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
Shilpak Bele,
Shravan Babu Girada,
Aramita Ray,
Abhishek Gupta,
Srinivas Oruganti,
Phanithi Prakash Babu,
Rahul SR Rayalla,
Shashi Vardhan Kalivendi,
Ahamed Ibrahim,
Vishwajeet Puri,
Venkateswar Adalla,
Madhumohan R Katika,
Richard DiMarchi,
Prasenjit Mitra
Affiliations
Shilpak Bele
Dr. Reddy’s Institute of Life Sciences University of Hyderabad Campus, Hyderabad, India; Manipal Academy of Higher Education, Manipal, India
Shravan Babu Girada
Dr. Reddy’s Institute of Life Sciences University of Hyderabad Campus, Hyderabad, India
Aramita Ray
Dr. Reddy’s Institute of Life Sciences University of Hyderabad Campus, Hyderabad, India
Abhishek Gupta
Department of Biomedical Sciences and Diabetes Institute, Ohio University, Athens, United States
Srinivas Oruganti
Dr. Reddy’s Institute of Life Sciences University of Hyderabad Campus, Hyderabad, India
Phanithi Prakash Babu
School of Life Sciences, University of Hyderabad, Hyderabad, India
Rahul SR Rayalla
School of Life Sciences, University of Hyderabad, Hyderabad, India
Shashi Vardhan Kalivendi
Department of Applied Biology, Indian Institute of Chemical Technology, Hyderabad, India
Ahamed Ibrahim
Division of Lipid Chemistry, National Institute of Nutrition Hyderabad, Hyderabad, India
Vishwajeet Puri
Department of Biomedical Sciences and Diabetes Institute, Ohio University, Athens, United States
Venkateswar Adalla
Medical Genomics, QIMR Berghofer Medical Research Institute, Herston, Australia
Madhumohan R Katika
Stem Cell and Regenerative Medicine Department, Nizam’s Institute of Medical Sciences, Hyderabad, India
Richard DiMarchi
Department of Chemistry, Indiana University, Bloomington, United States
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.
