Abhishek Kumar Singh, 1 Amit Arvind Joharapurkar, 2 Mohd. Parvez Khan, 3 Jay Sharan Mishra, 1 Nidhi Singh, 1 Manisha Yadav, 1 Zakir Hossain, 4 Kainat Khan, 3 Sudhir Kumar, 5 Nirav Anilkumar Dhanesha, 2 Devendra Pratap Mishra, 5 Rakesh Maurya, 5 Sharad Sharma, 6 Mukul Rameshchandra Jain, 2 Arun Kumar Trivedi, 1 Madan Madhav Godbole, 7 Jiaur Rahaman Gayen, 4 Naibedya Chattopadhyay, 3 and Sabyasachi Sanyal 1 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 2014;63:3530–3544 | DOI: 10.2337/db13-1619 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 multimeriza- tion, and functional differences of the multimers. We report discovery and characterization of 6-C-b-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 in- duced 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, b-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 adiponec- tin mimetic provides a promising therapeutic tool for the treatment of metabolic diseases. The anti-inflammatory adipocytokine adiponectin (1,2) signals through adiponectin receptors 1 and 2 (AdipoR1 and -2) (3). T-cadherin, a cadherin family member that lacks transmembrane and cytoplasmic domains, also binds adiponectin and is proposed to affect its bioavail- ability (4). Plasma adiponectin depletion is associated with type 2 diabetes, obesity, and cardiovascular dis- eases (5–7). Adiponectin administration or overexpres- sion ameliorates insulin resistance, metabolic syndrome, and atherosclerosis in animals (3,8–12) and enhances pancreatic b-cell survival (13). This evidence makes AdipoRs important therapeutic targets for metabolic diseases. 1 Biochemistry Division, Council of Scientific and Industrial Research-Central Drug Research Institute (CSIR-CDRI), Lucknow, Uttar Pradesh, India 2 Zydus Research Center, Moraiya, Ahmedabad, Gujarat, India 3 Division of Endocrinology, CSIR-CDRI, Lucknow, Uttar Pradesh, India 4 Division of Phramacokinetics, CSIR-CDRI, Lucknow, Uttar Pradesh, India 5 Division of Medicinal and Process Chemistry, CSIR-CDRI, Lucknow, Uttar Pradesh, India 6 Division of Toxicology, CSIR-CDRI, Lucknow, Uttar Pradesh, India 7 Department of Molecular Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India Corresponding author: Sabyasachi Sanyal, sanyal@cdri.res.in. Received 19 October 2013 and accepted 24 April 2014. This article contains Supplementary Data online at http://diabetes .diabetesjournals.org/lookup/suppl/doi:10.2337/db13-1619/-/DC1. A.K.S. and A.A.J. contributed equally to this work. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. 3530 Diabetes Volume 63, October 2014 PHARMACOLOGY AND THERAPEUTICS Downloaded from http://diabetesjournals.org/diabetes/article-pdf/63/10/3530/573544/3530.pdf by guest on 04 November 2022