Chronic glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism desensitizes adipocyte GIPR activity mimicking functional GIPR antagonism
Autor: | Todd Hager, Jae Lee, Hongyan Li, David Lloyd, James R. Falsey, Elizabeth A. Killion, Bin Wu, Larissa Atangan, Yuan Cheng, Michelle Chen, Murielle M. Véniant, Joan Helmering, Glenn Sivits |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
medicine.medical_specialty Science General Physics and Astronomy Adipose tissue 030209 endocrinology & metabolism Gastric Inhibitory Polypeptide Diet High-Fat General Biochemistry Genetics and Molecular Biology Antibodies Article Receptors Gastrointestinal Hormone 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine In vivo Adipocyte Internal medicine medicine Adipocytes Cyclic AMP Animals Humans Obesity Receptor lcsh:Science Cells Cultured Mice Knockout Pharmacology Multidisciplinary Chemistry Body Weight Cell Membrane Fatty Acids Antagonist General Chemistry In vitro Mice Inbred C57BL 030104 developmental biology Endocrinology Adipose Tissue Glucose-dependent insulinotropic polypeptide lcsh:Q Anti-Obesity Agents Antagonism |
Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-17 (2020) Nature Communications |
ISSN: | 2041-1723 |
Popis: | 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. Both agonism and antagonism of the glucose-dependent insulinotropic polypeptide receptor (GIPR) lead to weight loss in combination with glucagon-like peptide-1 receptor agonists in preclinical models. Here the authors show that this may be explained by desensitization of GIPR activity by chronic GIPR agonism in vitro and in vivo. |
Databáze: | OpenAIRE |
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