The role of GIP receptor in the CNS for the pathogenesis of obesity

Authors: FUKUDA, MAKOTO - Children'S Nutrition Research Center (CNRC)

Submitted to: Diabetes
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/1/2021
Publication Date: 6/27/2021
Citation: Fukuda, M. 2021. The role of GIP receptor in the CNS for the pathogenesis of obesity. Diabetes. https://doi.org/10.2337/dbi21-0001.
DOI: https://doi.org/10.2337/dbi21-0001

Interpretive Summary: Gastric inhibitory polypeptide (GIP) is a hormone produced in the gut and secreted after meals, especially with fatty foods. Recent studies suggest that inhibition of GIP or its receptor leads to weight loss. Further, a larger than usual dose of long-acting GIP agonists has a marked anti-obesity effect, but the exact mechanism of this effect remains largely unknown. The brain is capable of regulating both energy intake and expenditure and plays a critical role in human obesity. Most importantly, the GIP receptor is widely present throughout the brain, including areas responsible for energy homeostasis. This article reviewed and discussed the potential role of GIP in the brain in mediating its anti-obesity action. The role of the central nervous system (CNS) in energy balance was outlined, and discoveries delineating the role of GIP in the CNS were reviewed. This article proposes that the remarkable yet paradoxical anti-obesity effect of GIP may occur primarily via the brain. The proposed mechanism may lead to a novel therapy for obesity.

Technical Abstract: Glucose-dependent insulinotropic polypeptide (GIP, also known as gastric inhibitory polypeptide) is a hormone produced in the upper gut and secreted to the circulation in response to the ingestion of foods, especially fatty foods. Growing evidence supports the physiological and pharmacological relevance of GIP in obesity. In an obesity setting, inhibition of endogenous GIP or its receptor leads to decreased energy intake, increased energy expenditure, or both, eventually causing weight loss. Further, supraphysiological dosing of exogenous long-lasting GIP agonists alters energy balance and has a marked anti-obesity effect. This remarkable yet paradoxical anti-obesity effect is suggested to occur primarily via the brain. The brain is capable of regulating both energy intake and expenditure and plays a critical role in human obesity. Most importantly, the GIP receptor is widely distributed throughout the brain, including areas responsible for energy homeostasis. Recent studies have uncovered previously underappreciated roles of the GIP receptor in the brain in the context of obesity. This article highlights how the GIP receptor expressed by the brain impacts obesity-related pathogenesis.