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.
Highlights
Antagonism or agonism of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) prevents weight gain and leads to dramatic weight loss in combination with glucagonlike peptide-1 receptor agonists in preclinical models
We previously reported that the muGIPR-Ab dose-dependently inhibited GIP-stimulated cyclic adenosine monophosphate (cAMP) in vitro in the same assay reported here in Fig. 1a with IC50 = 89.6 nM, and in vivo, the maximum effect in the acute PD assay was achieved with muGIPR-Ab (25 mg/kg), which correlated with a mean serum concentration of 2250 nM, and allowed us to determine that muGIPR-Ab dosed 25 mg/kg every six days was sufficient to provide maximal target coverage[2]
Since 37.5 mg/kg of the LAAgonist is a suprapharmacological dose, we confirmed that both DA-GIP and the peptide portion of the LA-Agonist both at 250 nmol/kg robustly stimulated insulin secretion in diet-induced obese (DIO) mice, which was absent in DIO mice with pancreatic Gipr β-cell knockout (GiprβCell−/−; mice previously described2) (Supplemental Fig. 1d, e), confirming that high concentrations of GIPR agonists in vivo do not activate GLP-1 receptor (GLP-1R) mediated insulin secretion
Summary
Antagonism or agonism of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) prevents weight gain and leads to dramatic weight loss in combination with glucagonlike 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. 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. We establish that GIPR activity in adipocytes is partially responsible for the ability of muGIPR-Ab to prevent weight gain in DIO mice, demonstrating a role of adipocyte GIPR in the regulation of adiposity in vivo
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