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.

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