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

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 and David J. Lloyd ()
Additional contact information
Elizabeth A. Killion: Amgen Research, Department of Cardiometabolic Disorders, Amgen Inc., One Amgen Center Dr
Michelle Chen: Amgen Research, Department of Cardiometabolic Disorders, Amgen Inc., One Amgen Center Dr
James R. Falsey: Amgen Research, Department of Selection and Modality Engineering, Amgen Inc., One Amgen Center Dr
Glenn Sivits: Amgen Research, Department of Cardiometabolic Disorders, Amgen Inc., One Amgen Center Dr
Todd Hager: Amgen Research, Department of Translational Safety & Bioanalytical Sciences, Amgen Inc., One Amgen Center Dr
Larissa Atangan: Amgen Research, Department of Cardiometabolic Disorders, Amgen Inc., One Amgen Center Dr
Joan Helmering: Amgen Research, Department of Cardiometabolic Disorders, Amgen Inc., One Amgen Center Dr
Jae Lee: Amgen Research, Department of Cardiometabolic Disorders, Amgen Inc., One Amgen Center Dr
Hongyan Li: Amgen Research, Department of Translational Safety & Bioanalytical Sciences, Amgen Inc., One Amgen Center Dr
Bin Wu: Amgen Research, Department of Selection and Modality Engineering, Amgen Inc., One Amgen Center Dr
Yuan Cheng: Amgen Research, Department of Selection and Modality Engineering, Amgen Inc., One Amgen Center Dr
Murielle M. Véniant: Amgen Research, Department of Cardiometabolic Disorders, Amgen Inc., One Amgen Center Dr
David J. Lloyd: Amgen Research, Department of Cardiometabolic Disorders, Amgen Inc., One Amgen Center Dr

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18751-8

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