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.

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)-(+)-5,7,3',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 AdipoR1 overexpression 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.

• Authors: 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
• Journal: Diabetes (Diabetes) Vol. 63 Issue 10 Pg. 3530-44 (Oct 2014) ISSN: 1939-327X [Electronic] United States
• PMID: 24848063 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 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.

Chemical References

• Adiponectin
• Fatty Acids
• Insulin
• Receptors, Adiponectin
• Quercetin
• Glucose

Topics

• Adiponectin (blood)
• Animals
• Diabetes Mellitus, Type 2 (drug therapy, metabolism)
• Disease Models, Animal
• Fatty Acids (metabolism)
• Glucose (metabolism)
• Insulin (metabolism)
• Insulin Resistance
• Lipid Metabolism (drug effects)
• Mice
• Muscle, Skeletal (drug effects, metabolism)
• Obesity (metabolism)
• Quercetin (analogs & derivatives, pharmacology, therapeutic use)
• Receptors, Adiponectin (metabolism)
• Signal Transduction (drug effects)