DiabetesFeb 21, 2013

Obesity and high-fat diet reduce response to the diabetes drug exendin-4

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Apr 2, 2026

Abstract

Obese-prone rats exhibit reduced endogenous levels and impaired signaling compared to obese-resistant rats during high-energy/high-fat feeding.

Exogenous administration of the GLP-1R agonist effectively suppressed food intake in both obese-prone and obese-resistant rats when fed chow.
During high-energy/high-fat feeding, obese-prone rats showed significantly less suppression of food intake compared to obese-resistant rats across all tested doses of exendin-4.
Obese-prone rats had downregulated GLP-1 receptor mRNA expression in the vagal nodose ganglia.
Plasma GLP-1 levels were significantly lower in high-energy/high-fat-fed obese-prone rats compared to obese-resistant rats.
Obese-prone rats also displayed decreased protein levels of GLP-1 in the intestinal epithelium and a reduced number of L cells in the distal ileum.

Simplified

Gastrointestinal mechanisms involved in the suppression of appetite are compromised in obesity. Glucagon-like peptide-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, (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.

Key numbers

total:< 0.01; active:< 0.001

Decrease in Plasma Levels

Comparison of plasma levels in HE/HF-fed OP vs. OR rats

0.625 and 1.25 μg/kg

Sensitivity to Ex-4

Ex-4 doses tested in OP and OR rats during HE/HF feeding

< 0.0001

L Cells Count Reduction

Comparison of L cell counts in OP vs. OR rats on HE/HF diet

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Obesity and high-fat diet reduce response to the diabetes drug exendin-4

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