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. 2011 Jul 6;103(5):557-64.
doi: 10.1016/j.physbeh.2011.04.005. Epub 2011 Apr 15.

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

Diana L Williams  1 , Nina Hyvarinen, Nicole Lilly, Kristen Kay, Amanda Dossat, Eric Parise, Ann-Marie Torregrossa
Affiliations

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

Diana L Williams et al. Physiol Behav. .

Abstract

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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Figures

Figure 1
Figure 1
Body weight over time for rats in Experiments 1 and 4 (A) and Experiments 2 and 3 (B). Data are means ± SEM, *p < 0.05.
Figure 2
Figure 2
Food intake (kcal) 60 min after ip injection of either saline vehicle (open bars) or 100 μg/kg GLP-1 (black bars). All subjects were tested on standard chow before they were placed on LF or HF diet, and were then tested after 4 weeks on LF or HF diet. Each rat was tested once while consuming LF diet and once while consuming HF diet during the 60-min test period. Data are means ± SEM, *p < 0.05 relative to vehicle.
Figure 3
Figure 3
Food intake (kcal) 4 h (A) and 24 h (B) after ip injection of saline vehicle (open bars) or 1 μg/kg Ex4 (black bars). Panel C shows body weight change (g) over the 24 h following these injections. Rats were tested after 6 weeks on LF or HF diet. The results of 2 tests of Ex4 response are shown: the first test was conducted while rats consumed the diet on which they were maintained, whereas in the second test, they had access to their non-maintenance diet only. Data are means ± SEM, *p < 0.05 relative to vehicle.
Figure 4
Figure 4
Food intake (kcal) 60 min (A), 4 h (B) and 24 h (C) after ip injection of saline vehicle (open bars) or 10 μg/kg amylin (black bars). Body weight change is shown in panel D. HF-maintained rats were tested while consuming LF diet, to rule out an effect of low baseline intakes as the explanation for lack of GLP-1 and Ex4 effects. Data are means ± SEM, *p < 0.05 relative to vehicle.
Figure 5
Figure 5
Plasma levels of biologically active GLP-1 (pM) in rats maintained on LF or HF diet for 4 weeks. Data are means ± SEM, *p < 0.05.
Figure 6
Figure 6
Food intake (kcal) 60 min after ip injection of saline vehicle (open bars) or 100 μg/kg Ex9 (black bars). Rats were tested after 7 weeks on LF or HF diet. Data are means ± SEM, *p < 0.05 relative to vehicle.
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