High-fat diet changes the temporal profile of GLP-1 receptor-mediated hypophagia in rats

Am J Physiol Regul Integr Comp Physiol. 2013 Jul 1;305(1):R68-77. doi: 10.1152/ajpregu.00588.2012. Epub 2013 Apr 24.


Overconsumption of a high-fat diet promotes weight gain that can result in obesity and associated comorbidities, including Type 2 diabetes mellitus. Consumption of a high-fat diet also alters gut-brain communication. Glucagon-like peptide 1 (GLP-1) is an important gastrointestinal signal that modulates both short- and long-term energy balance and is integral in maintenance of glucose homeostasis. In the current study, we investigated whether high-fat diets (40% or 81% kcal from fat) modulated the ability of the GLP-1 receptor (GLP-1r) agonists exendin-4 (Ex4) and liraglutide to reduce food intake and body weight. We observed that rats maintained on high-fat diets had a delayed acute anorexic response to peripheral administration of Ex4 or liraglutide compared with low-fat diet-fed rats (17% kcal from fat). However, once suppression of food intake in response to Ex4 or liraglutide started, the effect persisted for a longer time in the high-fat diet-fed rats compared with low-fat diet-fed rats. In contrast, centrally administered Ex4 suppressed food intake similarly between high-fat diet-fed and low-fat diet-fed rats. Chronic consumption of a high-fat diet did not change the pharmacokinetics of Ex4 but increased intestinal Glp1r expression and decreased hindbrain Glp1r expression. Taken together, these findings demonstrate that dietary composition alters the temporal profile of the anorectic response to exogenous GLP-1r agonists.

Keywords: exendin-4; food intake; glucagon-like peptide 1; liraglutide; obesity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Weight / drug effects
  • Body Weight / physiology*
  • Diet, Fat-Restricted
  • Diet, High-Fat*
  • Eating / drug effects
  • Eating / physiology*
  • Energy Metabolism / drug effects
  • Energy Metabolism / physiology
  • Exenatide
  • Glucagon-Like Peptide 1 / adverse effects
  • Glucagon-Like Peptide 1 / analogs & derivatives
  • Glucagon-Like Peptide 1 / pharmacology
  • Glucagon-Like Peptide-1 Receptor
  • Glucose / metabolism
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / pharmacology
  • Liraglutide
  • Male
  • Malnutrition / chemically induced
  • Malnutrition / physiopathology*
  • Models, Animal
  • Peptides / adverse effects
  • Peptides / pharmacology
  • Rats
  • Rats, Long-Evans
  • Receptors, Glucagon / agonists*
  • Receptors, Glucagon / physiology*
  • Venoms / adverse effects
  • Venoms / pharmacology


  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Peptides
  • Receptors, Glucagon
  • Venoms
  • Liraglutide
  • Glucagon-Like Peptide 1
  • Exenatide
  • Glucose