Orally active osteoanabolic agent 6-C-β-D-glucopyranosyl-(2S, 3S)-(+)- 5,7, 3',4'- tetrahydroxydihydroflavonol binds to adiponectin receptors, with a preference for AdipoR1, induces adiponectin-associated signaling and improves metabolic health in a rodent model of diabetes.
Adiponectin is an adipocytokine that signals through plasma membrane-bound adiponectin receptors (AdipoR) -1 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.
# These authors contributed equally
- Received October 19, 2013.
- Accepted April 24, 2014.
- © 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. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.