What does this research mean for the field?

Peripheral GIPR-expressing Pdgfrβ+ pericytes in adipose tissue regulate lipid storage and adipose-liver metabolic crosstalk, and their disruption causes metabolic dysfunction independent of central GIPR actions. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This research aims to determine the role of GIPR in energy metabolism and lipid regulation within adipose tissue and its implications for obesity and fatty liver disease.

June 7, 2026

2531-P: Peripheral Glucose-Dependent Insulinotropic Peptide Receptor (GIPR) at the Intersection of Obesity and Fatty Liver Disease

Key Points

This research aims to determine the role of GIPR in energy metabolism and lipid regulation within adipose tissue and its implications for obesity and fatty liver disease.
Generated a pericyte-specific GIPR knockout mouse model by crossing Pdgfrβ-Cre-ERT2 mice with Gipr flx/flx animals.
Compared body weight, fat mass, and metabolic parameters between Gipr peri+/+ (control) and Gipr peri-/- (KO) mice after 26 weeks on a high-fat diet.
Analyzed transcriptional changes in adipose tissue and liver associated with GIPR disruption.
KOs exhibited greater body weight and fat mass, smaller visceral fat, and increased liver mass than controls.
KO mice had impaired glucose and lipid tolerance as well as reduced insulin sensitivity, with increased whole-body fatty acid oxidation.
Visceral AT and liver in KO mice showed upregulated inflammatory pathways and downregulated fatty acid metabolism genes, indicating metabolic dysregulation.

Abstract

Introduction and Objective: Central glucose-dependent insulinotropic peptide receptor (GIPR) signaling is associated with reduced body weight, food intake, and improved glucose and lipid control; however, the peripheral mechanisms underlying GIPR-based therapies for obesity and type 2 diabetes remain unclear. This uncertainty partly reflects debate over extra-central GIPR localization and function. We show that GIPR in brown adipose tissue facilitates postprandial lipid uptake and whole-body lipid oxidation in obese male mice. As adipose tissue (AT) plays a central role in glucose and lipid homeostasis and contains pericytes (Pdgfrβ+ cells) with adipogenic potential, we investigated whether GIPR+ and Pdgfrβ+expressing AT cells impact energy metabolism, a tissue lacking GIPR. Methods: We generated a pericyte-specific GIPR knockout mouse by crossing Pdgfrβ-Cre-ERT2 mice with Gipr flx/flx animals, yielding Gipr peri+/+ (control) and Gipr peri-/- (KO) mice. Results: Following 26 weeks of high-fat diet feeding (60% kcal fat), KOs displayed greater body weight and fat mass, smaller visceral fat, and fatter liver masses relative to controls. KO mice also exhibited impaired glucose and lipid tolerance, reduced insulin sensitivity, and increased whole-body fatty acid oxidation. Visceral AT from KO mice showed elevated aerobic capacity and lipoprotein lipase activity, with transcriptional upregulation of immune and inflammatory pathways and downregulation in fatty acid metabolism genes and adipogenesis. In parallel, livers from KO mice had upregulated inflammatory and lipid accumulation pathways, alongside reduced mitochondrial density and detoxification capacity. Conclusion: We identify GIPR-expressing Pdgfrβ+ in AT as key regulators of lipid storage and adipose-liver metabolic crosstalk. Disruption of this axis promotes AT lipid spillover and metabolic dysfunction that are independent of GIPR central actions. Disclosure J. Beaudry: None. Funding Canadian Institute for Health Research (186116)

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2531-P: Peripheral Glucose-Dependent Insulinotropic Peptide Receptor (GIPR) at the Intersection of Obesity and Fatty Liver Disease

Key Points

Abstract

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