Description
MBX-2982 is an agonist of GPR119. It reduces nuclear and total protein levels of sterol regulatory element binding protein 1 (SREBP-1) in HepG2 cells and rat primary hepatocytes under high-glucose and -insulin conditions and increases phosphorylation of the inhibitory form, SREBP-1c. MBX-2982 (10 mg/kg) inhibits hepatic lipid accumulation in wild-type, but not GPR119 knockout, mice fed a high-fat diet. It also increases plasma levels of glucagon-like peptide 1 (GLP-1; ) in mice when administered at a dose of 10 mg/kg prior to, and to a greater extent following, glucose administration. MBX-2982 increases glucokinase activity in an enzyme assay with an EC
50 value of 45.11 μM.
Uses
MBX-2982 is a selective, orally-available G protein-coupled receptor 119 (GPR119) agonist.
in vivo
To examine whether the observations in GLUTag and the primary intestinal cells has physiological relevance, C57BL/6 mice are treated with the GPR119 agonist MBX-2982 at a dose of 10 mg/kg. Note that in order to examine a direct GPR119 effect, no DPP-IV inhibitor is co-administered in this experiment, but a DPP-IV inhibitor is used to preserve active GLP-1 in the blood samples. The plasma GLP-1 levels from the mice dosed with MBX-2982 are increased without a glucose load, indicating that GPR119-mediated GLP-1 secretion is not dependent on glucose[2].
References
[1] Hothersall JD, et al. Sustained wash-resistant receptor activation responses of GPR119 agonists. Eur J Pharmacol. 2015 Sep 5;762:430-42. DOI:
10.1016/j.ejphar.2015.06.031[2] Lan H, et al. Agonists at GPR119 mediate secretion of GLP-1 from mouse enteroendocrine cells through glucose-independent pathways. Br J Pharmacol. 2012 Apr;165(8):2799-807. DOI:
10.1111/j.1476-5381.2011.01754.x[3] Yang JW, et al. GPR119: a promising target for nonalcoholic fatty liver disease. FASEB J. 2016 Jan;30(1):324-35. DOI:
10.1096/fj.15-273771
