Combination of Obesity and High-Fat Feeding Diminishes Sensitivity to GLP-1R Agonist Exendin-4
- 1Neurobiology of Ingestive Behavior, Institut National de la Recherche Agronomique (INRA), UMR 1319 Micalis, Jouy-en-Josas, France
- 2AgroParisTech, UMR Micalis, Jouy-en-Josas, France
- 3Université Pierre-et-Marie-Curie, Paris, France
- 4Department of Basic Medical Sciences, Western University of the Health Sciences, College of Osteopathic Medicine, Pomona, California
- 5Department of Health and Human Development, University “Stefan cel Mare” Suceava, Suceava, Romania
- Corresponding author: Mihai Covasa, .
Gastrointestinal mechanisms involved in the suppression of appetite are compromised in obesity. Glucagon-like peptide-1 (GLP-1) is released in response to nutrients, suppresses food intake, and has been shown to play a role in regulation of energy balance. It is not known whether obese-prone (OP) rats exhibit dysfunctional GLP-1 signaling that could contribute to decreased nutrient-induced satiation and hyperphagia. Therefore, we examined the effects of exogenous intraperitoneal administration of the GLP-1R agonist, exendin-4 (Ex-4), on food intake in OP and obese-resistant (OR) rats during chow or high-energy/high-fat (HE/HF) feeding. All doses of Ex-4 effectively suppressed intake in OP and OR rats fed chow; however, during HE/HF-feeding, OP rats suppressed intake significantly less than OR rats at all Ex-4 doses tested. This was associated with downregulation of GLP-1R mRNA expression in the vagal nodose ganglia of OP rats. Furthermore, HE/HF-fed OP rats had significantly lower plasma GLP-1 levels, decreased protein levels of GLP-1 in the intestinal epithelium, and reduced number of L cells in the distal ileum. These results demonstrate that HE/HF-feeding, coupled with OP phenotype, results in reduced endogenous GLP-1 and GLP-1R activation, indicating that impaired GLP-1 signaling during obesity may exacerbate hyperphagia and weight gain.
- Received September 1, 2012.
- Accepted February 9, 2013.
- © 2013 by the American Diabetes Association.
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