MS-275, a class 1 histone deacetylase inhibitor augments glucagon-like peptide-1 receptor agonism to improve glycemic control and reduce obesity in diet-induced obese mice

Elife. 2020 Dec 22:9:e52212. doi: 10.7554/eLife.52212.

Abstract

Given its glycemic efficacy and ability to reduce the body weight, glucagon-like peptide 1 receptor (GLP-1R) agonism has emerged as a preferred treatment for diabetes associated with obesity. We here report that a small-molecule Class 1 histone deacetylase (HDAC) inhibitor Entinostat (MS-275) enhances GLP-1R agonism to potentiate glucose-stimulated insulin secretion and decrease body weight in diet-induced obese (DIO) mice. MS-275 is not an agonist or allosteric activator of GLP-1R but enhances the sustained receptor-mediated signaling through the modulation of the expression of proteins involved in the signaling pathway. MS-275 and liraglutide combined therapy improved fasting glycemia upon short-term treatment and a chronic administration causes a reduction of obesity in DIO mice. Overall, our results emphasize the therapeutic potential of MS-275 as an adjunct to GLP-1R therapy in the treatment of diabetes and obesity.

Keywords: HDAC inhibition; cell biology; energy expenditure; glucagon-like peptide-1 receptor; glycemic control; insulin secretion; medicine; mouse; obesity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides / pharmacology*
  • Blood Glucose / drug effects*
  • Glucagon-Like Peptide-1 Receptor / agonists*
  • Glycemic Control / methods*
  • Histone Deacetylase Inhibitors / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Obesity*
  • Pyridines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Benzamides
  • Blood Glucose
  • Glucagon-Like Peptide-1 Receptor
  • Histone Deacetylase Inhibitors
  • Pyridines
  • entinostat

Associated data

  • GEO/GSE139147