Combination of Obesity and High-Fat Feeding Diminishes Sensitivity to GLP-1R Agonist Exendin-4

  1. Mihai Covasa1,2,4,5
  1. 1Neurobiology of Ingestive Behavior, Institut National de la Recherche Agronomique (INRA), UMR 1319 Micalis, Jouy-en-Josas, France
  2. 2AgroParisTech, UMR Micalis, Jouy-en-Josas, France
  3. 3Université Pierre-et-Marie-Curie, Paris, France
  4. 4Department of Basic Medical Sciences, Western University of the Health Sciences, College of Osteopathic Medicine, Pomona, California
  5. 5Department of Health and Human Development, University “Stefan cel Mare” Suceava, Suceava, Romania
  1. Corresponding author: Mihai Covasa, mcovasa{at}jouy.inra.fr.

Abstract

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.

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  1. Diabetes vol. 62 no. 7 2410-2415
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