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- Title
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.
- Authors
Singh, Abhishek Kumar; Joharapurkar, Amit Arvind; Khan, Mohd. Parvez; Mishra, Jay Sharan; Singh, Nidhi; Yadav, Manisha; Hossain, Zakir; Khan, Kainat; Kumar, Sudhir; Dhanesha, Nirav Anilkumar; Mishra, Devendra Pratap; Maurya, Rakesh; Sharma, Sharad; Jain, Mukul Rameshchandra; Trivedi, Arun Kumar; Godbole, Madan Madhav; Gayen, Jiaur Rahaman; Chattopadhyay, Naibedya; Sanyal, Sabyasachi
- 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 cardiovascular diseases. Adiponectin therapy, however, is yet unavailable owing to its large size, complex multimerization, and functional differences of the multimers. We report discovery and characterization of 6-C-β-D-glucopyranosyl-(2S,3S)-(+)-5,7,39,49-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 AdipoR1 overexpres-sion or silencing, respectively. GTDF improved metabolic health, characterized by elevated glucose clearance, β-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.
- Subjects
DIABETES; ADIPONECTIN; ADIPOKINES; CELL membranes; TYPE 2 diabetes
- Publication
Diabetes, 2014, Vol 63, Issue 10, p3530
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db13-1619