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Review
. 2022 Sep 28:13:956277.
doi: 10.3389/fendo.2022.956277. eCollection 2022.

Free fatty acid receptors in the endocrine regulation of glucose metabolism: Insight from gastrointestinal-pancreatic-adipose interactions

Yu-Feng Zhao  1
Affiliations
Review

Free fatty acid receptors in the endocrine regulation of glucose metabolism: Insight from gastrointestinal-pancreatic-adipose interactions

Yu-Feng Zhao. Front Endocrinol (Lausanne). .

Abstract

Glucose metabolism is primarily controlled by pancreatic hormones, with the coordinated assistance of the hormones from gastrointestine and adipose tissue. Studies have unfolded a sophisticated hormonal gastrointestinal-pancreatic-adipose interaction network, which essentially maintains glucose homeostasis in response to the changes in substrates and nutrients. Free fatty acids (FFAs) are the important substrates that are involved in glucose metabolism. FFAs are able to activate the G-protein coupled membrane receptors including GPR40, GPR120, GPR41 and GPR43, which are specifically expressed in pancreatic islet cells, enteroendocrine cells as well as adipocytes. The activation of FFA receptors regulates the secretion of hormones from pancreas, gastrointestine and adipose tissue to influence glucose metabolism. This review presents the effects of the FFA receptors on glucose metabolism via the hormonal gastrointestinal-pancreatic-adipose interactions and the underlying intracellular mechanisms. Furthermore, the development of therapeutic drugs targeting FFA receptors for the treatment of abnormal glucose metabolism such as type 2 diabetes mellitus is summarized.

Keywords: adipose tissue; free fatty acid receptors; gastrointestinal hormones; glucose metabolism; pancreatic islet cells.

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Conflict of interest statement

The authors declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The gastrointestinal-pancreatic-adipose (G-P-A) interactions and hormonal regulation of glucose metabolism. When the blood glucose levels elevate after ingestion, insulin and certain GI hormones increase and act on the main target organs that include liver, skeletal muscle and central nervous system to lower blood glucose. Adipokines regulate glucose metabolism by altering appetite, insulin secretion, insulin sensitivity and glucose utilization, which may be a long-term mechanism for glucose metabolism.
Figure 2
Figure 2
GPR40 regulates glucose metabolism via the G-P-A regulatory system. The activation of GPR40 by FFAs after fat ingestion potentiates the secretion of insulin, GLP-1, CCK and GIP, which contributes to the restrain of blood glucose elevation by acting on CNS, liver and skeletal muscle. Although GPR40 is not expressed in adipocytes, GPR40-potentiated insulin and GI hormones act on adipocytes to improve glucose uptake and utilization as well as adipokine secretion.
Figure 3
Figure 3
GPR120 regulates glucose metabolism via the G-P-A regulatory system. GPR120 activation after fat ingestion potentiates the secretion of GLP-1, CCK and GIP with the inhibition of ghrelin. Meanwhile, GPR120 activation increases adiponectin secretion. The GI hormones and adiponectin may act on CNS, liver and skeletal muscles to inhibit appetite, increase autonomous nerve activity, stimulate glycogen synthesis, and promote glucose utilization. GPR120 regulates the secretion of SS and PP in islets, which may influence the secretion of insulin in a paracrine manner. In addition, GPR120 regulates the function of adipocytes directly and indirectly via modulating the cytokine release from macrophages.
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