Maintenance on a high-fat diet impairs the anorexic response to glucagon-like-peptide-1 receptor activation

Apr 26, 2011Physiology & behavior

A high-fat diet reduces the appetite-suppressing response to glucagon-like peptide-1

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Abstract

Rats maintained on a high-fat diet showed no response to 100 μg/kg GLP-1 injections, unlike those on a low-fat diet.

High-fat diet maintenance is associated with impaired sensitivity to GLP-1, a signal that reduces food intake.
Rats on a low-fat diet reduced food intake in response to GLP-1, while those on a high-fat diet did not.
Even brief exposure to a high-fat diet can diminish the response to GLP-1 receptor activation.
Both diet groups exhibited anorexic responses to exendin-4, but only low-fat diet rats showed reduced intake and body weight after 24 hours.
In low-fat maintained rats, blocking GLP-1 receptors increased food intake, whereas high-fat maintained rats reduced intake in response to the same blocker.

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Previous data suggests that the adiposity signal leptin reduces food intake in part by enhancing sensitivity to short-term signals that promote meal termination, including glucagon-like peptide 1 (GLP-1). We hypothesized that maintenance on a high-fat (HF) diet, which causes resistance to leptin, would impair GLP-1's ability to reduce food intake. To test this hypothesis, we examined the anorexic responses to intraperitoneal injection of 100 μg/kg GLP-1 and 1 μg/kg exendin-4 (Ex-4), the potent, degradation resistant GLP-1 receptor agonist, in Wistar rats maintained on a low-fat (10%; LF) or HF (60%) diet for 4-6 weeks. Rats maintained on each of these diets were tested twice, once while consuming LF food and once while consuming HF food, to distinguish between effects of acute vs. chronic consumption of HF food. LF-maintained rats tested on LF diet reduced 60-min dark phase intake in response to GLP-1, but HF-maintained rats failed to respond to GLP-1 whether they were tested on HF or LF diet. LF-maintained rats tested on HF diet also showed no response, suggesting that even brief exposure to HF diet can impair sensitivity to GLP-1 receptor activation. Both LF- and HF-maintained rats showed significant anorexic responses to Ex4 at 4h post-treatment, but only LF-maintained rats had significantly reduced intake and body weight 24h after injections. To determine whether the ability of endogenous GLP-1 to promote satiation is impaired by HF maintenance, we examined the response to exendin 3 (9-39) (Ex9), a GLP-1 receptor antagonist. In LF-maintained rats, Ex9 increased intake significantly, but HF-maintained rats reduced food intake in response to Ex9. These data support the suggestion that maintenance on HF diet reduces the anorexic effects of GLP-1 receptor activation, and this phenomenon may contribute to overconsumption of high-fat foods.

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Maintenance on a high-fat diet impairs the anorexic response to glucagon-like-peptide-1 receptor activation

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