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Leptin-Induced Leptin Resistance Reveals Separate Roles for the Anorexic and Thermogenic Responses in Weight Maintenance

Geriatric Research (P.J.S., M.M., E.W.S., N.T.), Education and Clinical Center, Department of Veterans Affairs Medical Center, Gainesville, Florida 32608-1197; and Departments of Pharmacology and Therapeutics (P.J.S., M.M., Y.Z., E.W.S., N.T.) and Molecular Genetics (V.P., S.Z.), University of Florida College of Medicine, Gainesville, Florida 32610

Address all correspondence and requests for reprints to: Philip J. Scarpace, Ph.D., Geriatric Research, Education and Clinical Center (182), Department of Veterans Affairs Medical Center, Gainesville, Florida 32608-1197. E-mail: . scarpace{at}ufl.edu

The purpose of this study was to determine whether leptin induces leptin resistance by examining the temporal attenuation of the anorexic and energy expenditure responses to leptin. We administered recombinant adeno-associated virus encoding rat leptin cDNA or control viral vector into mildly obese rats for 138 d and compared these results with those from pair-fed rats. We measured food consumption, body weight, oxygen consumption, leptin signal transduction, and brown adipose tissue uncoupling protein 1. The anorexic response attenuated by d 25, whereas the increase in energy expenditure persisted for 83 d before attenuating. Despite attenuation of physiological responses, phosphorylated signal transducer and activator of transcription-3 remained elevated for the duration of the study. The temporal differential attenuation of the anorexic and thermogenic responses allowed us to determine the relative contributions of each response to weight maintenance. The anorexic response predominantly mediated the initial loss of body weight, but only the energy expenditure response was necessary to maintain the reduced weight. This study provides evidence that leptin induces leptin resistance. The leptin resistance was associated with persistent elevation in hypothalamic phosphorylated signal transducer and activator of transcription-3 and was characterized by a rapid attenuation of the anorexic response and slower onset for the attenuation of the energy expenditure response. We propose that both elevated leptin and obesity may be necessary for the development of leptin resistance.

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