Chronic high fat diet impairs glucagon like peptide-1 sensitivity in vagal afferents

Sep 18, 2020Biochemical and biophysical research communications

Long-term high-fat diet reduces gut hormone sensitivity in nerve signals to the brain

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Abstract

Chronic high fat diet impaired vagal afferent responses to GLP-1, resulting in reduced satiety signaling.

High fat fed mice showed lower activation of intestinal afferent nerves in response to GLP-1 compared to low fat fed mice.
GLP-1 increased excitability in vagal afferent nerves of low fat fed mice, but this effect was diminished in high fat fed neurons.
Systemic GLP-1 receptor stimulation had a reduced satiating effect in high fat fed mice relative to low fat fed mice.
Neuronal activation in the nucleus tractus solitarius was also reduced in high fat fed mice following GLP-1 treatment.
Impaired GLP-1 sensitivity may contribute to diminished satiety signaling in obesity.

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Dysfunction of the gut-brain axis is one of the potential contributors to the pathophysiology of obesity and is therefore a potential target for treatment. Vagal afferents innervating the gut play an important role in controlling energy homeostasis. There is an increasing evidence for the role of vagal afferents in mediating the anorexigenic effects of glucagon-like peptide-1 (GLP-1), an important satiety and incretin hormone. This study aimed to examine the effect of chronic high fat diet on GLP-1 sensitivity in vagal afferents. C57/BL6 mice were fed either a high-fat or low-fat diet for 6-8 weeks. To evaluate gastrointestinal afferent sensitivity and nodose neurons' response to GLP-1, extracellular afferent recordings and patch clamp were performed, respectively. Exendin-4 (Ex-4) was used as an agonist of the GLP-1 receptor. C-Fos Expression was examined as an indication of afferent input to the nucleus tractus solitarius (NTS). Food intake was monitored in real-time before and after Ex-4 treatment to monitor the consequence of the high fat diet on the satiating effect of GLP-1. In high fat fed (HFF) mice, GLP-1 caused lower activation of intestinal afferent nerves, and failed to potentiate mechanosensitive nerve responses compared to low fat fed (LFF). GLP-1 increased excitability in LFF and this effect was reduced in HFF neurons. Consistent with these findings on vagal afferent nerves, GLP-1 receptor stimulation given systemically, had a reduced satiating effect in HFF compared to LFF mice, and neuronal activation in the NTS was also reduced. The present study demonstrated chronic high fat diet impaired vagal afferent responses to GLP-1, resulting in impaired satiety signaling. GLP-1 sensitivity may account for the impairment of satiety signaling in obesity and thus a therapeutic target for obesity treatment.

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Chronic high fat diet impairs glucagon like peptide-1 sensitivity in vagal afferents

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