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Leptin Regulation of the Anorexic Response to Glucagon-Like Peptide-1 Receptor Stimulation

¹ Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington, Seattle, Washington
² VA Puget Sound Health Care System, Seattle, Washington
³ Department of Biological Structure, University of Washington, Seattle, Washington

Address correspondence and reprint requests to Diana L. Williams, University of Washington, Harborview Medical Center, 325 9th Ave., Box 359675, Seattle, WA 98104. E-mail: dianalw{at}u.washington.edu

Abbreviations: CCK, cholecystokinin; CNS, central nervous system; c-FLI, c-Fos–like immunoreactivity; Ex4, Exendin-4; GLP-1, glucagon-like peptide 1; GLP-1-R, GLP-1 receptor; NTS, nucleus of the solitary tract

Leptin reduces food intake in part by enhancing satiety responses to gastrointestinal signals produced in response to food consumption. Glucagon-like peptide 1 (GLP-1), secreted by the intestine when nutrients enter the gut, is one such putative satiety signal. To investigate whether leptin enhances the anorexic effects of GLP-1, rats received either saline or a subthreshold dose of leptin before intraperitoneal injection of either GLP-1 or Exendin-4 (Ex4; a GLP-1 receptor agonist). Leptin pretreatment strongly enhanced anorexia and weight loss induced by GLP-1 or Ex4 over 24 h. Conversely, fasting attenuated the anorexic response to GLP-1 or Ex4 treatment via a leptin-dependent mechanism, as demonstrated by our finding that the effect of fasting was reversed by physiological leptin replacement. As expected, Ex4 induced expression of c-Fos protein, a marker of neuronal activation, in hindbrain areas that process afferent input from satiety signals, including the nucleus of the solitary tract and area postrema. Unexpectedly, leptin pretreatment blocked this response. These findings identify physiological variation of plasma leptin levels as a potent regulator of GLP-1 receptor-mediated food intake suppression and suggest that the underlying mechanism is distinct from that which mediates interactions between leptin and other satiety signals.

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