Chronic glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism desensitizes adipocyte GIPR activity mimicking functional GIPR antagonism.

Abstract

Antagonism or agonism of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) prevents weight gain and leads to dramatic weight loss in combination with glucagon-like peptide-1 receptor agonists in preclinical models. Based on the genetic evidence supporting GIPR antagonism, we previously developed a mouse anti-murine GIPR antibody (muGIPR-Ab) that protected diet-induced obese (DIO) mice against body weight gain and improved multiple metabolic parameters. This work reconciles the similar preclinical body weight effects of GIPR antagonists and agonists in vivo, and here we show that chronic GIPR agonism desensitizes GIPR activity in primary adipocytes, both differentiated in vitro and adipose tissue in vivo, and functions like a GIPR antagonist. Additionally, GIPR activity in adipocytes is partially responsible for muGIPR-Ab to prevent weight gain in DIO mice, demonstrating a role of adipocyte GIPR in the regulation of adiposity in vivo.

• Authors: Elizabeth A Killion, Michelle Chen, James R Falsey, Glenn Sivits, Todd Hager, Larissa Atangan, Joan Helmering, Jae Lee, Hongyan Li, Bin Wu, Yuan Cheng, Murielle M Véniant, David J Lloyd
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 4981 (10 05 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 33020469 (Publication Type: Journal Article)

Chemical References

• Anti-Obesity Agents
• Antibodies
• Fatty Acids
• Receptors, Gastrointestinal Hormone
• Gastric Inhibitory Polypeptide
• gastric inhibitory polypeptide receptor
• Cyclic AMP

Topics

• Adipocytes (drug effects, metabolism)
• Adipose Tissue (drug effects, metabolism)
• Animals
• Anti-Obesity Agents (chemistry, pharmacology, therapeutic use)
• Antibodies (pharmacology, therapeutic use)
• Body Weight (drug effects)
• Cell Membrane (metabolism)
• Cells, Cultured
• Cyclic AMP (metabolism)
• Diet, High-Fat (adverse effects)
• Fatty Acids (metabolism)
• Gastric Inhibitory Polypeptide (pharmacology)
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Obesity (drug therapy, metabolism, pathology)
• Receptors, Gastrointestinal Hormone (agonists, antagonists & inhibitors, deficiency, metabolism)