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14
Micronutrient Deficiency States and Thermoregulation in the Cold

John L. Beard1

INTRODUCTION

Vitamins and minerals are essential to a myriad of physiologic functions, and a deficiency results in a wide variety of disorders. Among these disorders is the inability of mammals to maintain body temperature adequately in the cold. The purpose of this review is to present current concepts in temperature regulation, with particular emphasis on temperature maintenance in cold environments, and to relate physiologic changes caused by micronutrient deficiency to impaired thermoregulation.

It is well-established in a number of species that limitation of a single micronutrient can result in poor thermoregulatory performance (Lukaski and Smith, in press). Frequently, however, the causal relationship between specific metabolic alterations resulting from that nutrient deficiency and the decreased functional performance of the individual is unknown. Many of the micronutrient deficiency states that will be addressed in this chapter alter nearly all of the processes of heat production and conservation. Of the micronutrients to be

1  

John L. Beard, Nutrition Department, The Pennsylvania State University, University Park, PA 16803



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--> 14 Micronutrient Deficiency States and Thermoregulation in the Cold John L. Beard1 INTRODUCTION Vitamins and minerals are essential to a myriad of physiologic functions, and a deficiency results in a wide variety of disorders. Among these disorders is the inability of mammals to maintain body temperature adequately in the cold. The purpose of this review is to present current concepts in temperature regulation, with particular emphasis on temperature maintenance in cold environments, and to relate physiologic changes caused by micronutrient deficiency to impaired thermoregulation. It is well-established in a number of species that limitation of a single micronutrient can result in poor thermoregulatory performance (Lukaski and Smith, in press). Frequently, however, the causal relationship between specific metabolic alterations resulting from that nutrient deficiency and the decreased functional performance of the individual is unknown. Many of the micronutrient deficiency states that will be addressed in this chapter alter nearly all of the processes of heat production and conservation. Of the micronutrients to be 1   John L. Beard, Nutrition Department, The Pennsylvania State University, University Park, PA 16803

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--> discussed, only iron deficiency has any significant prevalence in the human population, although selenium deficiency is observed in certain specific regions of China. However, despite the recent evidence showing that peripheral conversion of the thyroid hormone thyroxin (T4) to tri-iodothysonine (T3) is performed by a selenium-dependent enzyme, there is no evidence linking selenium deficiency to poor thermoregulation in humans. Profound and severe exercise, especially of the types undertaken by military personnel in the course of their activities, can also cause a dramatic alteration in plasma concentrations of some of these micronutrients which may lead to acute transitory deficiency states in particular tissues. This notion has not been the experimental paradigm for any of these studies and, therefore, warrants further investigation. THERMAL BALANCE The body temperature of an animal is dependent on the balance between processes of heat gain and heat loss. These can be described mathematically by the heat-balance equation: where S = net rate of heat storage, M = metabolic heat production, W = mechanical work transferred to the environment, E = evaporative heat transfer, C = convective heat transfer, K = conductive heat transfer, and R = radiant heat exchange. In an environment that is below thermoneutrality, the sole means of heat gain for homeotherms2 is metabolic heat production. Heat loss can occur by evaporation, convection, conduction, radiation, and mechanical work. Metabolic heat in mammals comes from the following metabolic sources: basal metabolism, postprandial thermogenesis, diet-induced thermogenesis, shivering thermogenesis, and nonshivering thermogenesis (Gordon, 1993). Shivering and nonshivering thermogenesis are the main sources of heat production utilized during cold exposure, and both may be affected by micronutrient deficiency states. In the cold, peripheral vasomotor tone is increased via central nervous system control of smooth muscle in arterioles and arteriovenous anastomoses, leading to a decrease in convective and conductive heat loss (Grayson, 1990). There is reason to believe that the failure to control this process is the fundamental reason iron-deficient anemic humans (and animal models) fail to thermoregulate adequately (Beard et al., 1990a, b; Lukaski et al., 1990). 2   Any species that maintains a constant body temperature.

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--> Shivering is triggered by a fall in the temperature of the blood, due to body temperature, causing the hypothalamus to stimulate motor neuron activity. Subsequently, increased skeletal muscle tone in antagonistic muscle groups leads to a rhythmic oscillation, probably as a result of feedback from the muscle spindle reflex mechanism (Guyton, 1986). The inability of muscles to conduct this rhythmic muscle contraction may be the result of nutrient deficiency states that lead to a decrease in oxidative metabolism. This may clearly be the case for iron, copper, and zinc deficiency as described further in this chapter, as well as pyridoxine, and thiamin deficiency (Lukaski and Smith, in press) although only the mineral deficiency states have been characterized with regard to thermoregulation. Nonshivering thermogenesis occurs primarily in brown adipose tissue, a type of fat tissue that produces heat via uncoupling of oxidative phosphorylation in mitochondria (Himms-Hagen, 1981, 1986, 1990). In addition to providing heat for temperature regulation, brown adipose tissue also expends excess energy from overabundant caloric intake, termed diet-induced thermogenesis (Rothwell and Stock, 1983, 1986; Stock and Rothwell, 1991). Brown adipose tissue is the main organ for nonshivering thermogenesis in rodents and newborn mammals (Nedergaard et al., 1986), but most adult mammals, including adult humans, have only a small amount of detectable brown adipose tissue (Lean and James, 1986). The increase in thyroid hormone production and metabolism associated with cold exposure is the probable initiator of heat production in brown adipose tissue (Guyton, 1986). Thyroid hormones, particularly T3, stimulate a general increase in metabolism by increasing the activity of the enzyme sodium-potassium Adenosine Triphosphatase (Na-K ATPase) (the sodium pump) in the plasma membrane, decreasing the efficiency of oxidative phosphorylation (via changes in the properties of the inner mitochondrial membrane), and possibly increasing calcium ion cycling (Dauncey, 1990; van Hardeveld et al., 1986). T4, the primary secretory product of the thyroid gland, also plays a pivotal role in thermogenesis. T4 and its active metabolite, T3, serve to increase heat production by two independent mechanisms. First, they work in conjunction with the sympathetic nervous system to stimulate heat production in brown adipose tissue. Second, they cause a generalized increase in the metabolic rate of all tissues by stimulating NA-K ATPase-mediated ion transport across the plasma membrane. In response to cold, T4 production from the thyroid gland increases, often resulting in a rise in plasma T4 concentration (Fregly, 1989). More notable is a large increase in the level of plasma T3, a result of increased conversion of T4 to T3 by the enzyme thyroxine 5'-deiodinase (Scammell et al., 1988). The synthesis of this enzyme is under the control of both substrate (T4) availability and sympathetic innervation (Kaplan, 1986).

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--> IRON DEFICIENCY Several key observations have stimulated interest in the relationship between iron deficiency and thermoregulation. Iron-deficient anemic rats were found to be unable to maintain normal body temperature when exposed to cold (39°F [4°C]) (Beard et al., 1982, 1984; Dillmann et al., 1979, 1980). Accompanying the impairment in thermoregulation were a decrease in the rate of thyroid hormone turnover and an increase in the rate of norepinephrine turnover, as compared to those observed in noniron-depleted cold-exposed (control) rats. Iron-deficient humans are unable to maintain their body temperature during exposure to cool water (82°F [28°C]) (Beard et al., 1990a; Martinez-Torres et al., 1984) or cool air (61°F [16°C]) (Lukaski et al., 1990), compared to subjects with normal iron status and equivalent body composition. Additionally, the iron-deficient subjects had lower thyroid hormone (Beard et al., 1990a) and higher catecholamine responses to cold (Lukaski et al., 1990; Martinez-Torres et al., 1984), similar to the response of iron-deficient rats. After repletion with iron supplements, the previously iron-deficient human subjects showed improved ability to maintain body temperature in the cold. These observations clearly demonstrate the link between iron deficiency and poor thermoregulation. Anemia vs. Tissue Iron Deficiency Iron deficiency may exert its effects on thermoregulation through two distinct, yet related, mechanisms, one involving anemia and the other involving tissue iron deficiency. Iron-deficiency anemia results in decreased oxygen transport from the lungs to tissues, and this reduction in oxygen availability inhibits physiological responses to cold, including peripheral vasoconstriction, a heat-conserving process, and increased metabolic rate, a heat-generating process. Hypoxia, created by reducing the oxygen content or the pressure of inspired air, results in hypothermia in rodents (Gautier et al., 1991). The inability to conserve and produce body heat properly accounts for hypoxia-induced hypothermia (Wood, 1991). Lack of oxygen availability for aerobic metabolism causes a decrease in metabolic rate and, subsequently, a decrease in heat production. Hypoxic rats demonstrate decreased shivering and nonshivering thermogenesis (Gautier et al., 1991) and a decrease in body temperature set-point (Gordon and Fogelson, 1991). Impaired neural control of these processes may also account for the effects of hypoxia on thermoregulation (Mayfield et al., 1987). Tissue iron deficiency, apart from anemia, decreases the ability of muscles to utilize energy for muscular contraction, presumably via a decrease in the activity of mitochondrial iron-containing enzymes required for the oxidative production of ATP (Davies et al., 1984). This decrease in muscular function

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--> may impair the ability of iron-deficient animals to produce heat from shivering. The decrease in mitochondrial enzymes that results from iron deficiency may not be a significant factor, however, in limiting the heat production in iron-deficient rats. This is suggested by the observation that iron-deficient rats injected with pharmacological doses of norepinephrine are able to attain metabolic rates that are even higher than those of noniron-deficient control rats given the same dose of norepinephrine (Tobin and Beard, 1990). Iron-deficient anemic rats rapidly become hypothermic when placed in a cold environment (39°F [4°C]), and correcting their anemia by infusing them with red blood cells restores their thermoregulatory performance (Beard et al., 1984). Likewise, poor cold responses were induced in control rats by transfusion to a lower hematocrit level. Correcting anemia also improved thyroid response to cold. Whereas cold-exposed, anemic, iron-deficient rats did not increase their plasma T3 and thyroid-stimulating hormone (TSH) levels, correction of the anemia by transfusion resulted in a normal thyroid response to cold exposure (increased plasma T3 and TSH concentrations). Not all iron-deficiency-induced alterations are reversible by correction of anemia. After an increase in the hematocrit levels of iron-deficient rats, plasma norepinephrine concentrations remained elevated (Dillmann et al., 1979), and the norepinephrine content of heart and brown adipose tissue remained depressed (Beard et al., 1990b) compared to control rats with similar hematocrit values. Neurohormones Much of thermoregulation is ultimately controlled by central neural control of blood flow, heat production, and heat loss. Thus, the impact of micronutrient deficiency states on temperature regulation can often be traced to control of neurohormone production (Brigham and Beard, in press). There is also evidence that iron deficiency may alter neurohormonal control of thermoregulation centers in the central nervous system by way of an effect on dopamine, serotonin, and norepinephrine. The brains of iron-deficient rats were observed to contain excessive quantities of dopamine in the caudate-putamen region, and the number of D2 receptors in the brain was lowered by iron deficiency (Youdim et al., 1989). Beard and coworkers have recently extended these observations and determined, through the use of in vivo microdialysis, that extracellular dopamine is elevated in awake, freely moving animals who were made iron deficient by dietary means only (Beard et al., 1994). Thus, the down regulation of dopamine receptors by iron deficiency may be the result of a direct effect of iron on receptor biology or may be the result of elevated extracellular-fluid dopamine concentrations. This latter observation is consistent with evidence that dopamine-dependent circadian cycles are reversed in iron-deficient rats (Youdim and Yehuda, 1985), although others have not verified the circadian cycle effect (Hunt et al.,

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--> 1994). The ability of dopamine to down-regulate its own (D2) receptors and thus effectively decrease dopaminergic activity suggests a possible mechanism for the iron deficiency-mediated loss of thermoregulation. The decrease in dopaminergic neurotransmission caused by iron deficiency would inhibit the cold-mediated release of thyrotropin-releasing hormone (TRH) from the hypothalamus, as well as the release of TSH from the pituitary, which in turn would attenuate the synthesis and release of thyroid hormone. Norepinephrine metabolism is clearly altered by iron deficiency. Iron-deficient rats have increased blood and urinary norepinephrine levels compared to control rats (Beard et al., 1984; Dillmann et al., 1979, 1980), and this effect is more pronounced at lower temperatures. Likewise, norepinephrine concentrations in the blood and urine of iron-deficient humans are elevated (Vorhees et al., 1975; Wagner et al., 1979; Webb et al., 1982), and this effect is exacerbated as environmental temperature decreases (Martinez-Torres et al., 1984). Elevated levels of norepinephrine in the blood and urine of iron-deficient rats suggest that sympathetic activity is heightened by iron deficiency (Beard and Tobin, 1987; Beard et al., 1988) and is indicative of a hyperadrenergic state. These alterations are influenced by the severity of iron deficiency (Borel et al., 1991) and reversed by iron repletion, but not by correction of anemia (Beard et al., 1990b; Dillmann et al., 1979). When Smith and coworkers (1992b) administered chlorisondamine, a ganglionic blocker, to iron-deficient rats to interrupt neuronal firing, they observed a rapid increase in the norepinephrine content of iron-deficient hearts to control levels. Coupled with in vitro assessments of tyrosine hydroxylase activity, these results indicate that increased sympathetic firing rate, rather than impaired synthesis, accounts for the decreased norepinephrine content found in the tissues of iron-deficient rats and perhaps the increased concentrations of norepinephrine in the plasma and urine of iron-deficient humans. Thyroid Hormones In humans, iron-deficiency anemia is associated with changes in plasma thyroid hormone and norepinephrine concentrations that mirror those seen in iron-deficient rats. In all of the studies cited here (Beard et al., 1990a; Lukaski et al., 1990; Martinez-Torres et al., 1984), iron-deficient anemic subjects had a greater loss of body temperature in the cold than control subjects. In the two studies that matched levels of body fat across treatment groups (an important consideration for studying thermoregulation in humans), oxygen consumption during cold exposure was lower among iron-deficient anemic subjects (Beard et al., 1990a; Lukaski et al., 1990). Plasma T3 and T4 concentrations were lower in anemic than control subjects both before and during cold exposure (Beard et al., 1990a), and plasma norepinephrine levels were higher in iron-deficient subjects than in controls after cold exposure (Lukaski et al., 1990;

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--> Martinez-Torres et al., 1984). After iron-deficient subjects were given iron supplements, their ability to maintain normal body temperature in the cold improved, their oxygen consumption in the cold increased, and their plasma thyroid hormone levels partially normalized (Beard et al., 1990a; Lukaski et al., 1990). In rats, iron deficiency decreases plasma T3 and T4 concentrations at room temperature (68°-77°F [20°-25°C]), compared to those of control rats, and the normal increase in the plasma levels of T3 and T4 observed in control rats after cold exposure (39°F [4°C]) is not seen in iron-deficient rats (Beard et al., 1984, 1988; Dillmann et al., 1980; Tang et al., 1988). Additionally, the TSH response to cold in iron-deficient anemic rats was lower than that in control rats but was reversed by exchange transfusion of red blood cells (Beard et al., 1984). Iron repletion of iron-deficient rats normalized the plasma T3 response to cold within 6 days (Dillmann et al., 1980), a time span that allows for an increase in hematocrit to almost normal (> 80 percent of control) levels (Beard et al., 1990b). Injecting iron-deficient anemic rats with T3 (10 µg/kg body weight) improved the ability of iron-deficient rats to maintain body temperature at 39°F (4°C) (Beard et al., 1982), but injections of T4 had no such beneficial effect (Dillmann et al., 1980) because the conversion of T4 to T3 by the liver thyroxine 5'-deiodinase is decreased by iron deficiency (Smith et al., 1992a, b; Tobin and Beard, 1990b). This decrease is partially reversed by 7 days of iron repletion (Beard et al., 1990b), and the time course of its increase is paralleled by the rise in plasma T3 concentration that results. Likewise, T4 and T3 production rates, as assessed by plasma kinetics, are decreased by iron deficiency (Brigham, 1995). In summary, iron deficiency profoundly alters thyroid hormone in animal models and to a lesser extent in humans. The most recent kinetic studies suggest the primary effect is a central nervous system-modulated one; that is, iron deficiency changes the hypothalamic control of thyroid metabolism. The lesser effects in humans likely reflect the lesser severity of anemia than in animal models rather than a species-dependent effect. COPPER DEFICIENCY Copper is essential for the functioning of a number of essential oxidation-reduction enzymes, and a deficiency of this mineral is associated with anemia, neural degeneration, cardiac distress, and connective tissue dysfunction (O'Dell, 1990). A deficiency in copper in humans is associated with anemia, presumably due to the role of copper in ceruloplasmin metabolism and hence the incorporation of iron into transferrin or perhaps due to the increased rate of destruction of red cells resulting from a decrease in erythrocyte superoxide dismutase (Milne, 1994; Sandstead, 1995). One of the first documentations of copper deficiency in humans noted the presence of hypothermia along with a

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--> myriad of other clinical symptoms, but an underlying explanation was lacking (Menkes et al., 1962). Animal studies showed that a copper-deficient animal has a lowered body temperature along with lowered circulating thyroid hormone levels. This is reminiscent of the observation of poor thyroid function and thermoregulation seen in iron-deficient rats (Hall et al., 1990). These animals are also anemic although the anemia is not as severe as that of rats fed an iron-deficient diet. Thus these studies are confounded with iron-deficiency anemia as well as independent effects that are not easily determined. Some researchers, however, have argued that a copper-dependent cytochrome oxidase deficiency may lead directly to a thermoregulatory defect (Hall et al., 1990). ZINC DEFICIENCY In human zinc deficiency there is pronounced growth failure, multiorgan dysfunction, and a generalized systemic effect (Cousins and Hempe, 1990). Because zinc is required for proper functioning of nearly all cells with regard to both energy and protein metabolism, it is not surprising that a zinc deficiency is associated with poor thermoregulation. O'Dell and colleagues (1991) noted that zinc-deficient animals were hypothermic when the nutrient was withheld in utero and animals were examined later in life. Other studies in adult rats showed an inability of zinc-depleted rats to thermoregulate with cold air exposure (Topping et al., 1981). There is a clear effect of lowered zinc status on thyroid hormone metabolism in rats (Lukaski and Smith, in press; Lukaski et al., 1992). TRH secretion appears to be decreased in zinc deficiency along with circulating T3 and T4. Zinc depletion studies conducted in humans in metabolic wards reported a decrease in circulating total and free T4 concentrations, similar in magnitude to those observed in iron deficiency (Wada and King, 1986). This study carefully depleted subjects by a dietary restriction of zinc and observed a steady decline in circulating total and free T4 with lowered zinc status. It is not clear if thyroid kinetics are lowered, although there was a decrease in metabolic rate as thyroid levels were lowered. Results of animal studies further suggest that the decrease in TRH resulting from zinc depletion is due to the deficiency of a zinc-dependent enzyme involved in TRH synthesis (Lukaski et al., 1994). AUTHOR'S CONCLUSIONS Although most of this review has focused on the relationship of iron status to thermoregulation, this is not meant to infer that other micronutrients do not have profound effects. It only implies that this micronutrient is the one most thoroughly studied. One of the inherent difficulties in evaluating animal and human research with regard to micronutrient deficiency effects is that the

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--> assessment of nutrient status is difficult. Sufficiently sensitive indicators may not be available to allow accurate diagnosis of the size of reserves or even the extent of depletion. It is clear from other chapters in this volume that extreme physical activity can lead to alterations in the fluid and hydration status of individuals, in whom micronutrient status is also being determined. The extreme physical activity may change the status parameters themselves, thus confounding the capacity to evaluate a direct effect of a micronutrient on thermoregulation. When a chronic deficiency state occurs with the minerals copper, zinc, or iron, it is clear that poor thermoregulation will occur. Short-term deficiencies, however, such as those that may be produced by field exercises of only several weeks' duration, will likely not lead to a micronutrient deprivation unless there is preexisting reserve depletion. Nonetheless, certain micronutrients have a profound effect on performance, both physical and cognitive, and every precaution should be taken to minimize the likelihood of a deficiency state. REFERENCES Beard, J., and B. Tobin 1987 Feed efficiency and norepinephrine turnover in iron deficiency. Proc. Soc. Exp. Biol. Med. 184: 337–344. Beard, J., C.A. Finch, and W.L. Green 1982 Interactions of iron deficiency, anemia, and thyroid hormone levels in the response of rats to cold exposure. Life Sci. 30:691–697. Beard, J., W. Green, L. Miller, and C. Finch 1984 Effect of iron-deficiency anemia on hormone levels and thermoregulation during cold exposure. Am. J. Physiol. 247:R114–R119. Beard, J., B. Tobin, and S.M. Smith 1988 Norepinephrine turnover in iron deficiency at three environmental temperatures. Am. J. Physiol. 255:R90–R96. Beard, J.L., M.J. Borel, and J. Derr 1990a Impaired thermoregulation and thyroid function in iron-deficiency anemia. Am. J. Clin. Nutr. 52:813–819. Beard, J.L., B.W. Tobin, and S.M. Smith 1990b Effects of iron repletion and correction of anemia on norepinephrine turnover and thyroid metabolism in iron deficiency. Proc. Soc. Exp. Biol. Med. 193:306–312. Beard J.L., Q. Chen, J.R. Connor, and B.C. Jones 1994 Altered monoamine metabolism in caudate putamen of iron-deficient rats. Pharmacol. Biochem. Behav. 48:321–324. Borel, M.J., S.H. Smith, D.E. Brigham, and J.L. Beard 1991 The impact of varying degrees of iron nutriture on several functional consequences of iron deficiency in rats. J. Nutr. 121:729–736. Brigham, D. 1995 Thyroid Hormone Kinetics in Iron Deficiency at Two Environmental Temperatures. Doctoral Dissertation. The Pennsylvania State University, State College, Pa. Brigham, D., and J.L. Beard In Iron and thermoregulation: A review. In Critical Reviews in Food Science and Press Nutrition. Boca Raton, Fla.: CRC Press.

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--> Cousins, R.J., and J.M. Hempe 1990 Zinc Pp. 251–260 in Present Knowledge of Nutrition, 6th ed., M.L. Brown, ed. Washington, D.C.: International Life Sciences Institute, Nutrition Foundation . Dauncey, M.J. 1990 Thyroid hormones and thermogenesis. Proc. Nutr. Soc. 49:202–215. Davies, K.J.A., C.M. Donovan, C.J. Refino, G.A. Brooks, L. Packer, and P.R. Dallman 1984 Distinguishing effects of anemia and muscle iron deficiency on exercise bioenergetics in the rat. Am. J. Physiol. 246:E539–E543. Dillmann, E., D.G. Johnson, J. Martin, B. Mackler, and C. Finch 1979 Catecholamine elevation in iron deficiency. Am. J. Physiol. 237:R297–R300. Dillmann, E., C. Gale, W. Green, D.G. Johnson, B. Mackler, and C. Finch 1980 Hypothermia in iron deficiency due to altered triiodothyronine metabolism. Am. J. Physiol. 239:R377–R381 Fregly, M.J. 1989 Activity of the hypothalamic-pituitary-thyroid axis during exposure to cold. Pharmacol. Ther. 41:85–142. Gautier, H., M. Bonora, S.B. M'Barek, and J.D. Sinclair 1991 Effects of hypoxia and cold acclimation on thermoregulation in the rat. J. Appl. Physiol. 71:1355–1363. Gordon, C.J. 1993 Temperature Regulation in Laboratory Rodents. Cambridge, U.K.: Cambridge University Press. Gordon, C.J., and L. Fogelson 1991 Comparative effects of hypoxia on behavioral thermoregulation in rats, hamsters, and mice. Am. J. Physiol. 260:R120–R125. Grayson, J. 1990 Responses of the microcirculation to hot and cold environments. Pp. 221–234 in Thermoregulation: Physiology and Biochemistry, E. Schönbaum and P. Lomax, eds. New York: Pergamon Press. Guyton, A.C. 1986 Body temperature, temperature regulation, and fever. Pp. 849–860 in Textbook of Medical Physiology, 7th ed. Philadelphia: W.B. Saunders. Hall, C.B., C. Perreault, and H.C. Lukaski 1990 A low copper diet influences thermoregulation of the rat. Proc. N.D. Acad. Sci. 44:109. Himms-Hagen, J. 1981 Nonshivering thermogenesis, brown adipose tissue, and obesity. Pp. 85–99 in Nutritional Factors: Modulating Effects on Metabolic Processes, R.F. Beers and E.G. Bassett, eds. New York: Raven Press. 1986 Brown adipose tissue and cold-acclimation. Pp. 214–268 in Brown Adipose Tissue, P. Trayhurn and D.G. Nicholls, eds. London: Arnold. 1990 Brown adipose tissue thermogenesis: Interdisciplinary studies. Fed. Am. Soc. Exp. Biol. J. 4:2890–2898. Hunt, J.R. C.A. Zito, and J. Erjavec 1994 Severe and marginal iron deficiency affects spontaneous physical activity in rats. Am. J. Clin. Nutr. 59:413–419. Kaplan, M.M. 1986 Regulatory influences on iodothyronine deiodination in animal tissues. Pp. 231–253 in Thyroid Hormone Metabolism, G. Hennemann, ed. New York: Marcel Dekker. Lean, E.J., and P.T. James 1986 Brown adipose tissue in man. Pp. 339–365 in Brown Adipose Tissue, P. Trayhurn and D.G. Nicholls, eds. London: Arnold.

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--> Lukaski H., and S. Smith In Effects of altered vitamin and mineral nutritional status on temperature regulation and Press thermogenesis in the cold. In Handbook of Physiology. Washington, D.C.: American Physiological Society. Lukaski, H.C., C.B. Hall, and F.H. Nielsen 1990 Therrnogenesis and thermoregulatory function of iron-deficient women without anemia. Aviat. Space Environ. Med. 61:913-920. Lukaski H.C., C.B. Hall, and M.J. Marchello 1992 Impaired thyroid hormone status and thermoregulation during cold exposure of zinc- deficient rats. Horm. Metab Res. 24(8):363-366. Martinez-Torres, C., L. Cubeddu, E. Dillmann, G.L. Brengelmann, I. Leets, M. Layrisse, D.G. Johnson, and C. Finch 1984 Effect of low temperature on normal and iron-deficient subjects. Am. J. Physiol. 246:R380-R383. Mayfield, S.R., P.W. Shaul, W. Oh, and B.S. Stonestreet 1987 Anemia blunts the therrnogenic response to environmental cold stress in newborn piglets. Pediatr. Res. 21:482-486. Menkes, J.H., M. Alter, G.K. Steigleder, D.R. Weakley, and J.H. Sung 1962 A sex-linked recessive disorder with retardation of growth, peculiar hair, and focal cerebral and cerebellar degeneration. Pediatrics 29:764-779. Milne, D.B. 1994 Assessment of copper status. LIN Chem. 40(8): 1479-1484. Nedergaard, J., E. Connolly, and B. Cannon 1986 Brown adipose tissue in the mammalian neonate. Pp. 152-213 in Brown Adipose Tissue, P. Trayhurn and D.G. Nicholls, eds. London: Arnold. O'Dell, B.L. 1990 Copper. Pp. 261-267 in Present Knowledge of Nutrition, 6th ea., M.L. Brown, ed. Washington, D.C.: International Life Sciences Institute, Nutrition Foundation. Rothwell, N.J., and M.J. Stock 1983 Diet-induced thermogenesis. Pp. 208-233 in Mammalian Thermogenesis, L. Girardier and M.J. Stock, eds. London: Chapman and Hall. 1986 Brown adipose tissue and diet-induced thermogenesis. Pp. 269-298 in Brown Adipose Tissue, P. Trayhurn and D.G. Nicholls, eds. London: Arnold. 1988 Sandstead, H.H. I 995 Requirements and toxicity of essential trace mineals illustrated by copper and zinc. Am. J. Clin. Nutr. 61:621S-624S. Scammell, J.G., K.T. Shiverick, and M.J. Fregly 1988 In vitro hepatic deiodination of L-thyroxine to 3,5,3'-triiodothyronine in cold-acclimated rats. J. Appl. Physiol. (Respirat. Environ. Exercise Physiol.) 49:386-389. Smith, S.M., S.H. Smith, and J.L. Beard 1992a Metabolic rate and thyroxine monodeiodinase activity in iron-deficient female Sprague- Dawley rats: Effects of the ovarian steroids. J. Nutr. Biochem. 3:461066. Smith, S.M., D.R. Deaver, and J.L. Beard 1992b Heart norepinephrine content in iron-deficiency anemia. J. Nutr. Biochem. 3: 167-171. Stock, M.J., and N.J. Rothwell 1991 Diet-induced thermogenesis: A role for brown adipose tissue. Pp. 101-113 in Nutritional Factors: Modulating Effects on Metabolic Processes, R.F. Beers and E.G. Bassett, eds. New York: Raven Press. Tang, F., T.M. Wong, and T.T. Loh Effects of cold exposure or TRH on the serum TSH levels in the iron-deficient rat. Horm. Metabol. Res. 20:616-619.

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--> Tobin, B.W., and J.L. Beard 1990 Interactions of iron deficiency and exercise training relative to tissue norepinephrine turnover, triiodothyronine production and metabolic rate in rats. J. Nutr. 120:900–908. Topping, D.L., D.G. Clark, and I.E. Dreosti 1980 Impaired thermoregulation in cold exposed zinc deficient rats: Effect of nicotine. Nutr. Rep. Int. 24:643–648. van Hardeveld, C. 1986 Effects of thyroid hormones on oxygen consumption, heat production, and energy economy. Pp. 597–608 in Thyroid Hormone Metabolism, G. Hennemann, ed. New York: Marcel Dekker. Vorhees, L.M., M.J. Stuart, J.A. Stockman, and F.A. Oski 1975 Iron deficiency anemia and increased urinary norepinephrine excretion. Pediatrics 86:542–547. Wada L., and J.C. King 1986 Effect of low zinc on basal metabolic rate, thyroid hormones, and protein utilization. J. Nutr. 116:1045–1053. Wagner, A., N. Fortier, A. Giroux, J. Lukes, and L.M. Snyder 1979 Catecholamines in adult iron deficiency patients. Experientia 35:681–682. Webb, T.E., C.E. Krill, F.A. Oski, and K.C. Tsou 1982 Relationship of iron status to urinary excretion in children 7–12 years of age. J. Pediatr. Gastroenterol. Nutr. 1:207–209. Wood, S.C. 1991 Interactions between hypoxia and hypothermia. Ann. Rev. Physiol. 53:71–85. Youdim, M.B.H., and S. Yehuda 1985 Iron deficiency induces reversal of dopamine dependent circadian cycles: Differential response to d-amphetamine and TRH. Peptides 6:851–855. Youdim, M.B.H., D. Ben-Shachar, and S. Yehuda 1989 Putative biological mechanisms of the effect of iron deficiency on brain biochemistry and behavior. Am. J. Clin. Nutr. 50:607–617.