Obesity is the most prevalent nutritional disorder in Western societies. More than three in ten adult Americans weigh at least 20 percent in excess of their ideal body weight. Increased body weight is an important public health problem because it is associated with type II diabetes, hypertension and hyperlipidemia. Moreover, adults tend to gain weight as they get older. Our data suggests that the F-344/BN rat is a reasonable obesity model for human aging. These rats demonstrate a steady increase in body fat into early senescence similar to what occurs in humans. Leptin, the product of the ob gene, is an afferent signal molecule, synthesized by white adipose tissue, that interacts with the appetite and satiety centers in the brain to help regulate body weight. Obesity in humans, including late-onset obesity is usually associated with increased levels of circulating leptin, suggesting that this obesity is not caused by inadequate levels of leptin and that these obese humans are leptin resistant. Our data suggest that aged rats like obese humans are leptin resistant. This proposal will examine the cellular and molecular mechanisms of leptin resistance in the F- 344/BN rat model and the potential of reversing the leptin resistance by lowering serum leptin. Specifically, this grant seeks to address four questions: 1) Is there impaired responsiveness to centrally administered leptin in aged rats? 2) Is leptin receptor density and/or leptin receptor signal transduction impaired in the hypothalamus of aged rats? 3) Is the regulation of leptin gene expression impaired with age? 4) Can reduced feeding or dietary vitamin A supplementation decrease serum leptin and partially reverse the leptin resistance in aged rats? Leptin gene expression, feeding behavior and adiposity are interrelated through positive and negative feedback loops. If these feedback loops are maintained with age, then plasma leptin levels, the gene expression of leptin, and adiposity levels should remain constant. We predict that adiposity increases with age, in part, because the responsiveness to leptin declines with age. Our data indicate that leptin decreases food intake, increases oxygen consumption, and decreases NPY gene expression in the hypothalamus, whereas in older rats, these responses are blunted or absent. Moreover, the elevated serum leptin levels with obesity and with age may be harmful and may be contributing to the diabetes caused by obesity. Our data indicate that dietary vitamin A supplementation lowers serum leptin in young lean rats. The potential for vitamin A supplementation to reverse the age-related increase in serum leptin and restore leptin responsiveness is addressed in this proposal.
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