribution not identified). The semipurified diet furnished ME at an estimated 3.98 kcal·g-1 using the percentages and ME values of individual ingredients in the formula as provided by Merrill and Watt (1955). A third aging primate study, done at the University of Maryland, examined the effects of ME restriction and its relation to obesity and signs of diabetes in adult rhesus macaques (M. mulatta) (Hansen and Bodkin, 1993; Bodkin et al., 1995). After the macques reached full maturity, ME intake was restricted by weekly diet-intake adjustments to maintain a stable adult weight of 10-12 kg (Hansen and Bodkin, 1993). That method of caloric titration retarded middle-age-onset obesity (which is common in rhesus monkeys) and resulted in lower blood insulin concentrations and higher glucose tolerance in the diet-restricted animals (Hansen and Bodkin, 1993). After 9 years of diet restriction, the daily ME intake required to maintain a stable adult BW proved to be 40% less than the ME intake by ad libitum-fed controls. Seven older (average, 20.7 years) male rhesus macaques (M. mulatta) were kept on a restricted diet for about 9 years. Seven male rhesus of similar age (average, 21 years), with no evidence of diabetes or impaired glucose tolerance served as ad libitum-fed controls (Bodkin et al., 1995). Four of the ad libitum-fed males were offered a standard commercial monkey diet with a composition (by weight) of 17% protein, 70% carbohydrate, 13% fat, and ME at 3.5 kcal·g-1. Three ad libitum-fed males were provided a complete liquid diet (Ensure®, Ross Laboratories, Columbus, OH) designed for human consumption, containing 14% protein, 55% carbohydrate, 31% fat, and ME at 4.9 kcal·g-1 of DM. In dilute form, this product provided ME at 1.0 kcal·ml-1. The diet-restricted monkeys were fed the commercial monkey diet three times per day. Restrictions in diet intake resulted in an average 35% reduction in ME intake compared with the ad libitum-fed controls, or ME at 582 and 894 kcal·d-1, respectively (Bodkin et al., 1995). After 1 year of the NIA study, diet restriction appeared to have had a greater effect on BW gain among squirrel monkeys than among rhesus when absolute BW gain in diet-restricted animals was expressed as a percentage of that in controls (Ingram et al., 1990). When juvenile and adult rhesus macaques were diet restricted, absolute BW increases were 48% and 29% of those observed in ad libitum-fed controls, respectively. The absolute BW increases in the diet-restricted squirrel monkey juveniles and adults were only 35% and 24% of those in ad libitum-fed controls, respectively. When rates of BW gain in diet-restricted animals were expressed as a percentage of those in ad libitum-fed controls, relative gains were 46% and 49% for juvenile and adult rhesus macaques, respectively. For juvenile and adult squirrel monkeys, these estimates were 32% and 20%, respectively. Absolute diet consumption was reduced by 23% and 24% in diet-restricted juvenile and adult rhesus, respectively; the corresponding reductions in squirrel monkeys were 22% and 24%. Old monkeys of both species continued to gain BW when fed their respective diets. After 1 year of diet restriction, the adult rhesus macaques in the Wisconsin study were in apparent good health and had no clinical evidence of detrimental effects. The adult ad libitum-fed controls had dietary intakes below National Research Council (1978) recommendations (Ingram et al., 1990), but average BW increased by 9% during the first year of the study (Kemnitz et al., 1993). The diet-restricted monkeys did not gain BW and had 33% less body fat than the controls, but there were no lean body mass differences until after 2 years (Ramsey et al., 1997). Dual-energy x-ray absorptiometry (DEXA) was used to measure the effect of 20-30% dietary restriction on body composition at baseline and after 6, 12, and 18 months (Colman et al., 1998). At baseline, males had significantly (P < 0.05) greater values than females for BW, body mass index, total body lean tissue mass, appendicular skeletal mass, and total body bone mineral concentration. When analyzed longitudinally through 18 months, ad libitum-fed females had significantly increased BW, total body fat tissue mass, total body percent fat tissue mass, total body lean tissue mass, appendicular skeletal muscle mass, total body bone mineral concentration, and abdominal fat tissue mass relative to diet-
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 restricted females. Ad libitum-fed males had significantly increased BW, total body fat tissue mass, total body bone mineral concentration, and abdominal fat tissue mass relative to diet-restricted males. The primary effect of dietary restriction in both sexes was on total body fat tissue mass. The diet-restricted monkeys were restricted further after 18 months to re-establish a 30% difference in food intake between the two groups because the ad libitum-fed controls had voluntarily decreased their food intake. After 3 years of diet restriction (70% of the ME intake of controls), body fat mass and lean body mass were significantly (P < 0.05) lower than in the ad libitum-fed control group (Ramsey et al., 1997). A comparison of DEXA with traditional somatometric measures for determining body fat in adult male rhesus monkeys was made at various time points over a 4-year period (Colman et al., 1999). Additionally, the precision of these methods was assessed by repeated measures on the same individuals. DEXA estimates of body fat were positively correlated with body weights, body fat mass indices, body circumferences, and abdominal skinfold thicknesses. DEXA assessments of soft-tissue composition were precise, with low coefficients of variation. The majority of observed variability in somatometric measures was explained by subject variance rather than by inter- or intraobserver variability or observer experience level. These researchers concluded that noninvasive DEXA technology provides precise estimates of body composition that correlate well with the somatometric measures traditionally used in primate studies. No significant differences in physical activity were apparent between diet-restricted and ad libitum-fed rhesus macaques during the first 30 months of the Wisconsin study (Weed et al., 1997). This was similar to the finding of DeLany et al. (1998), at the University of Maryland, who reported that physical activity was similar for ad libitum-fed and diet-restricted male rhesus macaques when matched for age and BW. Nevertheless, Weed et al. (1997) reported that there were clearly discernable differences in diurnal and circadian activity in diet-restricted rhesus macaques after 6 years on the Wisconsin study. Some diet-restricted individuals exhibited increased pacing and grooming behaviors. These changes in activity were not, however, related to measured alterations in 24-hour energy balance. After 4.5 years, body composition and energy balance of 30 male rhesus in the NIA study were measured. The data were grouped by primate age: juveniles (6.5-7 years old), adults (8.5-10 years old), and old (over 24 years old). Both diet-restricted and ad libitum-fed monkeys were represented in the juvenile and adult groups, but all the old monkeys were ad libitum-fed (Lane et al., 1995a). Absolute body fat was not significantly altered by diet restriction, but the percentage of lean body mass decreased with age as the percentage of body fat increased. Despite substantial differences in food intake, the percentage of dietary energy that was apparently digestible (83%) was similar in all groups. The anti-aging effects of diet restriction are believed to be associated with changes in energy metabolism. Rectal body temperature decreased progressively with age from 2 to 30 years in rhesus macaques fed ad libitum but was about 0.5°C lower in age-matched monkeys subjected to 6 years of diet restriction (Lane et al., 1996). During short-term diet restriction, 24-hour energy expenditure was reduced by about 24% (Lane et al., 1996). Absolute energy expenditures (as determined by the doubly labeled water method) over 24 hours were consistently lower in diet-restricted monkeys; but when expressed as a function of metabolic mass, 24-hour energy expenditures and energy balances were not different between long-term diet-restricted and ad libitum-fed monkeys (Lane et al., 1995a). DeLany et al. (1998) found, however, that energy expenditure (also determined by the doubly labeled water method) was lower in rhesus monkeys that were diet-restricted for more than 10 years than in ad libitum-fed controls, even with correction for differences in body size with BW, surface area, or lean body mass as a covariate. Weekly adjustments of energy intake to maintain a stable BW over the long term were shown to prevent obesity and the onset of type II diabetes, a disease that develops in many middle-aged rhesus monkeys (Hansen and Bodkin, 1993). Ramsey et al. (1996) reported that nighttime energy expenditures (determined by indirect calorimetry) were significantly (P < 0.001) lower in rhesus macaques at the 24- and 30-month assessments of diet restriction than in ad libitum-fed controls after adjustment for lean body mass. However, morning, afternoon, and total energy expenditures did not differ between groups. Dietary intakes and morphologic measurements of the NIA rhesus macaques and squirrel monkeys were reported after 5 years on the study. The target diet restriction was to 70% of ad libitum intake; the average diet restriction for the two younger groups of rhesus macaques was to 67%, whereas the average diet restriction for the two younger groups of squirrel monkeys was to 78% (Weindruch et al., 1995). Nutritionally adequate restricted diets reduced BW and crown-rump length by 10-20% in rhesus monkeys. However, the influence of diet restriction on squirrel monkeys was less obvious, probably because the restriction did not reach the target for this species. Such health measures as body temperature, adiposity, blood pressure, and blood concentrations of glucose, insulin, and triglycerides were reduced, and there was a trend toward lower blood concentrations of glycosylated hemoglobin in the diet-restricted rhesus monkeys in the Wisconsin study after 5 years (Moon and Taylor, 1994; Weindruch, 1996). Insulin sensitivity, however, increased in the diet-restricted monkeys, and this was linked to changes in BW and abdominal girth.
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 by diet restriction in rats (Sell et al., 1996), and despite the lack of statistical significance, diet-restricted male Wistar rats and male rhesus monkeys generally exhibited a trend toward faster healing than their ad libitum-fed controls (Roth et al., 1997). Atherosclerosis Atherosclerosis remains one of the most important age-associated diseases in humans. Most studies that use nonhuman primates to examine the relation of diet to atherosclerotic risk include diets that are isocaloric but with modifications in concentrations of cholesterol, in fatty acid distribution, or in the relative proportions of energy from fat, carbohydrate, and protein (Verdery et al., 1997). Studies with the adult diet-restricted monkey model (intake reduced by 30%, 5% dietary fat, and cholesterol at 4.5 mg per 100 g) have produced decreased plasma concentrations of triglycerides and increased concentrations of HDL2b, the high-density lipoprotein subfraction associated with protection from atherosclerosis. Differences in plasma lipid and lipoprotein concentrations occurring with diet restriction could be accounted for, in part, by decreased BW and improved glucose regulation. The results suggest that diet restriction, as mediated by its beneficial effects on body composition and glucose metabolism, could affect human longevity by decreasing atherosclerotic incidence. Plasma concentrations of low-density lipoprotein (LDL) cholesterol were similar in ad libitum-fed and diet-restricted rhesus monkeys more than 5 years old (82 vs 72 mg·dl-1, respectively [Edwards et al., 1998]). However, LDL particles from diet-restricted animals had a significantly lower molecular weight (2.9 vs 3.2 g·µmol-1, respectively) and were depleted in triglyceride (249 vs 433 mol·particle-1, respectively) and phospholipid (686 vs 837 mol·particle-1, respectively). Thus, diet restriction might be an intervention that retards the consequences of aging, in part by altering factors that contribute to atherogenesis. BODY COMPOSITION Although it is well documented in the human-nutrition literature, relatively few studies have been conducted to determine the variability of body composition of nonhuman primates. Body composition is typically described in terms of body fat and lean body mass. Lean body mass (LBM) is defined as body weight minus ether-extractable fat and is thus synonymous with fat-free mass (Forbes, 1990). A number of factors influence body composition, including nutrient and energy intake, sex, age, and level of activity. Total dissections of pygmy chimpanzees suggest that males have a higher proportion of muscle relative to body weight than females (McFarland and Zihlman, 1994). Young adult (6-9 years old) and middle-age (13-19 years old) male rhesus macaques had more lean soft tissue and less body fat than females in the same age classes (Hudson et al., 1996). The percentage of body fat was greatest during middle age in females and during older adulthood (20-36 years old) in males. There was progressive loss of weight and lean body mass during older adulthood in both sexes in the same animals (Kemnitz, 1994). In adult rhesus macaques the androgenic hormones, testosterone and dihydrotestosterone, promote increases in body mass, which is largely attributable to accretion of lean tissue (Kemnitz et al., 1988). When body composition was measured in squirrel monkeys during growth, moisture and protein concentrations were found to be linearly related to body mass, but fat and ash were not (Russo et al., 1980). No sex differences were detected. The effects of nutrient and caloric intakes on body mass and composition are of particular interest. The influence of moderate caloric restriction (to 70% of ad libitum intake) on body mass and composition have been evaluated in Macaca mulatta (Wolden-Hanson et al. 1992). After 12 months of caloric restriction, body weights of restricted animals were 89% of weights of controls; the difference was attributed to reductions in body fat (65% of that in controls). After 24 months, restricted animals weighed 75% as much as control animals, with body fat and LBM40% and 93% of those in controls, respectively. Similar differences in body weight and LBMwere observed in animals that were ad libitum-fed or calorie-restricted (to 70% of ad libitum) over a 4.5-year period (Baer et al., 1998). However, there were no statistically significant differences in body fat (Table 9-6). Body composition was determined in lean (control) male squirrel monkeys, fatted controls, and obese monkeys. The mean body composition of lean animals, with body weights of 733-950 g, was 64.3% water, 21.7% protein, 7.0% fat, and 7.0% ash and miscellaneous. The validity of body-composition data is strongly related to the methods used to obtain them. Advantages and disadvantages of the various techniques used in human studies have been reviewed (Forbes, 1990). The animal-care TABLE 9-6 Physical Characteristics (Mean ± SD) of Control (Ad Libitum-Fed) and Diet-Restricted (30% Restriction) Macaca mulatta after 4.5 Years (Baer et al., 1998) Control (n = 9) Diet-Restricted (n = 10) Body weight, kg 8.8 ± 0.3 7.4 ± 0.3a Body mass index, kg·m-2 27.3 ± 0.8 22.6 ± 0.7a Lean body mass, % 7.7 ± 0.3 6.3 ± 0.3a Body fat, % 12.1 ± 2.2 14.2 ± 2.0 aMeans in the same row were different (P 0.05).
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 restrictions associated with use of nonhuman primates as study subjects limit the techniques that can be used. Meehan et al. (1989) evaluated deuterium oxide (D2O) dilution, bioelectric impedance (BIA), and skinfold thickness for assessing body composition in western lowland gorillas (Table 9-7).Body-composition estimates based on D2O dilution were not statistically different from those based on the BIA method. Skinfold measurements were highly variable and could not be correlated with either method. OBESITY Growth of primates includes changes in body composition (Alberts and Altmann, 2001). True growth can be defined as an increase in the size of muscles, bones, internal organs, and other associated parts of the body, as contrasted with fat deposition. After adult dimensions are reached, body remodeling continues; and during aging, the body tends to accumulate fat and lose lean. With a persistently positive energy balance, accumulations of adipose tissue cause body weights to increase, and this ultimately leads to obesity. A natural tendency for captive rhesus monkeys to develop obesity was observed first by Hamilton et al. (1972) and later by Kemnitz and co-workers (Kemnitz et al., 1989; Schwartz et al., 1993; Wolden-Hanson, et al., 1993) and by Jen et al. (1985). The incidence of obesity in free-ranging, provisioned rhesus monkeys on the Puerto Rico island of Cayo Santiago was 7% (Schwartz et al., 1993), which was about 20% less than observed in laboratory rhesus monkeys (Jen et al., 1985; Kemnitz et al., 1989). The frequency of obesity in rhesus monkeys in the wild is unknown but is believed to be lower (Kemnitz et al., 1989). Studies on development of spontaneous obesity in other macaque species have been reviewed (Kemnitz, 1984). The incidence and degree of obesity in bonnet macaques, stumptailed macaques, and pigtailed macaques appear to be similar to those in the much more extensively studied rhesus monkey. A rather high incidence (20-60%, depend TABLE 9-7 Body Fat (%) Determined with Three Methods in Western Lowland Gorillas (Meehan et al., 1989) Method Mean ± SD Min Max Female D2O 29.5 ± 4.1a 6.7 44.5 BIA 35.4 ± 2.3a 27.0 50.4 Skinfold 20.3 ± 1.1b 16.8 25.9 Male D2O 15.9 ± 2.2a 8.1 19.8 BIA 22.1 ± 3.1a 12.4 30.2 Skinfold 19.9 ± 0.7b 18.1 22.1 a,bStatistically significant difference among methods (P < 0.05, Tukey test). ing on age) of spontaneous obesity has been noted in squirrel monkeys raised in the laboratory on semipurified liquid diets (Ausman et al., 1981). In contrast with squirrel monkeys, cebus monkeys (Cebus albifrons) did not exhibit a trend toward obesity before or after sexual maturation when maintained and fed similarly for a 7-year period (Ausman et al., 1981). In all settings, it is apparent that only some animals become obese. The data suggest there may be an individual genetic predisposition to obesity in the monkey, as in humans. Furthermore, in monkeys, the predisposition might be species-specific. When unlimited calories are available, only some animals—those with a genetic predisposition—develop obesity. The genetic components of this phenomenon are not understood. The rhesus monkey has been used as a model for studies of the causes and effects of obesity in humans by both Wisconsin and Maryland groups. The measures used to describe obesity include a variety of combinations of somatometric, compositional, and body weight data. The definition of obesity in one study was based on body weight: obese monkeys were those which had body weights greater than 2 standard deviations (SD) above the mean for their sex (Kemnitz et al., 1989). A remarkably high correlation (r = 0.978) has been found between body mass index (body mass [or weight] in kilograms divided by the square of crown-rump length in meters) and body fat mass in a group of seven obese and seven normal-weight males and females. Body fat was estimated with tritiated water (for method, see Kemnitz and Francken, 1986). Jen et al. (1985) developed a similar measure, termed the obesity index Rh (body mass [or weight] in kilograms divided by the square of crown-rump length in centimeters), to characterize the fatness of individual rhesus macaques. This measurement was chosen as an appropriate descriptor of obesity based on its high correlation with body weight and blood concentrations of insulin and glucose and its lack of correlation with height. When fat constituted over 25% of body mass, Jen et al. (1985) defined the monkeys as obese. All monkeys had body weights over 13 kg. Monkeys weighing 13-15 kg varied in fatness, but in all monkeys weighing over 15 kg, more than 25% of body mass was fat. The obese rhesus monkeys in most studies have been fed ad libitum. There was a natural tendency for such monkeys to gradually fatten so that by the age of about 9 years some were obese (Kemnitz, 1984). In the studies of Hansen and colleagues (Hansen and Bodkin, 1993; Hansen et al., 1995) with nonobese animals in the 9-year age range, two groups of animals were selected for longitudinal study. One group of six monkeys had their weights measured and kept constant by food restriction in what was termed “a body weight clamp”; food intake was measured at the start of the study, and then only the amount of food required to maintain constant body weights was fed for the rest of the study. A comparison group of six age- and sex-matched
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 animals were fed ad libitum. Food for these groups was either a dry extruded commercial monkey diet or a commercial liquid diet for humans (Ensure®, Ross Laboratories, Columbus, OH). In analysis of the results, distinctions were not made for the diet used. Complete 3-year data sets on all animals were examined after the animals had been in the study for 9 years (Hansen et al., 1995). Remarkably, food intakes by the ad libitum and the weight-stabilized groups were relatively constant over the 3 years of data reporting; the weight-stabilized group consumed ME at an average (± SEM) of 591 ± 32 kcal·d-1 and the ad libitum group at 1,001 ± 79 kcal·d-1. Body weights were significantly different between the two groups, and these values remained relatively constant and near the mean weights (± SEM) at the age of 20 years of 11.0 ± 0.5 kg and 18.0 ± 1.5 kg in the weight-stabilized and ad libitum groups, respectively. Body fat (± SEM), estimated with the tritiated-water technique, was 21.3 ± 3.3% for the weight-stabilized group and 33.6 ± 4.0% for the ad libitum group. The energy consumed by both groups was essentially the same, ME at 54-55 kcal·kg-1 of body weight, and appeared to remain nearly constant throughout the 3 years of observation, although a trend for a slight decrease (about 10% over 3 years) was evident in the weight-stabilized group. The data indicate that the caloric intake per unit lean body mass was higher in obese than in nonobese animals (ME at 84 vs 68 kcal·BWkg-1). However, it was not established whether that represented a difference between groups in the efficiency of energy use, inasmuch as the mass of adipose tissue was over twice as great in the ad libitum group and the energy required to carry and maintain this extra weight is unknown. Social rank among monkeys in a group may be associated with obesity (Kemnitz, 1984). The dominant animal tends to determine the time that others spend in feeding in any particular location. In captive groups, subordinate animals eat only after the dominant animal is satisfied. That pattern of hierarchic behavior might result in excessive energy intake by more dominant animals; their obesity could be partly a result of social organization. Furthermore, when social order is disrupted, as when animals co-exist in an urban environment with humans or when social groups are altered by the addition of new members, obesity might be inhibited by disruption of the dominance hierarchy. In one study of male cynomolgus macaques, disruption of social order by substitution of new monkeys for former group members was used to induce stress; although obesity was not defined, regional distribution of fat was altered in such a way that stressed monkeys accumulated more intra-abdominal fat (Jayo et al., 1993). The distribution of body fat varies among animals. Central obesity occurs when the predominant site of adipose-tissue accumulation is the abdomen and upper body. Central obesity, typically including intra-abdominal fat accumulation, represents the distribution of adipose tissue that has been most strongly associated with defects in lipid and carbohydrate metabolism, including insulin resistance and glucoregulatory dysfunction (Kemnitz and Francken, 1986; Hansen et al., 1995), and with cardiovascular disease (Shively and Clarkson, 1988; Cefalu and Wagner, 1997) in monkeys. In a recent study (Coleman et al., 1999), adipose-tissue distribution shifted as body-weight differences increased between ad libitum-fed rhesus monkeys and diet-restricted monkeys. The percentage of body fat present in the abdomen of ad libitum-fed animals progressively increased for about 90 months of observation. At the start of the study, the average monkey weight was 11 kg, and about 40% of the body fat was in the abdomen. Ad libitumfed monkeys grew to over 14 kg, and abdominal fat increased to 45% of body fat. In contrast, the body weight of diet-restricted monkeys decreased from 11 kg to about 9 kg, and the percentage of total body fat present in the abdomen decreased to about 35%. After 90 months, the mass of total body fat was about 3 times higher in ad libitum-fed than in diet-restricted animals. Assuming an analogy with humans, the central obesity that occurs spontaneously in rhesus monkeys appears to confer increased cardiovascular-disease risk, although measurements of cardiovascular-disease end points themselves have not been extensively studied. Hamilton et al. (1972) first reported that plasma cholesterol, triglycerides, and ß-lipoproteins were increased in obese rhesus monkeys. Hannah et al. (1991) later analyzed the plasma-lipoprotein profile and demonstrated an increase in plasma concentration of very-low-density lipoprotein cholesterol and triglycerides and a decrease in HDL cholesterol in obese, insulin-resistant rhesus monkeys. Both those changes in lipoproteins would tend to increase the risk of coronary heart disease. Conversely, by inhibiting the development of obesity with diet restriction, Edwards and co-workers (1998) showed that, although LDL cholesterol concentrations were unchanged, LDL particles were modified in composition and had a decreased tendency to interact with arterial proteoglycans. Diet restriction thus appeared to block one of the proposed mechanisms of atherosclerosis, or ‘‘hardening of the arteries’’, in which LDL particles are trapped in the arterial intima and effectively stimulate inflammatory responses. No direct measurements of atherosclerosis have been reported in obese, diabetic rhesus monkeys, although experimental atherosclerosis in this species has been well characterized (Armstrong, 1976). The use of Western (fat-and cholesterol-enriched) diets to induce hyperlipidemia is a prerequisite for promoting the development of atherosclerosis, and the likelihood that effects of obesity on atherogenesis will be observed in the absence of this dietary background seems small. Most of the studies on obesity have not used this type of diet.
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 High intakes of energy-dense diets by immature animals can result in a high growth rate that potentially induces obesity as these animals mature. Overfeeding during infancy apparently does not result in increased fat-cell numbers but rather promotes increased fat-cell size, particularly in female baboons (Lewis et al., 1989). Newborn baboons (Papio cynocephalus) were fed a commercial milk-replacer diet modified to contain ME at 40.5, 67.5, and 94.5 kcal per 100 g to produce underfed, normally fed, and overfed male and female infants at the age of 4 months. From the age of 4 months to 5 years, male and female baboons were fed a similar diet formulated to contain 40% of ME calories as lard, 39% as carbohydrate, and 21% as protein. Cholesterol was supplemented at 1.7 mg·kcal-1 of ME. At 5 years, females that had been overfed as infants had a significantly greater percentage of body mass that was fat, and mean fat cell volume was greater, when compared with females that were underfed or normally fed as infants. However, infant food intake did not significantly influence body composition or fat-cell number in 5-year-old male baboons. Nevertheless, in the context of the fat cell studies in baboons, it should be noted that obesity has not been described in this species. Such a fat-cell response in baboons might not be applicable to a species that develops spontaneous obesity, such as the rhesus monkey. Regulation of Glucose Metabolism Reductions in fasting blood glucose resulting from diet restriction first became apparent in the Wisconsin rhesus macaques (M. mulatta) after 24 months (Kemnitz et al. 1994a), and in the NIH rhesus males after 36 months (Lane et al., 1995b). Differences in age at initiation of diet restriction, relative fractions of life span on diet restriction, severity of diet restriction, differences in body composition, and concentrations of sucrose in the diet were regarded as potential contributors to that discrepancy between studies (Lane et al., 1995b). It was noted, however, that differences in blood glucose concentration between ad libitum-fed and diet-restricted monkeys were observed in the Wisconsin monkeys shortly after the imposition of additional diet restriction 18 months into the study (Kemnitz et al., 1994a). After 8.5 years, a longitudinal study of semiannual glucose tolerance tests in the Wisconsin rhesus monkeys revealed that diet-restricted monkeys had increased insulin sensitivity, increased plasma glucose disappearance rate, reduced fasting plasma insulin concentration, and reduced insulin response to glucose compared to ad libitum-fed controls (Gresl et al., 2001). Chronic dietary restriction appeared to protect against development of insulin resistance in aging rhesus macaques and also might have improved glucoregulatory measures compared with those of otherwise normoinsulinemic monkeys. Cefalu et al. (1997) reported that insulin sensitivity, as measured with frequent intravenous glucose-tolerance tests, was increased in purchased, feral adult cynomolgus macaques (M. fascicularis) after 1 year of diet restriction (target of 30% below ad libitum-fed, 34% actual). BW, total abdominal fat, and intra-abdominal fat, determined by computed tomographic scan, were all lower in diet-restricted than in ad libitum-fed cynomolgus monkeys. Those results demonstrate that diet restriction can ameliorate pathologic fat deposition; this change might be associated with a substantial improvement in peripheral-tissue insulin sensitivity. Reductions in fasting blood glucose became apparent in NIH diet-restricted rhesus macaques (M. mulatta) after 3-4 years of restriction (Lane et al., 1995b). Maximal glucose concentrations, reached during intravenous glucose-tolerance tests, increased with age but were lower in diet-restricted monkeys than in ad libitum-fed controls. Several measures of the insulin response (baseline, maximum, and integrated areas under the curve) increased with age and were lower in diet-restricted monkeys. The age-related increase in maximal blood glucose concentration in ad libitum-fed monkeys, after intravenous glucose challenge, was probably related to decreased insulin sensitivity, inasmuch as insulin levels measured concurrently with glucose peaks during intravenous infusions were significantly increased among older, heavier animals. The age-related increase in the maximal glucose peak was inhibited in monkeys subjected to long-term diet restriction, and this difference between dietary treatments might be linked to increased insulin sensitivity in diet-restricted monkeys. Hansen and Bodkin (1993) reported that glucose disappearance rate was greater in diet-restricted rhesus monkeys than in ad libitum-fed controls, and insulin resistance was lower in diet-restricted, older rhesus (Bodkin et al., 1995). Those findings suggest that long-term diet restriction can be an effective means of mitigating the development of potentially pathologic insulin resistance in older rhesus monkeys. Diabetes Captive orangutans (Pongo spp.) have a propensity to become obese and develop diabetes (Gresl et al., 2000). Intravenous glucose tolerance tests performed on 30 orangutans ranging in age from 3.5-40.5 years revealed two diabetic and two potentially prediabetic individuals. Mean ± SE fasting plasma or serum glucose and insulin concentrations were 113 ± 16 mg·dl-1 and 45 ± 7 µU·ml-1, respectively. The two diabetic orangutans had fasting glucose concentrations of 380 and 562 mg·dl-1 and fasting insulin concentrations of 21 and 14 µU·ml-1. Their insulin responses during the intravenous glucose tolerance tests were low or non-detectable. Nearly half of all orangutans exhibited delayed or attenuated acute insulin responses.
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 The development of obesity in rhesus monkeys appears to be necessary, if not sufficient, for the development of insulin resistance and later non-insulin-dependent diabetes (type II diabetes) (Ausman et al., 1981; Hansen and Bodkin, 1986; Bodkin et al., 1995). Hansen and Bodkin (1986) characterized the development of obesity and diabetes in 42 male rhesus monkeys 3-28 years old and weighing 5-31.7 kg. All animals were fed ad libitum, and the diet was either a commercial monkey diet (Monkey Chow®, Purina Mills Inc., St. Louis, MO) or a liquid diet for humans (Ensure®, Ross Laboratories, Columbus, OH). Rhesus monkeys appeared to advance through a series of eight stages in which age, body weight, and percentage of body fat progressively increased, insulin resistance increased, and the plasma-glucose disappearance rate decreased. In about the sixth stage, when the monkeys’ average age was about 16 years, body weight had increased to over 17 kg, body fat was near 35% of body weight, and fasting plasma insulin had risen almost tenfold to over 415 µU·ml-1 of plasma. Glucose disposal rate, measured as the slope of the impaired glucose-tolerance test disappearance curve, had decreased by 33%. In the final two stages of progression to frank diabetes, plasma glucose disappearance rate fell another 30%, fasting plasma-glucose rose to over 10 mmol·L-1, body weight fell, and body fat decreased. In this study of 3-6 years, seven of 42 monkeys progressed to overt diabetes, and 14 showed transitions suggesting that they would eventually become diabetic. Although all monkeys were obese before the onset of type II diabetes, some monkeys with similar degrees of obesity showed no progression toward the disease. Thus, obesity appears to be necessary but not sufficient for diabetes development. Whether intervention and weight reduction after the development of obesity might reduce the incidence of diabetes development was not examined. However, dietary restriction that prevents the development of obesity does prevent the development of impaired glucose tolerance, hyperglycemia, and hyperinsulinemia (Kemnitz et al., 1994b; Bodkin et al., 1995; Gresl et al., 2001) and of type II diabetes (Hansen and Bodkin, 1993). In the Hansen and Bodkin study (1993), eight adult male rhesus monkeys (average age, 11 years) were diet-restricted (just enough diet to maintain constant body weights) for an average of 7 years, whereas a group of 19 age-matched controls were fed ad libitum. At the end of the study, the diet-restricted group had an average body weight of 10.4 kg, whereas the ad libitum-fed group had an average body weight of 16.1 kg, with a range of values that were up to 100% greater than in the diet-restricted group. In the ad libitum group by the end of the study, four animals were frankly diabetic, and six had developed impaired glucose tolerance and hyperinsulinemia and were considered to be prediabetic. None of the animals that maintained normal weight in the diet-restricted group developed any of those changes in glucose metabolism. As the data indicate, diet restriction was effective in preventing both obesity and diabetes; again, the two disease syndromes are closely linked, although the molecular basis is unclear. Examination of potential molecular interactions that might underlie the development of insulin resistance and type II diabetes in the rhesus monkey has been attempted. The insulin receptor has two isoforms that are derived from alternate splicing of exon 11 in the insulin-receptor gene, and this splice variation has been examined in obese, hyperinsulinemic rhesus monkeys (Huang et al., 1994; Huang et al., 1996). A patterned increase in the proportion of the shorter, exon 11-negative insulin-receptor mRNA in liver was described in rhesus monkeys as they progressed from normal through prediabetic to frank diabetic status (Huang et al., 1996). The pattern is similar to that seen in muscle (Huang et al., 1994), although the percentage of the exon 11-negative form of the insulin-receptor mRNA in muscle was almost twice that seen in liver, and the pattern of increase in this form of the insulin receptor is apparently similar to the pattern seen in humans (Huang et al., 1996). The functional significance of such a modification of the insulin receptor is not understood. The presence of hyperleptinemia in obese, hyperinsulinemic rhesus monkeys has been reported (Bodkin et al., 1996). Leptin is a hormone made in adipose tissue; its absence has been found to be the cause of obesity in the genetically obese ob/ob mouse model by Friedman and colleagues (Zhang et al., 1994). The function of leptin is not completely understood, but it appears that when it is absent, satiety is not sensed and food consumption continues in an uncontrolled manner, leading to the gross obesity observed in the ob/ob mouse. Paradoxically, increased blood concentrations of leptin have been observed in obese humans (Maffei et al., 1995), presumably as a result of the increased mass of adipose tissue. The observation of increased leptin in obese rhesus monkeys, therefore, does not define the role of leptin in the development of obesity; it only shows similarities to the observations made in humans. The monkey studies did show a strong correlation between leptin concentrations and body fat and fasting plasma insulin concentrations (Bodkin et al., 1996), but correlations with glucose disposal were less remarkable. Ramsey et al. (2000) reported a correlation of 0.8-0.9 between body fat and blood leptin concentrations. Other studies in rhesus monkeys showed that the response of the brain to leptin can be modulated by the ability of the hormone to cross the blood-brain barrier (Ramsey et al., 1998). Leptin directly infused into the brain decreased food intake by as much as 50%, whereas leptin injections into plasma had no effect on food intake, although plasma concentrations of leptin increased by as much as a factor of 100. The mechanism that facilitates leptin movement across the blood-brain barrier needs to
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 be found because it could play a key role in the brain’s signal to limit food intake in response to leptin. Thus, the role of leptin in the development of obesity in the monkey remains unclear, but its identification has led to many new experimental approaches that might eventually facilitate a better understanding of the causes of obesity. Studies have been done to identify the potential roles of expression of the nuclear hormone receptors, termed peroxisome proliferator-activated receptors (PPAR γ1 and PPAR γ2), in obesity in rhesus monkeys (Hotta et al., 1998). These transcription activators were selected for study because it was observed that they are highly expressed in adipocytes (Hotta et al., 1998), that thiazolodinedione ligands for the receptors are effective antidiabetics and sensitize target tissues to insulin (Kemnitz et al., 1994a), and that the ratio of PPAR γ1 to PPAR γ2 was altered in obesity in humans (Vidal-Puig et al., 1997), although not in rodents (Vidal-Puig et al., 1996). When the abdominal subcutaneous adipose tissue of 28 normal, obese, and type II diabetic rhesus monkeys was examined, the mRNA abundance of PPAR γ did not correlate with body weight, but the ratio of PPAR γ1 to PPAR γ2 mRNA correlated highly with body weight and with fasting plasma insulin concentration (Hotta et al., 1998). The difference between the two forms of PPAR γ results from alternative splicing that modifies the n-terminal portion of the protein. The mechanism that leads to a difference in insulin sensitivity is not known. One study has shown that insulin sensitivity and blood concentrations of glucose, insulin, and lipids were reduced in a dose-dependent fashion in obese rhesus monkeys by pioglitazone, a member of the thiazolodinedione class of compounds (Kemnitz et al., 1994a). Those outcomes presumably result from the drug interactions with PPAR γ receptors—but, again, the mechanism(s) through which the various end-point alterations occur are not fully explained. PPAR γ responses to pioglitazone in muscle, adipose tissue, liver, and pancreas might all contribute to the phenotype of the response. Collectively, the studies done thus far suggest the presence of a molecular basis of insulin resistance, obesity, and diabetes. However, the players and their interrelationships are not all determined. The use of mouse genetics, molecular biology to understand nuclear hormone receptors, and the monkey models of obesity and diabetes might well all be key components in the search that will eventually lead to an understanding of the molecular mechanisms of these diseases. Appropriate nutrition of the research subjects will be essential for derivation of the needed information. REFERENCES Alberts, S.C. and J. Altmann. 2001. Immigration and hybridization patterns of yellow and anubis baboons in and around Amboseli, Kenya. Am. J. Primatol. 53:139-154. Armstrong, M.L. 1976. Atherosclerosis in rhesus and cynomolgus monkeys. Prim. Med. 9:16-40. Ausman, L.M., K.C. Hayes, A. Lage, and D.M. Hegsted. 1970. Nursery care and growth of Old and New World infant monkeys. Lab. Anim. Care 20:907-913. Ausman L.M., K.C. Hayes, and D.M. Hegsted. 1972. Protein deficiency and carbohydrate tolerance of the infant squirrel monkey (Saimiri sciureus) . J. Nutr.102:1519-1528. Ausman L.M., D.L. Gallina, K.C. Hayes, and D.M. Hegsted. 1976. Hematological development of the infant squirrel monkey (Saimiri sciureus). Folia Primatol. 26:292-300. Ausman L.M., D.L. Gallina, M. Camitta, L.C. Flath, and D.M. Hegsted. 1977. Acute erythroid hypoplasia in malnourished infant squirrel monkeys fed isolated soy protein. Am. J. Clin. Nutr. 30:1713-1720. Ausman, L.M., K.M. Rasmussen, and D.L. Gallina. 1981. Spontaneous obesity in maturing squirrel monkeys fed semipurified diets. Am. J. Physiol. 241:R315-R321. Ausman, L.M., D.L. Gallina, and R.J. Nicolosi. 1985. Nutrition and metabolism of the squirrel monkey. Pp. 349-378 in Handbook of Squirrel Monkey Research, L.A. Rosenblum and C.L. Coe, Eds. New York: Plenum Press. Ausman, L.M., D.L. Gallina, K.C. Hayes, and D.M. Hegsted. 1986. Comparative assessment of soy and milk protein quality in infant cebus monkeys . Am. J. Clin. Nutr. 43:112-117. Ausman, L.M., D.L. Gallina, and D.M. Hegsted. 1989. Protein-calorie malnutrition in squirrel monkeys: adaptive response to calorie deficiency. Am. J. Clin. Nutr. 50:19-29. Austad, S.N. 1997. Small nonhuman primates as potential models of human aging. ILAR J. 38:142-147. Baer, D.J., M.A. Lane, W.V. Rumpler, D. Ingram, and G. Roth. 1998. Bioenergetics and aging in monkeys: is less more? Pp. 8-11 in Proc. 2nd Symp. Comp. Nutr. Soc., Banff, Alberta, Canada. Blomquist, A.J., and H.F. Harlow. 1961. The infant rhesus monkey program at the University of Wisconsin Primate Laboratory. Proc. Anim. Care Panel 11:57-64. Bodkin, N.L., H.I. Ortmeyer, and B.C. Hansen. 1995. Long-term dietary restriction in older-aged rhesus monkeys: effects on insulin resistance. J. Gerontol. Biol. Sci. 50A:B142-B147. Bodkin, N.L., M. Nicolson, H.K. Ortmeyer, and B.C. Hansen. 1996. Hyperleptinemia: relationship to adiposity and insulin resistance in the spontaneously obese rhesus monkey. Horm. Metab. Res. 28:674-678. Bowden, D.M. (Ed.). 1979. Aging in Nonhuman Primates. New York: Van Nostrand Reinhold Co. Bowman, J.E., and P.C. Lee. 1991. A test of the threshold weaning weight among captive rhesus macaques. Am. J. Phys. Anthro. 14(Suppl.):52. Bowman J.E., and P.C. Lee. 1995. Growth and threshold weaning weights among captive rhesus macaques. Am. J. Phys. Anthro. 96:159-175. Brown, C. 1979. Hand-rearing Senegal bushbabies (Galago senegalensis) at the Wildlife Breeding Centre. Int. Zoo Yrbk. 19:261-262. Brown, T., H.W. Clark, and J.S. Bailey. 1974. Natural occurrence of rheumatoid arthritis in great apes—a new animal model. Pp. 43-79 in Proc. Zool. Soc. Philadelphia Cent. Symp. Sci. Res. Buss, D.H. 1968a. Gross composition and variation of the components of baboon milk during natural lactation. J. Nutr. 96:421-426. Buss, D.H. 1968b. Gross composition and variation of the components of baboon milk during artificially stimulated lactation. J. Nutr. 96:427-432. Buss, D.H. 1975. Composition of milk from a golden lion marmoset. Lab. Prim. Newsl. 14:17-18. Buss, D.H., and R.W. Cooper. 1970. Composition of milk from talapoin monkeys. Folia Primatol. 13:196-206. Buss, D.H., and F.H. Kriewaldt. 1968. A machine for milking baboons. Lab. Anim. Care. 18:644-647. Buss, D.H., and W.R. Voss. 1971. Evaluation of four methods for estimating the milk yield of baboons. J. Nutr. 101:901-910.
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 Buss, D.H., and R.W. Cooper. 1972. Composition of squirrel monkey milk. Folia Primatol. 17:285-291. Buss, D.H., W.R. Voss, and A.H. Nora. 1970. A brief note on a modified formula for hand-rearing infant baboons. Int. Zool. Yrbk. 10:133-134. Buss, D.H., R.W. Cooper, and K. Wallen. 1976. Composition of lemur milk . Folia Primatol. 26:301-305. Cefalu, W.T., and J.D. Wagner. 1997. Aging and atherosclerosis in human and nonhuman primates. Age 20:15-28. Cefalu, W.T., J.D. Wagner, Z.Q. Wang, A.D. Bell-Farrow, J. Collins, D. Haskell, R. Bechtold, and T. Morgan. 1997. A study of caloric restriction and cardiovascular aging in cynomolgus monkeys (Macaca fascicularis): a potential model for aging research. J. Gerontol. 52A:B10-B19. Champ, J., and M.D. Brinkley. 1996. Do nutritional factors reduce bone loss with advancing age in the rhesus monkey? J. Am. Geriatrics Soc. 44:A2. Champ, J.E., N. Binkley, T. Havighurst, R.J. Colman, J.W. Kemnitz, and E.B. Roecker. 1996. The effect of advancing age on bone mineral content of female monkeys. Bone 19:485-492. Cicmanec, J.L., D.M. Hernandez, S.R. Jenkins, A.K. Campbell, and J.A. Smith . 1979. Hand-rearing infant callithrichids (Saguinus spp and Callithrix jacchus), owl monkeys (Aotus trivirgatus), and capuchins (Cebus albifrons). Pp. 307-312 in Nursery Care of Nonhuman Primates, G.C. Ruppenthal, Ed. New York: Plenum. Colman, R., and J.W. Kemnitz. 1998. Aging experiments using nonhuman primates. Pp. 249-267 in Methods in Aging Research, B.P. Yu, Ed. Boca Raton, FL: CRC Press. Colman, R.J., E.B. Roecker, J.J. Ramsey, and J.W Kemnitz. 1998. The effect of dietary restriction on body composition in adult male and female rhesus macaques. Aging: Clin. Exp. Res. 10:83-92. Colman, R.J., J.C. Hudson, H.S. Barden, and J.W. Kemnitz. 1999. A comparison of dual-energy X-ray absorptiometry and somatometrics for determining body fat in rhesus macaques. Obesity Res. 7:90-96. Colman, R.J., J.W. Kemnitz, M.A. Lane, D.H. Abbott, and N. Binkley. 1999a. Skeletal effects of aging and menopausal status in female rhesus macaques. J. Clin. Endocrinol. Metab. 84:4144-4148. Colman, R.J., M.A. Lane, N. Binkley, F.H. Wegner, and J.W. Kemnitz. 1999b. Skeletal effects of aging in male rhesus monkeys. Bone 24:17-23. Colman, R.J., J.J. Ramsey, E.B. Roecker, T. Havighurst, J.C. Hudson, and J.W. Kemnitz, 1999. Body fat distribution with long-term dietary restriction in adult male rhesus macaques. J. Gerontol. [A] 54A:B283-B290. Cousins, D. 1979. External measurements and weights of captive gorillas. Int. Zoo News 26:12-17. Cowgill, U.M., S.J. States, and K.J. States. 1989. A twenty-five-year chronicle of a group of captive nocturnal prosimians (Perodicticus potto). Mammal Rev. 19:83-89. Dang, D., G. Chaouat, A. Delmas, J. Hureau, G. Hidden, and J. Lassau. 1992. Assessment of factors responsible for variability of birth weight in the long-tailed macaque (Macaca fascicularis). Folia Primatol. 59:149-156. Davidson, L.A., and B. Lönnerdal. 1986. Isolation and characterization of rhesus monkey milk lactoferrin. Pediat. Res. 20:197-201. Davis, R.T., and C.W. Leathers (Eds.). 1985. Behavior and Pathology of Aging in Rhesus Monkeys. New York: Alan R. Liss, Inc. DeLany, J.P., B.C. Hansen, N.L. Bodkin, J.Hannah, and G.A. Bray. 1998. Long-term calorie restriction reduces energy expenditure in aging monkeys. J. Gerontol. A. Biol. Sci. Med. Sci. 54:B5-B11. DeRousseau, C.J. 1985a. Aging in the musculoskeletal system of rhesus monkeys: III. Bone loss. Am. J. Phys. Anthropol. 68:157-167. DeRousseau, C.J. 1985b. Aging in the musculoskeletal system of rhesus monkeys: II. Degenerative joint disease. Am. J. Phys. Anthropol. 67:177-184. DeRousseau, C.J. 1994. Primate gerontology: an emerging discipline. Pp. 127-153 in Biological Anthropology and Aging: Perspectives on Human Variation over the Life Span, D.E. Crews and R.M. Garroto, Eds. New York: Oxford Univ. Press. Edwards, I.J., L.L. Rudel, J.G. Terry, J.W. Kemnitz, R. Weindruch, and W.T. Cefalu, 1998. Caloric restriction in rhesus monkeys reduces low density lipoprotein interaction with arterial proteoglycans. J. Gerontol. [B] 53A:B443-B448. Edwards, M.S. 1995. Comparative Adaptations to Folivory in Primates. Ph.D. Dissertation. Michigan State Univ., East Lansing, MI. Erb, R.E., N.E. Sitarz, and P.V. Malven. 1977. Blood plasma and prolactin, and effects of sampling technique on composition of milk from suckled ewes. J. Dairy Sci. 60:197-203. Fleischman, R.W. 1963. The care of infant rhesus monkeys (Macaca mulatta). Lab. Anim. Care 13:703-710. Forbes, G.B. 1990. Body composition. Pp. 7-12 in Present Knowledge in Nutrition, 6th ed., M.L. Brown, Ed. Washington, DC: Int. Life Sci. Inst. Nutr. Found. Fragaszy D.M., and K. Bard. 1997. Comparison of development and life history in Pan and Cebus. Int. J. Primatol. 18:683-701. Fragaszy, D.M., and L.E. Adams-Curtis. 1998. Growth and reproduction in captive tufted capuchins (Cebus apella). Am. J. Primatol. 44:197-203. Fomon, S.J. 1993. Nutrition of normal infants. St. Louis: Mosby. 475 pp. Gavan, J.A. 1953. Growth and development of the chimpanzee: a longitudinal and comparative study. Human Biol. 25:93-143. Golub, M.S., M.E.Gershwin, L.S. Hurley, W.Y. Saito, and A.G. Hendrickx. 1984. Studies of marginal zinc deprivation in rhesus monkeys. V. Growth of infants in the first year. Am. J. Clin. Nutr. 40:1192-1202. Golub M.S., M.E. Gershwin, L.S. Hurley, A.G. Hendrickx, and W.Y. Saito. 1985. Studies of marginal zinc deprivation in rhesus monkeys: infant behavior. Am. J. Clin. Nutr. 42:1229-1239. Golub, M.S., M.E. Gershwin, B. Lonnerdal, C.L Keen, L.S. Hurley, and A.G. Hendrickx. 1990. Problems associated with long-term feeding of purified diets in rhesus monkeys. Primates 31:579-588. Golub, M.S., C.L. Keen, A.G. Hendrickx, and M.E. Gershwin. 1991. Food preference of young rhesus monkeys fed marginally zinc deficient diets . Primates 32:49-59. Goy, R.W., and J.W. Kemnitz. 1983. Early, persistent, and delayed effects of virilizing substances delivered transplacentally to female rhesus fetuses. Pp. 303-314 in Application of Behavioral Pharmacology in Toxicology. G. Zbinden, V. Cuomo, G. Racagni, and B. Weiss, Eds. New York: Raven Press. Gresl, T.A., S.T. Baum, and J.W. Kemnitz. 2000. Glucose regulation in captive Pongo pygmaeus abeli, P.p. pygmaeus, and P.p. abeli x P.p. pygmaeus orangutans. Zoo Biol. 19:193-208. Gresl, T.A., R.J. Colman, E.B. Roecker, T.C. Havighurst, Z. Huang, D.B. Allison, R.N. Bergman, and J.W. Kemnitz. 2001. Dietary restriction and glucose regulation in aging rhesus monkeys: a follow-up report at 8.5 yr. Am. J. Physiol.: Endocrinol. Metab. 281:E757-E765. Gucwinska, H., and A. Gucwinski. 1968. Breeding the Zanzibar galago (Galago senegalensis zanzibaricus) at Wroclaw Zoo. Int. Zoo Yrbk. 8:111-114. Hamada, Y., T. Udono, M. Teramoto, and T. Sugawara. 1996. The growth pattern of chimpanzees: somatic growth and reproductive maturation in Pan troglodytes. Primates 37:279-295. Hamilton, C.L., P.T. Kuo, and L.Y. Feng. 1972. Experimental production of syndrome of obesity, hyperinsulinemia and hyperlipidemia in monkeys. Proc. Soc. Exp. Biol. Med. 140:1005-1008. Hannah, J.S., R.B. Verdery, N.L. Bodkin, B.C. Hansen, N.A. Le, and B.V. Howard. 1991. Changes in lipoprotein concentrations during the development of noninsulin-dependent diabetes mellitus in obese rhesus monkeys (Macaca mulatta). J. Clin. Endocrinol. Metab. 72:1067-1072. Hansen, B.C. 1992. Obesity and diabetes in monkeys. Pp. 256-265 in Obesity, P. Bjorntorp and M.M. Brodoff, Eds. New York: Lippincott. Hansen, B.C., and Bodkin, N.L. 1986. Heterogeneity of insulin responses: phases leading to Type 2 (non-insulin-dependent) diabetes mellitus in the rhesus monkey. Diabetologia 29:713-719.
OCR for page 178
Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 Hansen, B.C., and N.L. Bodkin. 1993. Primary prevention of diabetes mellitus by prevention of obesity in monkeys. Diabetes 42:1809-1814. Hansen, B.C., K.L.C. Jen, and P. Kribbs. 1981. Regulation of food intake in monkeys: response to caloric dilution. Physiol. Behavior 26:479-486. Hansen, B.C., H.K. Ortmeyer, and N.L. Bodkin. 1995. Prevention of obesity in middle-aged monkeys: food intake during body weight clamp. Obesity Res. 3(Suppl. 2):199S-204S. Hayflick, L. 1985. Theories of biological aging. Exptl. Gerontol. 20:145-159. Hayes, K.C., Z.F. Stephan, and J.A. Sturman. 1980. Growth depression in taurine-depleted infant monkeys. J. Nutr. 110:119-125. Haynes, D.C., M.E. Gershwin, M.S. Golub, A.T.W. Cheung, L.S. Hurley, and A.G. Hendrickx. 1985. Studies of marginal zinc deprivation in rhesus monkeys: VI. Influence on the immunohematology of infants in the first year. Am. J. Clin. Nutr. 42:252-262. Hendrickx, A.G. 1984. Studies of marginal zinc deprivation in rhesus monkeys. V. Fetal and infant skeletal effects . Am. J. Clin. Nutr. 40:1203-1212. Holmes, K.R., D.E. Haines, and J.A. Bollert. 1968. Laboratory observations on a prosimian primate (Galago senegalensis). Lab. Anim. Care 18:475-477. Hopf S. 1970. Report on a hand-reared squirrel monkey (Saimiri sciureus). Z. Tierpsychol. 27:610-21. Hotta, K., T.A. Gustafson, S. Yoshioka, H.K. Ortmeyer, N.L. Bodkin, and B.C. Hansen. 1998. Relationships of PPARγ1 and PPARγ2 mRNA levels to obesity, diabetes and hyperinsulinaemia in rhesus monkeys. Int. J. Obesity 22:1000-1010. Howard, C.F. 1983. Diabetes and carbohydrate impairment in nonhuman primates. Pp. 1-36 in Nonhuman Primate Models for Human Diseases, W.R. Dukelow, Ed. Boca Raton, FL: CRC Press, Inc. Huang, Z., N.L. Bodkin, H.K. Ortmeyer, B.C. Hansen, and A.R. Shuldiner. 1994. Hyperinsulinemia is associated with altered insulin receptor mRNA splicing in muscle of the spontaneously obese diabetic rhesus monkey. J. Clin. Invest. 94:1289-1296. Huang, Z., N.L. Bodkin, H.K. Ortmeyer, M.E. Zenilman, N.J.G. Webster, B.C. Hansen, and A.R. Shuldiner. 1996. Altered insulin receptor messenger ribonucleic acid splicing in liver is associated with deterioration of glucose tolerance in the spontaneously obese and diabetic rhesus monkey: analysis of controversy between monkey and human studies. J. Clin. Endocrinol. Metab. 81:1552-1556. Hudson, J.C., S.T. Baum, D.M. Frye, E.B. Roecker, and J.W. Kemnitz. 1996. Age and sex differences in body size and composition during monkey adulthood. Aging: Clin. Exp. Res. 8:197-204. Ingram, D.K., R.G. Cutler, R. Weindruch, D.M. Renquist, J.J. Knapka, M. April, C.T. Belcher, M.A. Clark, C.D. Hatcherson, B.M. Marriott, and G.S. Roth. 1990. Dietary restriction and aging: the initiation of a primate study. J. Gerontol. Biol. Sci. 45:B148-B163. Ingram, D.K., M.A. Lane, R.G. Cutler, and G.S. Roth. 1993. Longitudinal study of aging in monkeys: effects of diet restriction. Neurobiol. Aging 14:687-688. Jackson E.M., D.S. Lewis, C.A. McMahan, and G.E. Mott. 1993. Preweaning diet affects bile lipid composition and bile acid kinetics in infant baboons. J. Nutr. 123:1471-1479. Jacobson, H.N., and W.F. Windle. 1960. Observations on mating, gestation, birth, and postnatal development of Macaca mulatta. Biol. Neonatorum 3:105-120. Jayo, J.M., C.A. Shively, J.R. Kaplan, and S.B. Manuck. 1993. Effects of exercise and stress on body fat distribution in male cynomolgus monkeys. Int. J. Obesity 17:597-604. Jen, K.-L.C., B.C. Hansen, and B.L. Metzger. 1985. Adiposity, anthropometric measures and plasma insulin levels of rhesus monkeys. Int. J. Obesity 9:213-224. Jenness, R. 1979. The composition of human milk. Semin. Perinatol.3:225-239. Jenness, R. and R.E. Sloan. 1970. The composition of milk of various species: a review. Dairy Sciences Abstract. 32:599-612. Kaplan, J. 1970. Hand-rearing infant squirrel monkeys. Lab. Prim. Newsl. 9:5-8. Kaplan, J.N. 1979. Growth and development of infant squirrel monkeys during the first six months of life. Pp. 153-164 in Nursery Care of Nonhuman Primates, G.C. Ruppenthal, Ed. New York: Plenum. Kaplan, J.R., S.B. Manuck, T.B. Clarkson, and R.W. Pritchard. 1985. Animal models of behavioral influences on atherogenesis. Adv. Behavior. Med. 1:115-163. Kaye H., M.L. Povar, and A.M. Schrier. 1966. Rearing of Macaca mulatta from birth. Lab. Anim. Care 16:476-486. Keen C.L., B. Lönnerdal, M.S. Golub, J.Y. Uriu-Hare, K.L. Olin, A.G. Hendrickx, and M.E Gershwin. 1989. Influence of marginal maternal zinc deficiency on pregnancy outcome and infant zinc status in rhesus monkeys. Pediatric Res. 26:470-477. Kemnitz, J.W. 1984. Obesity in macaques: spontaneous and induced. Adv. Vet. Sci. Comp. Med. 28:81-114. Kemnitz, J.W. 1994. Effects of gender and age on body size and composition of rhesus monkeys (Macaca mulatta). Am. J. Primatol. 33:220 (Abstr.). Kemnitz, J.W., and Francken, G.A. 1986. Characteristics of spontaneous obesity in male rhesus monkeys. Physiol. Behav. 38:477-483. Kemnitz, J.W., K.K. Sladky, T.J. Flitsch, S.M. Pomerantz, and R.W. Goy. 1988. Androgenic influences on body size and composition of adult rhesus monkeys. Am. J. Physiol. 255:E857-E864. Kemnitz, J.W., R.W. Goy, T.J. Flitsch, J.L. Lohmiller, and J.A. Robinson. 1989. Obesity in male and female rhesus monkeys: fat distribution, gluocoregulation, and serum androgen levels. J. Endocrinol. Invest. 69:287-293. Kemnitz, J.W., R. Weindruch, E. Roecker, K. Crawford, P.L. Kauffman, and W.B. Ershler. 1993. Dietary restriction of adult male rhesus monkeys: design, methodology, and preliminary findings from the first year of the study. J. Gerontol. Biol. Sci. 48:B17-B26. Kemnitz, J.W., E.B. Roecker, R. Weindruch, D.F. Olson, S.T. Baum, and R.N. Bergman. 1994a. Dietary restriction increases insulin sensitivity and lowers blood glucose in rhesus monkeys. Am. J. Physiol. 266:E540-E547. Kemnitz, J.W., D.F. Elson, E.B. Roecker, S.T. Baum, R.N. Bergman, and M.D. Meglasson. 1994b. Pioglitazone increases insulin sensitivity, reduces blood glucose, insulin, and lipid levels, and lowers blood pressure in obese, insulin-resistant rhesus monkeys. Diabetes 43:204-211. Kerr G.R., A.S. Chamove, H.F. Harlow, and H.A. Waisman. 1969a. The development of infant monkeys fed low phenylalanine diets. Pediatric Res. 3:305-312. Kerr G.R., G. Scheffler, and H.A. Weisman. 1969b. Growth and development of infant M. mulatta fed a standardized diet. Growth 33:185-199. King, J.E., and P.A. King. 1970. Early behavior in hand-reared squirrel monkeys (Saimiri sciureus). Develop. Psychobiol. 2:251-256. Kirkwood, J.K. 1983. Effects of diet on health, weight and litter-size in captive cotton-top tamarins Saguinus oedipus. Primates 24:515-520. Kunz, C., and B. Lönnerdal. 1994. Isolation and characterization of a 21 kDa whey protein in rhesus monkey (Macaca mulatta) milk. Comp. Biochem. Physiol. B: Biochem. Mol. Biol. 108:463-469. Lane, M.A., D.K. Ingram, R.G. Cutler, J.J. Knapka, D.E. Barnard, and G.S. Roth. 1992. Dietary restriction in nonhuman primates: progress report on the NIA study. Pp. 36-45 in Physiopathological Processes of Aging Towards a Multicausal Interpretation, N. Fabris, D. Harman, D.L. Knook, E. Steinhagen-Thiessen, and I. Zs-Nagy, Eds. New York: New York Academy of Sciences. Lane, M.A., D.J. Baer, E.M. Tilmont, W.V. Rumpler, D.K. Ingram, G.S. Roth, and R.G. Cutler. 1995a. Energy balance in rhesus monkeys (Macaca mulatta) subjected to long-term dietary restriction. J.Gerontol. 50A:B295-302.
OCR for page 179
Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 Lane, M.A., S.S. Ball, D.K. Ingram, R.G. Cutler, J. Engel, V. Read, and G.S. Roth. 1995b. Diet restriction in rhesus monkeys lowers fasting and glucose-stimulated glucoregulatory end points. Am. J. Physiol. 268 (Endocrinol. Metab.) 31:E941-E948. Lane M.A., A.Z. Reznick, E.M. Tilmont, A. Lanir, S.S. Ball, V. Read, D.K. Ingram, R.G. Cutler, and G.S. Roth. 1995c. Aging and food restriction alter some indices of bone metabolism in male rhesus monkeys (Macaca mulatta). J. Nutr. 125:1600-1610. Lane, M.A., D.J. Baer, W.V. Rumpler, R. Weindruch, D.K. Ingram, E.M. Tilmont, R.G. Cutler, and G.S. Roth. 1996. Calorie restriction lowers body temperature in rhesus monkeys, consistent with a postulated antiaging mechanism in rodents. Proc. Natl. Acad. Sci. 93:4159-4164. Lane, M.A., D.K. Ingram, S.S. Ball, and G.S. Roth. 1997. Dehydroepian-drosterone sulfate: a biomarker of primate aging slowed by calorie restriction. J. Clin. Endocrinol. Metab. 82:2093-2096. Leigh, S.R. 1994. Relations between captive and noncaptive weights in anthropoid primates. Zoo Biol. 13:21-43. Lewis D.S., G.E. Mott, C.A. McMahan, E.J. Masoro, K.D. Carey, and H.C. McGill, Jr. 1988. Deferred effects of preweaning diet on atherosclerosis in adolescent baboons. Arteriosclerosis 8:274-280. Lewis, D.S., H.A. Bertrand, C.A. McMahan, H.C. McGill, Jr., K.D. Carey, and E.J. Masoro. 1989. Influence of preweaning food intake on body composition of young adult baboons. Am. J. Physiol. 257 (Regulatory Integrative Comp. Physiol.) 26:R1128-R1135. Lewis, D.S., C.A. McMahan, and G. E. Mott. 1993. Breast feeding and formula feeding affect differently plasma thyroid hormone concentrations in infant baboons. Biol. Neonate 63:327-335. Liu, H. J., P.I. Oteiza, M.E. Gershwin, M.S. Golub, and C.L. Keen. 1992. Effects of maternal marginal zinc deficiency on myelin protein profiles in the suckling rat and infant rhesus monkey. Biol. Trace Element Res. 34:55-56. Long, J.O., and R.W. Cooper. 1968. Physical growth and dental eruption in captive-bred squirrel monkeys, Saimiri sciureus (Letica, Columbia) . Pp. 193-205 in The Squirrel Monkey, L.A. Rosenblum and R.W. Cooper, Eds. New York: Academic Press. Lönnerdal, B., C.L. Keen, C.E. Glazier and J. Anderson. 1984. A longitudinal study of rhesus monkeys (Macaca mulatta) milk composition: trace elements, minerals, protein, carbohydrate and fat. Pediatric Res. 18:911-914. Lönnerdal, B. C.L. Keen, J.G. Bell, M.S. Golub, A.G. Hendrickx, and M.E. Gershwin. 1990a. Effect of marginal maternal zinc intake on zinc absorption and growth of 3-month-old infant rhesus monkeys. Am. J. Dis. Children 144:1007-1010. Lönnerdal, B.; C.L. Keen, A.G. Hendrickx, M.S. Golub, and M.E. Gershwin. 1990b. Influence of dietary zinc and iron on zinc retention in pregnant rhesus monkeys and their infants. Obstetr. Gynecol. 75:369-374. Lucas, A. 1990. Does early diet program future outcome? Acta Pediatr. Scand. Suppl. 365:58-67. Lundrigan, B. 1996. Standard methods for measuring mammals. Pp. 566-570 in Captive Management of Mammals. Chicago: Chicago Univ. Press. Maffei, M., J. Halaas, E. Ravussin, R.E. Partley, G.H. Lee, Y. Zhang, H. Fei, S.L.R. Kim, S. Ranganathan, and P.A. Kern. 1995. Leptin levels in human and rodent: measurement of plasma leptin and obRNA in obese and weight-reduced subjects. Nature Med. 1:1155-1161. McCay, C.M., M.F. Crowell, and L.A. Maynard. 1935. The effect of retarded growth upon the length of the life span and upon the ultimate body size. J. Nutr. 10:63-79. McFarland, R.K., and A.L. Zihlman. 1994. Variation in body composition in pygmy chimpanzees: a preliminary report. Am. J. Primatol. 33:228. McMahan, C.A., H.S. Wigodsky, and G.T. Moore. 1976. Weight of the infant baboon (Papio cynocephalus) from birth to fifteen weeks. Lab. Anim. Sci. 26:928-931. Meehan, T.P., P.L. Wolff, D.J. Baer, W.V. Rumpler, B.R. Raphael, and O.T. Oftedal. 1989. Methods of estimating body composition, with preliminary observations on the relationship between obesity and fertility. Pp. 47-48 in Proc. Eighth Dr. Scholl Conf. Nutr. Captive Wild Anim. Chicago, IL. Merrill, A.L., and B.K. Watt. 1955. Derivation of current calorie factors. Pp. 24-43 in Energy Value of Foods, Basis and Derivation., Agr. Res. Serv., USDA, Agriculture Handbook No. 74, Washington, DC: U.S. Government Printing Office. Merry, B.J., and A.M. Holehan. 1979. Onset of puberty and duration of fertility in rats fed a restricted diet. J. Reprod. Fertil. 57:253-259. Milton, K., and M. Demment. 1988. Digestion and passage kinetics of chimpanzees fed high and low fiber diets and comparison with human data. J. Nutr. 118:1082-1088. Moon, M.A., and F.E. Taylor. 1994. Low-cal diets, can they prolong life? NIH Natl. Ctr. Res. Resources Reporter 18:4-7. Moore, G.T., and L.B. Cummins. 1979. Nursery rearing of infant baboons. Pp. 145-151 in Nursery Care of Nonhuman Primates, G.C. Ruppenthal, Ed. New York: Plenum. Mott, G.E., C.A. McMahan, J.L. Kelley, C.M. Farley, and H.C. McGill, Jr. 1982. Influence of infant and juvenile diets on serum cholesterol, lipoprotein cholesterol, and apolipoprotein concentrations in juvenile baboons (Papio sp.). Atherosclerosis 45:191-202. Mott, G.E., E.M. Jackson, C.A. McMahan, C.M. Farley, and H.C. McGill, Jr. 1985. Cholesterol metabolism in juvenile baboons: influence of infant and juvenile diets. Arteriosclerosis 5:347-354. Mott, G.E., E.M. Jackson, C.A. McMahan, and H.C. McGill, Jr. 1990. Cholesterol metabolism in adult baboons is influenced by infant diet. J. Nutr. 230:243-251. Mott, G.E., D.S. Lewis, and C.A. McMahan. 1993a. Infant diet affects serum lipoprotein concentrations and cholesterol esterifying enzymes in baboons. J. Nutr. 123:155-163. Mott, G.E., L. DeLallo, D.M. Driscoll, C.A. McMahan, and D.S. Lewis. 1993b. Influence of breast and formula feeding on hepatic concentrations of apolipoprotein and low density lipoprotein receptor mRNAs. Biochim. Biophys. Acta 1169:59-65. Myher, J.J., A. Kusis, C. Tildon, and O.T. Oftedal. 1994. A cross-species comparison of neutral lipid composition of milk fat of prosimian primates. Lipids 29:411-419. National Research Council. 1978. Nutrient Requirements of Nonhuman Primates. Washington, DC: National Academy of Sciences. Neville, M.C., C.E. Casey, M.R. Neifert, and J.M. Seacat. 1986. Nutrient intake by breast-fed infants during the first five days after birth. Am J Dis Child. 140:933-936. Nishikawa, I., G. Kawanishi, F. Cho, S. Honjo, T. Hatakeyama, and H. Wako. 1976. Chemical composition of Cynomolgus monkey milk. Exp. Anim. 25:253-264. Oftedal, O.T. 1984. Milk composition, milk yield and energy output at peak lactation: a comparative review. Symp. Zool. Soc. Lond. No. 51, pp. 33-85. Oftedal, O.T. 1991. The nutritional consequences of foraging in primates: the relationship of nutrient intakes to nutrient requirements. Phil. Trans. R. Soc. London B 334:161-170. Orgeldinger, M. 1994. Monitoring body weight in captive primates with special reference to siamangs. Int. Zoo News 41:17-26. Patiño, E.M., C.C.R. de Oliveira, C.C.D. Zetterman, J.T. Borda, and J.C. Ruiz. 1997 . Hand-rearing Cebus apella. Lab Prim. Newsletter 36:15-17. Pilson, M.E.Q., and R.W. Cooper. 1967. Composition of milk from Galago crassicaudatus. Folia Primatol. 5:88-91. Polberger, S., M.P. Fletcher, T.W. Graham, V. Vruwink, M.E. Gershwin, and B. Lönnerdal. 1996. Effect of infant formula zinc and iron level on zinc absorption, zinc status, and immune function in infant rhesus monkeys. J. Pediatr. Gastroenterol. Nutr. 22:134-143.
OCR for page 180
Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 Power, M.L., and O.T. Oftedal. 1996. Differences among captive callitrichids in the digestive responses to dietary gum. Am. J. Primatol. 40:131-144. Ramsey, J.J., E.B. Roecker, R. Weindruch, S.T. Baum, and J.W. Kemnitz. 1996. Thermogenesis of adult male rhesus monkeys: results through 66 months of dietary restriction. FASEB J. 10:A726. Ramsey, J.J., E.B. Roecker, R. Weindruch, and J.W. Kemnitz. 1997. Energy expenditure of adult male rhesus monkeys during the first 30 mo of dietary restriction. Am. J. Physiol. 272 (Endocrinol. Metab.) 35:E901-E907. Ramsey, J.J., J.W. Kemnitz, R.J. Colman, D. Cunningham, and A.G. Swick. 1998. Different central and peripheral responses to leptin in rhesus monkeys: brain transport may be limited. J. Clin. Endocrinol. Metab. 83:3230-3235. Ramsey, J.J., R.J. Colman, N.C. Binkley, J.D. Christensen, T.A. Gresl, J.W. Kemnitz, and R. Weindruch. 2000. Dietary restriction and aging in rhesus monkeys: the University of Wisconsin study. Exp. Gerontol. 35:1131-1149. Rasmussen, K.M., S.W. Thenen, and K.C. Hayes. 1980. Effect of folic acid supplementation on pregnancy in the squirrel monkey (Saimiri sciureus). J. Med. Primatol. 9:169-184. Roberts, S.B., T.J. Cole, and W.A. Coward. 1985. Lactational performance in relation to energy intake in the baboon. Am. J. Clin. Nutr. 41:1270-1276. Roecker, E.B., J.W. Kemnitz, W.B. Ershler, and R. Weindruch. 1996. Reduced immune response in rhesus monkeys subjected to dietary restriction. J. Gerontol. A. Biol. Sci. Med. Sci. 51:B276-279. Roth, G.S., M.R. Blackman, D.K. Ingram, M.A. Lane, S.S. Ball, and R.G. Cutler. 1993. Age-related changes in androgen levels of rhesus monkeys subjected to diet restriction. Endocrinol. J. 1:227-234. Roth, G.S., D.K. Ingram, and M.A. Lane. 1995. Slowing aging by caloric restriction. Nat. Med. 1:414-415. Roth, G.S., M.A. Kowatch, J.Hengemihle, D.K. Ingram, E.L. Spangler, L.K. Johnson, and M.A. Lane. 1997. Effect of age and caloric restriction on cutaneous wound closure in rats and monkeys. J. Gerontol. 52A:B98-B102. Ruppenthal, G.C. 1979. Survey of protocols for nursery-rearing infant Macaques. Pp. 165-185 in Nursery Care of Nonhuman Primates, G.C. Ruppenthal, Ed. New York: Plenum. Russo. A.R., L.M. Ausman, D.L. Gallina, and D.M. Hegsted. 1980. Developmental body composition of the squirrel monkey (Saimiri sciureus). Growth 44:271-286. Sackett, G.P., R.A. Holm, and C.E. Fahrenbruch. 1979. Ponderal growth in colony and nursery-reared pigtail macaques (Macaca nemestrina). Pp. 187-202 in Nursery Care of Nonhuman Primates, G.C. Ruppenthal, Ed. New York: Plenum. Samonds, K.W., and D.M. Hegsted. 1973. Protein requirements of young cebus monkeys (Cebus albifrons and apella). Am. J. Clin. Nutr. 26:30-40. Samonds, K.W., and D.M. Hegsted. 1978. Protein deficiency and energy restriction in young cebus monkeys. Proc. Natl. Acad. Sci. 75: 1600-1604. Schwartz, S.M., Kemnitz, J.W., and Howard, C.F., Jr. 1993. Obesity in free-ranging rhesus macaques. Int. J. Obesity 17:1-9. Sell, D.R., M.A. Lane, W.A. Johnson, E.J. Masoro, O.B. Mock, K.M. Resiser, J.F. Fogarty, R.G. Cutler, D.K. Ingram, G.S. Roth, and V.M. Monnier. 1996. Longevity and the genetic determination of collagen glycoxidation kinetics in mammalian senescence. Proc. Natl. Acad. Sci. 93:485-490. Shively, C.A., and T.B. Clarkson. 1988. Regional obesity and coronary artery atherosclerosis in females: a non-human primate model. Acta Med. Scand. Suppl. 723:71-78. Short R., D.D. Williams, and D.M. Bowden. 1987. Cross-sectional evaluation of potential biological markers of aging in pigtailed macaques: effects of age, sex, and diet. J. Gerontol. 42:644-654. Silva, M., and J.A. Downing. 1995. CRC Handbook of Mammalian Body Masses. Boca Raton, FL: CRC Press. Smith, A.H., T.M. Butler, and N. Pace. 1975. Weight growth of colony-reared chimpanzees. Folia Primatol. 24:29-59. Stephan, Z.F., M.J. Armstrong, and K.C. Hayes. 1981. Bile lipid alterations in taurine-depleted monkeys. Am. J. Clin. Nutr. 34:204-210. Strobel D.A., and H.H. Sandstead. 1984. Social and learning changes following prenatal or postnatal zinc deprivation in rhesus monkeys. Pp. 121-138 in Neurology and Neurobiology 11(Pt B). Also as The Neurobiology of Zinc: Deficiency, Toxicity, and Pathology, C.J. Frederickson, G.A. Howell, E.J. Kasarskis, Eds. New York: Alan R. Liss, Inc. Sturman, J.A., G.Y. Wen, H.M. Wisniewski, and M.D. Neuringer. 1984. Retinal degeneration in primates raised on a synthetic human infant formula. Int. J. Develop. Neurosci. 2:121-129. Sturman, J.A., J.M. Messing, S.S. Rossi, A.F. Hofmann, and M.D. Neuringer. 1988. Tissue taurine content and conjugated bile acid composition of rhesus monkey infants fed a human infant soy-protein formula with or without taurine supplementation for 3 months. Neurochem. Res. 13:311-316. Sumner, D.R., M.E. Morbeck, and J.J. Lobick. 1989. Apparent age-related bone loss among adult female Gombe chimpanzees. Am. J. Phys. Anthropol. 79:225-234. Tannenbaum, A. 1940. The initiation and growth of tumors. Introduction. 1. Effects of underfeeding. Am. J. Cancer 38:335-350. Taylor, J.J., and M. Tompkinson. 1975. A comparative study of primate breast milk. Rep. Jersey Wildl. Pres. Trust 12:76-77. Tilden C.D., and O.T. Oftedal. 1997. Milk composition reflects pattern of maternal care in prosimian primates. Am. J. Primatol. 41:195-211. Terranova, C.J., and B.S. Coffman. 1997. Body weights of wild and captive lemurs. Zoo Biol. 16:17-30. Turton, J.A., D.J. Ford, J. Bleby, B.M. Hall, and R. Whiting. 1978. Composition of the milk of the common marmoset (Callithrix jacchus) and milk substitutes used in hand-rearing programmes, with special reference to fatty acids. Folia Primatol. 29:64-79. Udono, T., S. Sadaoka, M. Inoue, A. Takenaka, and O. Takenaka. 1989. Feeding of the chimpanzee in Sanwakagaku Kenkyusho Reichourui Center, Co., Ltd. and paternity discrimination. Primate Res. 5:157-(in Japanese). Valerio, D.A., P.T. Johnson, and G.E. Thompson. 1972. Breeding the greater bushbaby, Galago crassicaudatus, in a laboratory environment. Lab. Anim. Sci. 22:203-206. Van Wagenen, G., H.E. Himwich, and H.R. Catchpole. 1941. Composition of the milk of the monkey (M. mulatta). Proc. Soc. Exptl. Biol. Med. 48:133-134. Verdery, R.B., D.K. Ingram, G.S. Roth, and M.A. Lane. 1997. Caloric restriction increases HDL2 levels in rhesus monkeys (Macaca mulatta). Am. J. Physiol. 273 (Endocrinol. Metab.) 36:E714-E719. Vice, T.E., H.A. Britton, I.A. Ratner, and S.S. Kalter. 1966. Care and raising of newborn baboons. Lab. Anim. Care 16:12-22. Vidal-Puig, A., R.V. Considine, M. Jimenez-Liñn, A. Werman, W.J. Pories, J.F. Caro, and J.S. Flier. 1997. Peroxisome proliferator-activated receptor gene expression in human tissues: effects of obesity, weight loss, and regulation by insulin and glucocorticoids. J. Clin. Invest. 99:2416-2422. Vidal-Puig, A., M. Jimenez-Linñ an, B.B. Lowell, A. Hamann, E. Hu, B. Spiegelman, J.S. Flier, and D.E. Moller. 1996. Regulation of PPAR γ gene expression by nutrition and obesity in rodents. J. Clin. Invest. 97:2553-2561. vom Saal, F.S., C.E. Finch, and J.F. Nelson. 1994. Natural history and mechanisms of reproductive aging in humans, laboratory rodents, and other selected vertebrates. Pp. 1213-1313 in The Physiology of Reproduction, 2nd ed., E. Knobil and J.D. Neill, Eds. New York: Raven Press, Ltd.
OCR for page 181
Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 Weed, J.J., M.A. Lane, G.S. Roth, D.L. Speer, and D.K. Ingram. 1997. Activity measures in rhesus monkeys on long-term calorie restriction. Physiol. Behav. 62:97-103. Weindruch, R. 1995. Immunogerontologic outcomes of dietary restriction started in adulthood. Nutr. Rev. 53(4):S66-S71. Weindruch, R. 1996. Caloric restriction and aging. Sci. Am. 274:46-52. Weindruch, R., and R.L. Walford. 1988. The Retardation of Aging and Disease by Dietary Restriction. Springfield, IL: Charles C. Thomas. Weindruch, R., B.M. Marriott, J. Conway, J.J. Knapka, M.A. Lane, R.G. Cutler, G.S. Roth, and D.K. Ingram. 1995. Measures of body size and growth in rhesus and squirrel monkeys subjected to long-term dietary restriction. Am. J. Primatol. 35:207-228. Weindruch, R., M.A. Lane, D.K. Ingram, W.B. Ershler, and G.S. Roth. 1997. Dietary restriction in rhesus monkeys: lymphopenia and reduced mitogen-induced proliferation in peripheral blood mononuclear cells. Aging Clin. Exp. Res. 9:304-308. Wilen, R., and F. Naftolin. 1978. Pubertal age, weight, and weight gain in the individual female New World monkey (Cebus albifrons). Primates 19:769-774. Willcox, K.K., K.Y. Lei, and D.D. Williams. 1986. Aging and dietary influences on plasma lipoproteins and apolipoproteins in nonhuman primates. Metabol. 35:1062-1069. Wolden-Hanson, T., S. Baum, D. Frye, H. Barden, E. Roecker and J.W. Kemnnitz. 1992. The effects of moderate caloric restriction on body composition and oxygen consumption in rhesus monkeys. Am. J. Primatol. 27:64 (Abstr.). Wolden-Hanson, T., G.A. Davis, S.T. Baum, and J.W. Kemnitz. 1993. Insulin levels, physical activity and urinary catecholamine excretion of obese and nonobese rhesus monkeys. Obesity Research: 1:5-17. Zhang, Y., R. Proenca, M. Maffei, M. Barone, L. Leopold, and J.M. Friedman. 1994. Positional cloning of the mouse obese gene and its human homologue. Nature 372:425-432.
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