Role of FFAR3 in ketone body regulated glucagon-like peptide 1 secretion

TL;DR

This study explores how ketone bodies block GLP-1 hormone release through a receptor called FFAR3 in gut cells, which could lead to new diabetes treatments.

Contribution

The study identifies FFAR3 as a key receptor through which ketone bodies inhibit GLP-1 secretion, offering a novel target for diabetes therapies.

Findings

FFAR3 expression in gut cells is significantly influenced by diet, especially high-fat diets.

Ketone bodies inhibit GLP-1 secretion via FFAR3 and the Gαi/o signaling pathway in enteroendocrine cells.

The number of enteroendocrine cells is affected by diet in normal weight individuals but not in obese subjects.

Abstract

Roux-en-Y gastric bypass (RYGB) is an effective treatment for obesity, resulting in long-term weight loss and rapid remission of type 2 diabetes mellitus. Improved glucagon-like peptide 1 (GLP-1) levels is one factor that contributes to the positive effects. Prior to RYGB, GLP-1 response is blunted which can be attributed to intestinal ketogenesis. Intestinal produced ketone bodies inhibit GLP-1 secretion in enteroendocrine cells via an unidentified G-protein coupled receptors (GPCRs). A possible class of GPCRs through which ketone bodies may reach are the free fatty acid receptors (FFARs) located at the basolateral membrane of enteroendocrine cells.

To evaluate FFAR3 expression in enteroendocrine cells of the small intestine under different circumstances, such as diet and bariatric surgery, as well as explore the link between ketone bodies and GLP-1 secretion.

FFAR3 and enteroendocrine cell expression was analyzed using Western blot and immunohistochemistry in biopsies from healthy volunteers, obese patients undergoing RYGB and mice. GLUTag cells were used to study GLP-1 secretion and FFAR3 signaling pathways.

The expression of FFAR3 is markedly influenced by diet, especially high fat diet, which increased FFAR3 protein expression. Lack of substrate such as free fatty acids in the alimentary limb after RYGB, downregulate FFAR3 expression. The number of enteroendocrine cells was affected by diet in the normal weight individuals but not in the subjects with obesity. In GLUTag cells, we show that the ketone bodies exert its blocking effect on GLP-1 secretion via the FFAR3, and the Gαi/o signaling pathway.

Our findings that ketone bodies via FFAR3 inhibits GLP-1 secretion bring important insight into the pathophysiology of T2D. This highlights the role of FFAR3 as a possible target for future anti-diabetic drugs and treatments.

Image 1

•In small intestinal, FFAR3 expression in enteroendocrine cells is markedly influenced by diet, especially high fat diet.•The number of enteroendocrine cells is affected by diet in normal weight individuals but not in the subjects with obesity.•Intestinal produced ketone bodies inhibit GLP-1 secretion in enteroendocrine cells via FFAR3 and Gαi/o signaling pathway.

In small intestinal, FFAR3 expression in enteroendocrine cells is markedly influenced by diet, especially high fat diet.

The number of enteroendocrine cells is affected by diet in normal weight individuals but not in the subjects with obesity.

Intestinal produced ketone bodies inhibit GLP-1 secretion in enteroendocrine cells via FFAR3 and Gαi/o signaling pathway.

Figures