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      Mechanisms controlling hormone secretion in human gut and its relevance to metabolism

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          Abstract

          The homoeostatic regulation of metabolism is highly complex and involves multiple inputs from both the nervous and endocrine systems. The gut is the largest endocrine organ in our body and synthesises and secretes over 20 different hormones from enteroendocrine cells that are dispersed throughout the gut epithelium. These hormones include GLP-1, PYY, GIP, serotonin, and CCK, each of which play pivotal roles in maintaining energy balance and glucose homeostasis. Some are now the basis of several clinically used glucose-lowering and weight loss therapies. The environment in which these enteroendocrine cells exist is also complex, as they are exposed to numerous physiological inputs including ingested nutrients, circulating factors and metabolites produced from neighbouring gut microbiome. In this review, we examine the diverse means by which gut-derived hormones carry out their metabolic functions through their interactions with different metabolically important organs including the liver, pancreas, adipose tissue and brain. Furthermore, we discuss how nutrients and microbial metabolites affect gut hormone secretion and the mechanisms underlying these interactions.

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          Most cited references129

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          Anatomy and regulation of the central melanocortin system.

          Roger Cone (2005)
          The central melanocortin system is perhaps the best-characterized neuronal pathway involved in the regulation of energy homeostasis. This collection of circuits is unique in having the capability of sensing signals from a staggering array of hormones, nutrients and afferent neural inputs. It is likely to be involved in integrating long-term adipostatic signals from leptin and insulin, primarily received by the hypothalamus, with acute signals regulating hunger and satiety, primarily received by the brainstem. The system is also unique from a regulatory point of view in that it is composed of fibers expressing both agonists and antagonists of melanocortin receptors. Given that the central melanocortin system is an active target for development of drugs for the treatment of obesity, diabetes and cachexia, it is important to understand the system in its full complexity, including the likelihood that the system also regulates the cardiovascular and reproductive systems.
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            Gut-expressed gustducin and taste receptors regulate secretion of glucagon-like peptide-1.

            Glucagon-like peptide-1 (GLP-1), released from gut endocrine L cells in response to glucose, regulates appetite, insulin secretion, and gut motility. How glucose given orally, but not systemically, induces GLP-1 secretion is unknown. We show that human duodenal L cells express sweet taste receptors, the taste G protein gustducin, and several other taste transduction elements. Mouse intestinal L cells also express alpha-gustducin. Ingestion of glucose by alpha-gustducin null mice revealed deficiencies in secretion of GLP-1 and the regulation of plasma insulin and glucose. Isolated small bowel and intestinal villi from alpha-gustducin null mice showed markedly defective GLP-1 secretion in response to glucose. The human L cell line NCI-H716 expresses alpha-gustducin, taste receptors, and several other taste signaling elements. GLP-1 release from NCI-H716 cells was promoted by sugars and the noncaloric sweetener sucralose, and blocked by the sweet receptor antagonist lactisole or siRNA for alpha-gustducin. We conclude that L cells of the gut "taste" glucose through the same mechanisms used by taste cells of the tongue. Modulating GLP-1 secretion in gut "taste cells" may provide an important treatment for obesity, diabetes and abnormal gut motility.
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              Glucose Sensing in L Cells: A Primary Cell Study

              Summary Glucagon-like peptide-1 (GLP-1) is an enteric hormone that stimulates insulin secretion and improves glycaemia in type 2 diabetes. Although GLP-1-based treatments are clinically available, alternative strategies to increase endogenous GLP-1 release from L cells are hampered by our limited physiological understanding of this cell type. By generating transgenic mice with L cell-specific expression of a fluorescent protein, we studied the characteristics of primary L cells by electrophysiology, fluorescence calcium imaging, and expression analysis and show that single L cells are electrically excitable and glucose responsive. Sensitivity to tolbutamide and low-millimolar concentrations of glucose and α-methylglucopyranoside, assessed in single L cells and by hormone secretion from primary cultures, suggested that GLP-1 release is regulated by the activity of sodium glucose cotransporter 1 and ATP-sensitive K+ channels, consistent with their high expression levels in purified L cells by quantitative RT-PCR. These and other pathways identified using this approach will provide exciting opportunities for future physiological and therapeutic exploration.

                Author and article information

                Journal
                J Endocrinol
                J. Endocrinol
                JOE
                The Journal of Endocrinology
                Bioscientifica Ltd (Bristol )
                0022-0795
                1479-6805
                January 2020
                18 November 2019
                : 244
                : 1
                : R1-R15
                Affiliations
                [1 ]College of Medicine and Public Health , Flinders University, Adelaide, South Australia, Australia
                [2 ]Nutrition and Metabolism , South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
                Author notes
                Correspondence should be addressed to D J Keating: Damien.keating@ 123456flinders.edu.au

                *(A M Martin and E W Sun contributed equally to this work)

                Article
                JOE-19-0399
                10.1530/JOE-19-0399
                6892457
                31751295
                38a87959-b003-4dd2-832a-651b7cc21f4f
                © 2019 The authors

                This work is licensed under a Creative Commons Attribution 4.0 International License.

                History
                : 29 October 2019
                : 18 November 2019
                Categories
                Review

                Endocrinology & Diabetes
                glp-1,pyy,serotonin,cck,gip,obesity,diabetes,microbiome,liver,pancreas,adipose tissue
                Endocrinology & Diabetes
                glp-1, pyy, serotonin, cck, gip, obesity, diabetes, microbiome, liver, pancreas, adipose tissue

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