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Review
. 2025 Dec;603(24):7645-7659.
doi: 10.1113/JP286293. Epub 2024 Nov 22.

Incretin hormones and obesity

Constanza Alcaino  1 , Frank Reimann  1 , Fiona M Gribble  1
Affiliations
Review

Incretin hormones and obesity

Constanza Alcaino et al. J Physiol. 2025 Dec.

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.

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Conflict of interest statement

FMG and FR have received grant funding for separate projects from AstraZeneca and Eli Lilly. They received sponsorship for hosting the European Incretin Study Group meeting in Cambridge 2024 from Eli Lilly, AstraZeneca, Sun Pharma and Mercodia.

Figures

Figure 1
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 SGLT1, 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 Gαq type (FFAR1, FFAR2, FFAR4 for long‐ and short‐chain fatty acids and CASR and GPR142 for aromatic amino acids). Gαq 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 Gαi‐coupled (FFAR2, FFAR3 and FFAR4), which inhibit adenyl‐cyclase (AC) and cAMP production. By contrast, some medium‐chain fatty acid (OR51E1/E2), bile acid (GPBAR1) and monoacylglycerol (GPR119) receptors increase cAMP via Gαs‐coupling and induce hormone release. Abbreviations: SGLT1, sodium‐coupled glucose cotransporter 1; VGCCs, voltage‐gated calcium channels; ER, endoplasmic reticulum; cAMP, cyclic adenosine monophosphate; AC, adenylyl cyclase; GPCRs, G‐protein coupled receptors; FFAR1–4, free fatty acid receptor 1–4; CASR, calcium sensing receptor; IP3, inositol phosphate 3; OR51E1/E2, olfactory receptor 51E1 and E2; GPBAR1, G‐protein coupled bile acid receptor 1.
Figure 2
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.
See this image and copyright information in PMC

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