Incretin hormones and obesity

Abstract

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) play critical roles in co-ordinating postprandial metabolism, including modulation of insulin secretion and food intake. They are secreted from enteroendocrine cells in the intestinal epithelium following food ingestion, and act at multiple target sites including pancreatic islets and the brain. With the recent development of agonists targeting GLP-1 and GIP receptors for the treatment of type 2 diabetes and obesity, and the ongoing development of new incretin-based drugs with improved efficacy, there is great interest in understanding the physiology and pharmacology of these hormones.

Keywords: GIP; GLP‐1; enteroendocrine; gut hormone; incretin; obesity.

Graphical abstract. The incretin system in obesity.

The incretin hormones GIP (yellow) and GLP-1 (blue) are produced by the proximal and distal small intestinal epithelium, where they are released postprandially into the bloodstream to modulate a myriad of physiological and metabolic functions. GIP is mostly produced by K-cells in the duodenum and jejunum, whereas GLP-1 is produced by L-cells mostly in the ileum and large intestine. These incretin hormones act on the pancreas causing an increase in insulin secretion. GIP increases glucagon production, whereas GLP-1 decreases it. These hormones have been shown to reduce food intake, causing weight loss. Central GLP-1 increases nausea, whereas GIP has been shown to decrease nausea by acting on GIP receptors in the brainstem.

Figure 1. Nutrient sensing by Enteroendocrine cells.

Carbohydrates, amino acids, fats, and bile acids can activate small intestinal EECs either from the apical (top) or basolateral (bottom) sides. Glucose is transported alongside Na+ ions by SGLT-1, which can cause a membrane depolarisation that activates VGCCs, bringing Ca2+ inside the cell and evoking the release of hormones via vesicular exocytosis. Fatty acids and amino acids can activate GPCRs of the G⍰q type (FFAR1, FFAR2, FFAR4 for long- and short-chain fatty acids and CASR and GPR142 for aromatic amino acids). G⍰q coupling induces an increase of IP3, which activates IP3R in the ER also inducing Ca2+ increase and hormone release. Some fatty acid receptors are also G⍰i-coupled (FFAR2, FFAR3 and FFAR4), which inhibit adenyl-cyclase (AC) and cAMP production. In contrast, some medium-chain fatty acid (OR51E1/E2), bile acid (GPBAR1) and monoacylglycerol (GPR119) receptors increase cAMP via G⍰s-coupling and induce hormone release. Abbreviations: sodium-coupled glucose cotransporter 1 (SGLT-1), voltage-gated calcium channels (VGCCs), endoplasmic reticulum (ER), cyclic adenosine monophosphate (cAMP), adenylyl cyclase (AC), G-protein coupled receptors (GPCRs), free fatty acid receptor 1-4 (FFAR1-4), calcium sensing receptor (CASR), inositol phosphate 3 (IP3), endoplasmic reticulum (ER), Olfactory receptor 51E1 and E2 (OR51E1/E2) and the G-protein coupled bile acid receptor 1 (GPBAR1).

Figure 2. Gut brain signalling.

Hormonal and neuronal signals from the gut underlie a variety of sensations related to the control of food ingestion. A number of gut hormonal signals converge at the Area Postrema (AP) and nucleus of the solitary tract (NTS) in the brainstem, where different neuronal populations (represented by different colours) underlie nausea and food intake suppression. GIPR positive neurones in the AP are predominantly GABA-ergic and inhibit other pathways such as GLP-1-induced nausea. Further characterisation of the neurocircuitry in the AP and NTS, as well as nuclei in the hypothalamus (not shown), underlying food intake regulation is an area of intense scientific focus.