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

Shravan Babu Girada¹  Ahamed Ibrahim²  Srinivas Oruganti³  Venkateswar Adalla³  Prasenjit Mitra⁴  Vishwajeet Puri⁵  Shilpak Bele⁶  Abhishek Gupta⁶  Aramita Ray⁶  Phanithi Prakash Babu⁶  Madhumohan R Katika⁷  Rahul SR Rayalla⁸  Shashi Vardhan Kalivendi⁸  Richard DiMarchi⁹ 

[1] Manipal Academy of Higher Education, Manipal, India;Department of Applied Biology, Indian Institute of Chemical Technology, Hyderabad, India;Department of Biomedical Sciences and Diabetes Institute, Ohio University, Athens, United States;Department of Chemistry, Indiana University, Bloomington, United States;Division of Lipid Chemistry, National Institute of Nutrition Hyderabad, Hyderabad, India;Dr. Reddy’s Institute of Life Sciences University of Hyderabad Campus, Hyderabad, India;Medical Genomics, QIMR Berghofer Medical Research Institute, Herston, Australia;School of Life Sciences, University of Hyderabad, Hyderabad, India;Stem Cell and Regenerative Medicine Department, Nizam’s Institute of Medical Sciences, Hyderabad, India;

关键词: glucagon-like peptide-1 receptor;    HDAC inhibition;    insulin secretion;    obesity;    energy expenditure;    glycemic control;   

DOI  :  10.7554/eLife.52212

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown