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

Leptin Regulation of the Anorexic Response to Glucagon-Like Peptide-1 Receptor Stimulation Diana L. Williams 1 , Denis G. Baskin 1 2 3 and Michael W. Schwartz 1 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 Abstract 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. 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 Footnotes M.W.S. is a member on an advisory panel for or a committee of Amylin, Abbott, and Takeda Pharmaceuticals and has received consulting fees from Phenomix, Merck, Cypress Bioscience, Bristol Myers Squibb, and Amgen. The costs of publication of this article were defrayed in part by the payment of page cha