Novel role of GLP-1 receptor signaling in energy expenditure during chronic high fat diet feeding in rats

Apr 15, 2018Physiology & behavior

New role of GLP-1 receptor signaling in controlling energy use during long-term high-fat diet in rats

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Abstract

Daily injections of a GLP-1 receptor antagonist reduced body weight gain in rats fed a high fat diet.

Blocking GLP-1 receptor signaling did not change food intake in either chow or high fat diet-fed rats over five weeks.
Increased energy expenditure was observed in high fat diet-fed rats receiving the GLP-1 receptor antagonist.
Chronic treatment with the antagonist led to glucose intolerance in chow-fed rats, but this effect was not seen in high fat diet-fed rats.
The findings indicate that GLP-1 receptor signaling may influence energy expenditure more than eating behavior during high fat diet consumption.

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OBJECTIVE: Glucagon-like peptide-1 (GLP-1) secreted from intestinal L-cells plays a major role in meal termination and glucose-dependent insulin secretion. Several lines of evidence indicate, however, that the acute satiating and incretin effects of GLP-1 are attenuated with high fat diet (HFD) exposure. Here we tested the hypothesis that endogenous GLP-1 differentially affects energy balance and glucose homeostasis dependent on whether rats are fed chow or HFD (60% energy from fat).

METHODS: We blocked GLP-1 receptor (GLP-1R) signaling by daily intraperitoneal (IP) injection of the GLP-1R antagonist exendin (9-39) (Ex9, 10 μg/kg) or vehicle for 5 weeks in male Sprague-Dawley rats fed either chow or HFD, recorded body weight (BW) and food intake throughout, and assessed energy expenditure (3rd week) and glucose tolerance (4th week).

RESULTS: Five week daily Ex9 injections reduced BW gain in HFD-fed rats, but did not affect BW in chow-fed rats. On the other hand, chronic Ex9 treatment did not affect daily food intake in either chow or HFD-fed rats during the entire study. The reduced BW gain in HFD-fed rats was associated with an increase in energy expenditure. Interestingly, chronic Ex9 treatment induced glucose intolerance in chow-fed rats, but not in HFD-fed rats, suggesting a differential role of GLP-1R signaling in glucose metabolism during chow and HFD feeding.

CONCLUSIONS: Our findings reveal a novel role of GLP-1R signaling, modulating energy expenditure rather than eating behavior during HFD feeding. Furthermore, these results suggest a previously unrecognized contribution of GLP-1R signaling to the pathophysiology of obesity.

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Novel role of GLP-1 receptor signaling in energy expenditure during chronic high fat diet feeding in rats

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