Contrasting roles for GLP-1R and GIPR in a model of diet-induced obesity.

Sep 11, 2025Journal of molecular endocrinology

How GLP-1R and GIPR Affect Weight and Blood Sugar in Obesity

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Abstract

Obese high-fat-fed GLP-1 receptor knockout mice exhibited altered glucose and insulin tolerance, along with hepatic steatosis.

Global deletion of the GLP-1 receptor is associated with impaired regulation of blood glucose and lipid levels.
GIP receptor knockout mice showed partial resistance to diet-induced obesity compared to wild-type mice.
This resistance in GIPR knockout mice was linked to a slight decrease in food intake.
Wild-type mice treated with a GIPR antagonist also experienced reduced food intake, preventing weight gain on a high-fat diet.
The findings suggest that the GLP-1 receptor plays a critical role in glycemic control, while the GIP receptor may influence body weight management.

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The glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) are important incretin receptors that are therapeutic targets for the treatment of type 2 diabetes and obesity. This study extensively characterised the metabolic phenotype of mice with global deletion of either the GLP-1R or GIPR side by side under identical conditions. Age-matched male wild-type (WT) C57Bl6NTac, GLP-1RKO or GIPRKO mice were placed on a high-fat or chow diet for 12 weeks, and a range of in vivo (weight gain, food intake, glucose tolerance, insulin tolerance, and whole-body energy metabolism) and ex vivo (white adipocyte lipolysis, brown adipose tissue and liver mitochondrial function, adipocyte and islet size, and hepatic steatosis) parameters were measured. While both WT and GLP-1RKO mice gained weight similarly on a HFD, obese high-fat-fed GLP-1RKO mice had altered glucose and insulin tolerance, and exhibited hepatic steatosis, highlighting the physiological importance of the GLP-1R in the regulation of blood glucose and lipid homoeostasis. In contrast, GIPRKO mice were partially resistant to diet-induced obesity compared to the WT mice, which was associated with a small reduction in food intake and intact epididymal and subcutaneous white adipocyte β-adrenoceptor-mediated lipolysis. Similarly, WT mice treated with a GIPR antagonist prevented weight gain due to a reduction in food intake on a HFD. These findings provide further support that the GLP-1R is important for normal glycaemic control, whereas the GIPR may play a role in the regulation of body weight.

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Contrasting roles for GLP-1R and GIPR in a model of diet-induced obesity.

Abstract

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