Orally active osteoanabolic agent GTDF binds to adiponectin receptors, with a preference for adipoR1, induces adiponectin-associated signaling, and improves metabolic health in a rodent model of diabetes

Abhishek Kumar Singh, Amit Arvind Joharapurkar, Mohd Parvez Khan, Jay Sharan Mishra, Nidhi Singh, Manisha Yadav, Zakir Hossain, Kainat Khan, Sudhir Kumar, Nirav Anilkumar Dhanesha, Devendra Pratap Mishra, Rakesh Maurya, Sharad Sharma, Mukul Rameshchandra Jain, Arun Kumar Trivedi, Madan Madhav Godbole, Jiaur Rahaman Gayen, Naibedya Chattopadhyay, Sabyasachi Sanyal

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Adiponectin is an adipocytokine that signals through plasma membrane-bound adiponectin receptors 1 and 2 (AdipoR1 and -2). Plasma adiponectin depletion is associated with type 2 diabetes, obesity, and cardio-vascular diseases. Adiponectin therapy, however, is yet unavailable owing to its large size, complex multi merization, and functional differences of the multimers. We report discovery and characterization of 6-C-β-D-glucopyranosyl-(2S,3S)-(+)-5,7,3',4'-tetrahydroxydihydroflavonol (GTDF) as an orally active adiponectin mimetic. GTDF interacted with both AdipoRs, with a preference for AdipoR1. It induced adiponectin-associated signaling and enhanced glucose uptake and fatty acid oxidation in vitro, which were augmented or abolished by AdipoRI overexpression or silencing, respectively. GTDF improved metabolic health, characterized by elevated glucose clearance, ß-cell survival, reduced steatohepatitis, browning of white adipose tissue, and improved lipid profile in an AdipoR1-expressing but not an AdipoR1-depleted strain of diabetic mice. The discovery of GTDF as an adiponectin mimetic provides a promising therapeutic tool for the treatment of metabolic diseases.

Original languageEnglish (US)
Pages (from-to)3530-3540
Number of pages11
JournalDiabetes
Volume63
Issue number10
DOIs
StatePublished - Oct 1 2014

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Singh, A. K., Joharapurkar, A. A., Khan, M. P., Mishra, J. S., Singh, N., Yadav, M., Hossain, Z., Khan, K., Kumar, S., Dhanesha, N. A., Mishra, D. P., Maurya, R., Sharma, S., Jain, M. R., Trivedi, A. K., Godbole, M. M., Gayen, J. R., Chattopadhyay, N., & Sanyal, S. (2014). Orally active osteoanabolic agent GTDF binds to adiponectin receptors, with a preference for adipoR1, induces adiponectin-associated signaling, and improves metabolic health in a rodent model of diabetes. Diabetes, 63(10), 3530-3540. https://doi.org/10.2337/db13-1619