Despite sharing incretin activity with glucagon-like peptide 1 (GLP-1), the development of gastric inhibitory polypeptide (GIP)-based drugs has been hindered by the minor effects of native GIP on appetite and body weight and genetic studies associating loss-of-function with reduced obesity. Yet, pharmacologically optimized GIP-based molecules have demonstrated profound weight lowering benefits of GIPR agonism when combined with GLP-1-based therapies, which has re-energized deeper exploration of the molecular mechanisms and downstream signaling of GIPR. Interestingly, both GIPR agonism and antagonism offer metabolic benefits, leading to differing viewpoints on how to target GIPR therapeutically. Here we summarize the emerging evidence about the tissue-specific mechanisms that positions GIP-based therapies as important targets for the next generation of anti-obesity and metabolic therapies.
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Chronic GIPR agonism results in pancreatic islet GIPR functional desensitisation.
Mol Metab
January 2025
Section of Endocrinology and Investigative Medicine, Imperial College London, United Kingdom. Electronic address:
Objective: There is renewed interest in targeting the glucose-dependent insulinotropic polypeptide receptor (GIPR) for treatment of obesity and type 2 diabetes. G-protein coupled receptor desensitisation is suggested to reduce the long-term efficacy of glucagon-like-peptide 1 receptor (GLP-1R) agonists and may similarly affect the efficacy of GIPR agonists. We explored the extent of pancreatic GIPR functional desensitisation with sustained agonist exposure.
View Article and Find Full Text PDFThe GIP receptor activates futile calcium cycling in white adipose tissue to increase energy expenditure and drive weight loss in mice.
Cell Metab
January 2025
Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:
Obesity is a chronic disease that contributes to the development of insulin resistance, type 2 diabetes (T2D), and cardiovascular risk. Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) and glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) co-agonism provide an improved therapeutic profile in individuals with T2D and obesity when compared with selective GLP-1R agonism. Although the metabolic benefits of GLP-1R agonism are established, whether GIPR activation impacts weight loss through peripheral mechanisms is yet to be fully defined.
View Article and Find Full Text PDFSpecific loss of GIPR signaling in GABAergic neurons enhances GLP-1R agonist-induced body weight loss.
Mol Metab
November 2024
Department of Surgery, University of Michigan, Ann Arbor, MI, USA. Electronic address:
Objectives: Dual incretin agonists are among the most effective pharmaceutical treatments for obesity and type 2 diabetes to date. Such therapeutics can target two receptors, such as the glucagon-like peptide-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor in the case of tirzepatide, to improve glycemia and reduce body weight. Regarding body weight effects, GIPR signaling is thought to involve at least two relevant mechanisms: the enhancement of food intake reduction and the attenuation of aversive effects caused by GLP-1R agonists.
View Article and Find Full Text PDFGLP-1 and GIP agonism has no direct actions in human hepatocytes or hepatic stellate cells.
Cell Mol Life Sci
November 2024
Department of Physiology, CIMUS, University of Santiago de Compostela, 15782, Santiago de Compostela, Spain.
The use of incretin agonists for managing metabolic dysfunction-associated steatohepatitis (MASH) is currently experiencing considerable interest. However, whether these compounds have a direct action on MASH is still under debate. This study aims to investigate whether GLP-1R/GIPR agonists act directly in hepatocytes and hepatic stellate cells (HSCs).
View Article and Find Full Text PDFThe unexpected role of GIP in transforming obesity treatment.
Trends Endocrinol Metab
August 2024
Pharmacology and Systems Physiology, College of Medicine, University of Cincinnati, Cincinnati, OH, USA. Electronic address:
Despite sharing incretin activity with glucagon-like peptide 1 (GLP-1), the development of gastric inhibitory polypeptide (GIP)-based drugs has been hindered by the minor effects of native GIP on appetite and body weight and genetic studies associating loss-of-function with reduced obesity. Yet, pharmacologically optimized GIP-based molecules have demonstrated profound weight lowering benefits of GIPR agonism when combined with GLP-1-based therapies, which has re-energized deeper exploration of the molecular mechanisms and downstream signaling of GIPR. Interestingly, both GIPR agonism and antagonism offer metabolic benefits, leading to differing viewpoints on how to target GIPR therapeutically.
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