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Tetrahydroxydihydroflavonol Binds to Adiponectin Receptors, with a Preference for Adipor1

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Page 1 of 56 Diabetes 1 Orally active osteoanabolic agent 6-C-β-D-glucopyranosyl-(2S, 3S)-(+)- 5,7, 3',4'- 2 tetrahydroxydihydroflavonol binds to adiponectin receptors, with a preference for AdipoR1, 3 induces adiponectin-associated signaling and improves metabolic health in a rodent model of 4 diabetes. 5 Running title: GTDF is an orally active adiponectin mimetic 6 Abhishek Kumar Singh1,#, Amit Arvind Joharapurkar2,#, Mohd. Parvez Khan3, Jay Sharan Mishra1, 7 Nidhi Singh1, Manisha Yadav1, Zakir Hossain4, Kainat Khan3, Sudhir Kumar5, Nirav Anilkumar 8 Dhanesha2, Devendra Pratap Mishra5, Rakesh Maurya5, Sharad Sharma6, Mukul Rameshchandra 9 Jain2, Arun Kumar Trivedi1, Madan Madhav Godbole7, Jiaur Rahaman Gayen4 , Naibedya 10 Chattopadhyay2 and Sabyasachi Sanyal1,* 11 12 Authors’ affiliations: 13 1Biochemistry Division, CSIR-Central Drug Research Institute, 10 Janakipuram Extn, Sitapur Road, Lucknow 14 226031, UP, India. 2Zydus Research Center, Sarkhej-Bavla NH#8A, Moraiya, Ahmedabad 382210, Gujarat, 15 India. 3Division of Endocrinology, CSIR-Central Drug Research Institute, 10 Janakipuram Extn, Sitapur Road, 16 Lucknow 226031, UP, India. 4Division of Phramacokinetics, CSIR-Central Drug Research Institute, 10 17 Janakipuram Extn, Sitapur Road, Lucknow 226031, UP, India. 5Division of Medicinal and Process Chemistry, 18 CSIR-Central Drug Research Institute, 10 Janakipuram Extn, Sitapur Road, Lucknow 226031, UP, India. 19 6Division of Toxicology, CSIR-Central Drug Research Institute, 10 Janakipuram Extn, Sitapur Road, Lucknow 20 226031, UP, India. 7Department of Molecular Medicine, Sanjay Gandhi Postgraduate Institute of Medical 21 Sciences, Lucknow 226014, UP, India. 22 # These authors contributed equally 23 *Address correspondence to Sabyasachi sanyal, e mail: [email protected], Biochemistry Division, 24 CSIR-Central Drug Research Institute, 10 Janakipuram Extn, Sitapur Road, Lucknow 226031, UP, 25 India ; Tel: (+91)-9792366322; Fax: (+91)-(522)-2771941 26 Word Count 5412 27 Number of Figures 7 1 Diabetes Publish Ahead of Print, published online May 21, 2014 Diabetes Page 2 of 56 1 ABSTRACT 2 Adiponectin is an adipocytokine that signals through plasma membrane-bound adiponectin 3 receptors (AdipoR) -1 and -2. Plasma adiponectin depletion is associated with type 2 4 diabetes, obesity and cardiovascular diseases. Adiponectin therapy however, is yet 5 unavailable owing to its large size, complex multimerization and functional differences of the 6 multimers. We report discovery and characterization of 6-C-β-D-glucopyranosyl-(2S, 3S)- 7 (+)- 5,7, 3',4'- tetrahydroxydihydroflavonol (GTDF) as an orally active adiponectin mimetic. 8 GTDF interacted with both AdipoRs, with a preference for AdipoR1. It induced adiponectin- 9 associated signaling and enhanced glucose uptake and fatty acid oxidation in vitro, which 10 were augmented or abolished by AdipoR1 overexpression or silencing respectively. GTDF 11 improved metabolic health, characterized by elevated glucose-clearance, β-cell-survival, 12 reduced steatohepatitis, browning of white adipose tissue and improved lipid profile in an 13 AdipoR1-expressing but not an AdipoR1-depleted strain of diabetic mice. The discovery of 14 GTDF as an adiponectin mimetic provides a promising therapeutic tool for the treatment of 15 metabolic diseases. 16 17 18 19 20 21 22 23 24 25 2 Page 3 of 56 Diabetes 1 The anti-inflammatory adipocytokine adiponectin (1; 2) signals through adiponectin 2 receptors (AdipoR) -1 and -2 (3). T-cadherin, a cadherin family member that lacks 3 transmembrane and cytoplasmic domains also binds adiponectin, and is proposed to affect its 4 bioavailability (4). Plasma adiponectin depletion is associated with type 2 diabetes, obesity 5 and cardiovascular diseases (5-7). Adiponectin administration or overexpression ameliorates 6 insulin resistance, metabolic syndrome and atherosclerosis in animals (3; 8-12) and enhances 7 pancreatic β cell survival (13). These evidences make AdipoRs important therapeutic targets 8 for metabolic diseases. 9 Structurally, adiponectin belongs to the complement 1q family (1; 14; 15). 10 Adipoenctin monomer is a 30 kDa protein consisting of an N-terminal collagenous and a C- 11 terminal globular domains (1). Mammalian plasma adiponectin is present in several 12 multimeric forms; low-molecular-weight dimer or trimers, medium-molecular-weight 13 hexamers or high-molecular-weight (HMW) dodecamers and 18 mers (10; 16-18). The 14 globular domain of adiponectin (gAd) can form trimers and was initially shown to exist as a 15 proteolytic cleavage product in human plasma (10), although subsequent studies failed to 16 detect it in circulation, its ability to modulate AdipoRs is undisputed. All these forms display 17 different levels of physiological activity and the HMW complex is considered the most 18 clinically relevant form (10; 16-18). The HMW full-length adiponectin and gAd 19 preferentially signal through AdipoR2 and AdipoR1 respectively (3). Given the 20 multimerization-related complexities of adiponectin structure and function, it appears that 21 small molecule AdipoR ligands may provide the only viable therapeutic option against 22 diseases associated with defects in adiponectin expression or action. 23 We have previously identified GTDF, a novel natural analog of the dietary flavonoid 24 quercetin, as a potent orally bioavailable osteoanabolic compound that induced proliferation, 25 differentiation and mineralization of cultured primary osteoblasts at a nanomolar 3 Diabetes Page 4 of 56 1 concentration that was 1000 fold less than effective concentration of quercetin or queretin-O- 2 glucoside, and restored trabecular bones of osteopenic rats on a par with parathyroid hormone 3 (19). While studying its mechanism of action, we found that GTDF induced rapid AMP– 4 dependent protein kinase (AMPK), AKT and p38 phosphorylation and elevated PGC-1α 5 expression in osteoblasts. GTDF also deacetylated tumor suppressor P53 via indirect 6 activation of NAD-dependent deacetylase Sirtuin1 (sirt1) [(20), and manuscript in 7 preparation, SS and NC)]. Literature search revealed that adiponectin elicits similar cellular 8 signaling (1; 3; 11). Interestingly, the quercetin group of compounds display functional 9 properties similar to adiponectin, such as AMPK activation, glucose uptake enhancement, 10 induction of fatty acid oxidation-related genes and amelioration of diabetes and insulin 11 resistance in vivo (21-23). We thus asked if GTDF, quercetin or other naturally occurring 12 quercetin analogs could be adiponectin mimetics. Here we report detailed characterization of 13 GTDF as an adiponectin mimetic that improves metabolic health in a rodent model of 14 diabetes. 15 16 RESEARCH DESIGN AND METHODS 17 Materials and kits: All cell culture reagents were from Invitrogen, Life Technologies 18 (Carlsbad, CA). Fine chemicals were from Sigma-Aldrich (St. Louis, MO) unless otherwise 19 indicated. Epoxy agarose beads conjugated with GTDF were constructed at Shantani Biotech 20 (Pune, India). Globular adiponectin (gAd) was purchased from Enzo Life Sciences 21 (Farmingdale, NY) and ATGen Global (Gyeonggi-do, South Korea) and compared; gAd 22 from both sources showed identical activity; gAd from ATGen Global was used in this study. 23 GW7647 was from Sigma-Aldrich, full length human AdipoR1 and AdipoR2 mammalian 24 expression constructs were from Open Biosystems (Huntsville, AL). 125I-gAd was from 25 Phoenix Pharmaceuticals (Burlingame, CA), 125I (20 MBq) used for radiolabeling GTDF was 4 Page 5 of 56 Diabetes 1 from BARC (Mumbai, India). Glycogen assay kit was from Sigma-Aldrich (St. Louis, 2 Missouri). Serum concentrations of triglycerides, nonesterified free fatty acids (NEFA), 3 HDL, LDL,VLDL, total cholesterol, beta-hydroxybutyrate, and creatinine were determined 4 using kits purchased from Pointe Scientific (Canton, MI, USA).Circulating glucagon, insulin, 5 C-peptide, leptin, adiponectin, ghrelin, corticosterone and markers of inflammation (MCP-1, 6 TNF-α, and IL-6) were estimated using enzyme-linked immunosorbent assay (ELISA) assay 7 kits (R&D Systems, Minneapolis, MN). Serum concentrations of sodium and potassium were 8 measured using a Cobas c system (Roche Diagnostics; Indianapolis, IN). TUNEL assay kit 9 was from Roche Applied Science (Indianapolis, IN). Plasma membrane extraction kit was 10 from Biovision (Milpitas, CA). 11 Cell culture and induction of differentiation 12 HEK-293, CHO, C2C12 and 3T3L-1 cell-lines were cultured as reported (24). Mouse stromal 13 vascular fraction (SVF) was prepared from epididymal fat pad by collagenase digestion. 14 Human SVFs were prepared from human lipoaspirates (subcutaneous), collected following 15 approval of Institutional Ethical Committee. Cells were differentiated in presence of GTDF 16 or vehicle for 10d (3T3L-1 and mouse SVF) or 21d (human SVF), using standard procedure, 17 and then analyzed by QPCR, immunoblotting or microscopy. 18 Iodination and purification of 125I-GTDF 19 GTDF was radio-labeled as previously described for quercetin1 with minor modifications. 20 Briefly, 10µl of 125I (20 MBq; BARC, Mumbai, India) was added to 100µg GTDF in 5% 21 acetic acid/methanol, then chloramine-T (4µg in MilliQ H2O) was added, and the mixture 22 was allowed to react at room temperature (240C) for 5 min. The reaction was terminated by 23 adding 60µl sodium metabisulphite (4mg/ml in MilliQ H2O).The reaction mixture was dried 24 by passing nitrogen and was dissolved into methanol (100 µl). Reverse phase TLC (RP-18 5 Diabetes
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  • The Expanded Endocannabinoid System/Endocannabinoidome As a Potential Target for Treating Diabetes Mellitus

    The Expanded Endocannabinoid System/Endocannabinoidome As a Potential Target for Treating Diabetes Mellitus

    Current Diabetes Reports (2019) 19:117 https://doi.org/10.1007/s11892-019-1248-9 OBESITY (KM GADDE, SECTION EDITOR) The Expanded Endocannabinoid System/Endocannabinoidome as a Potential Target for Treating Diabetes Mellitus Alain Veilleux1,2,3 & Vincenzo Di Marzo1,2,3,4,5 & Cristoforo Silvestri3,4,5 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Purpose of Review The endocannabinoid (eCB) system, i.e. the receptors that respond to the psychoactive component of cannabis, their endogenous ligands and the ligand metabolic enzymes, is part of a larger family of lipid signals termed the endocannabinoidome (eCBome). We summarize recent discoveries of the roles that the eCBome plays within peripheral tissues in diabetes, and how it is being targeted, in an effort to develop novel therapeutics for the treatment of this increasingly prevalent disease. Recent Findings As with the eCB system, many eCBome members regulate several physiological processes, including energy intake and storage, glucose and lipid metabolism and pancreatic health, which contribute to the development of type 2 diabetes (T2D). Preclinical studies increasingly support the notion that targeting the eCBome may beneficially affect T2D. Summary The eCBome is implicated in T2D at several levels and in a variety of tissues, making this complex lipid signaling system a potential source of many potential therapeutics for the treatments for T2D. Keywords Endocannabinoidome . Bioactive lipids . Peripheral tissues . Glucose . Insulin Introduction: The Endocannabinoid System cannabis-derived natural product, Δ9-tetrahydrocannabinol and its Subsequent Expansion (THC), responsible for most of the psychotropic, euphoric to the “Endocannabinoidome” and appetite-stimulating actions (via CB1 receptors) and immune-modulatory effects (via CB2 receptors) of marijuana, The discovery of two G protein-coupled receptors, the canna- opened the way to the identification of the endocannabinoids binoid receptor type-1 (CB1) and − 2 (CB2) [1, 2], for the (eCBs).