1. 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
- Author
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Richard D. DiMarchi, Rahul Sr Rayalla, Venkateswar Adalla, Vishwajeet Puri, Prasenjit Mitra, Shravan Babu Girada, Ahamed Ibrahim, Aramita Ray, Srinivas Oruganti, Abhishek Gupta, Phanithi Prakash Babu, Shashi Vardhan Kalivendi, Shilpak Bele, and Madhumohan R. Katika
- Subjects
Blood Glucose ,Male ,0301 basic medicine ,insulin secretion ,obesity ,Mouse ,Pyridines ,HDAC inhibition ,Pharmacology ,Rats, Sprague-Dawley ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,energy expenditure ,Biology (General) ,glucagon-like peptide-1 receptor ,Entinostat ,General Neuroscience ,Histone deacetylase inhibitor ,General Medicine ,Benzamides ,Medicine ,hormones, hormone substitutes, and hormone antagonists ,Research Article ,medicine.drug ,Agonist ,endocrine system ,QH301-705.5 ,medicine.drug_class ,Science ,030209 endocrinology & metabolism ,Glycemic Control ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Diabetes mellitus ,medicine ,Animals ,Glycemic efficacy ,General Immunology and Microbiology ,business.industry ,Liraglutide ,Cell Biology ,medicine.disease ,Rats ,Histone Deacetylase Inhibitors ,Mice, Inbred C57BL ,030104 developmental biology ,chemistry ,Histone deacetylase ,business ,Diet-induced obese - 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.
- Published
- 2020
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