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.
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.
Biochemistry Division, Council of Scientific and Industrial Research-Central Drug Research Institute (CSIR-CDRI), Lucknow, Uttar Pradesh, India.
Abhishek Kumar
AK
Singh
Zydus Research Center, Moraiya, Ahmedabad, Gujarat, India.
Amit Arvind
AA
Joharapurkar
Division of Endocrinology, CSIR-CDRI, Lucknow, Uttar Pradesh, India.
Mohd Parvez
MP
Khan
Biochemistry Division, Council of Scientific and Industrial Research-Central Drug Research Institute (CSIR-CDRI), Lucknow, Uttar Pradesh, India.
Jay Sharan
JS
Mishra
Biochemistry Division, Council of Scientific and Industrial Research-Central Drug Research Institute (CSIR-CDRI), Lucknow, Uttar Pradesh, India.
Nidhi
N
Singh
Biochemistry Division, Council of Scientific and Industrial Research-Central Drug Research Institute (CSIR-CDRI), Lucknow, Uttar Pradesh, India.
Manisha
M
Yadav
Division of Phramacokinetics, CSIR-CDRI, Lucknow, Uttar Pradesh, India.
Zakir
Z
Hossain
Division of Endocrinology, CSIR-CDRI, Lucknow, Uttar Pradesh, India.
Kainat
K
Khan
Division of Medicinal and Process Chemistry, CSIR-CDRI, Lucknow, Uttar Pradesh, India.
Sudhir
S
Kumar
Zydus Research Center, Moraiya, Ahmedabad, Gujarat, India.
Nirav Anilkumar
NA
Dhanesha
Division of Medicinal and Process Chemistry, CSIR-CDRI, Lucknow, Uttar Pradesh, India.
Devendra Pratap
DP
Mishra
Division of Medicinal and Process Chemistry, CSIR-CDRI, Lucknow, Uttar Pradesh, India.
Rakesh
R
Maurya
Division of Toxicology, CSIR-CDRI, Lucknow, Uttar Pradesh, India.
Sharad
S
Sharma
Zydus Research Center, Moraiya, Ahmedabad, Gujarat, India.
Mukul Rameshchandra
MR
Jain
Biochemistry Division, Council of Scientific and Industrial Research-Central Drug Research Institute (CSIR-CDRI), Lucknow, Uttar Pradesh, India.
Arun Kumar
AK
Trivedi
Department of Molecular Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.
Madan Madhav
MM
Godbole
Division of Phramacokinetics, CSIR-CDRI, Lucknow, Uttar Pradesh, India.
Jiaur Rahaman
JR
Gayen
Division of Endocrinology, CSIR-CDRI, Lucknow, Uttar Pradesh, India.
Naibedya
N
Chattopadhyay
Biochemistry Division, Council of Scientific and Industrial Research-Central Drug Research Institute (CSIR-CDRI), Lucknow, Uttar Pradesh, India sanyal@cdri.res.in.
Sabyasachi
S
Sanyal
D052242:Adiponectin / Q000097:blood*; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D011794:Quercetin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D054419:Receptors, Adiponectin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D052242:Adiponectin; D005227:Fatty Acids; D007328:Insulin; D054419:Receptors, Adiponectin; D011794:Quercetin; D005947:Glucose