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1 Pharmacology, University of Florida, Gainesville, Florida, United States
2 Pharmacology, University of Florida, Gainesville, Florida, United States; Geriatric Research, Education and Clinical Center, University of Florida, VA Medical Center, Gainesville, Florida, United States
* To whom correspondence should be addressed. E-mail: scarpace{at}ufl.edu.
High-fat feeding induces a transient increase in caloric intake and enhances energy expenditure. We hypothesized that leptin is necessary for the homeostatic restoration of the high-fat enhanced caloric intake and may mediate the increase in BAT UCP1 protein. We employed a leptin antagonist to examine the role of leptin in these biological processes. Simultaneous central administration of leptin and increasing doses of the leptin antagonist revealed a dose-dependent inhibition of leptin-induced hypothalamic STAT3 phosphorylation, and a 7-day infusion of the leptin antagonist produced the predicted increase in food intake and weight gain. When delivered with exogenous leptin in a 7-day infusion, the leptin antagonist blocked leptin-mediated anorexic effects as well as the increase in BAT UCP1 protein and STAT3 phosphorylation. Rats were then provided with a high-fat (HF) diet (60% kcal as fat) or chow and simultaneously infused with antagonist (25µg/d, lateral ventricle) for 7 days and compared to vehicle infused chow-fed rats. Daily caloric intake of both HF groups peaked on day 2. HF feeding elevated caloric intake that nearly normalized by day 7, whereas in the presence of the antagonist, caloric intake remained elevated. Moreover, the HF-mediated augmentation in UCP1 in brown adipose tissue was prevented by the antagonist. These results demonstrate that leptin is essential for the homeostatic restoration of caloric intake following high-fat feeding; and this leptin antagonist is able to block central leptin signaling and leptin-mediated UCP1 elevation.
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