PMID- 34785210 OWN - NLM STAT- MEDLINE DCOM- 20220307 LR - 20220307 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 913 DP - 2021 Dec 15 TI - Adiponectin receptors by increasing mitochondrial biogenesis and respiration promote osteoblast differentiation: Discovery of isovitexin as a new class of small molecule adiponectin receptor modulator with potential osteoanabolic function. PG - 174634 LID - S0014-2999(21)00790-1 [pii] LID - 10.1016/j.ejphar.2021.174634 [doi] AB - Previously, we established adiponectin receptors (AdipoRs) as osteoanabolic target. To discover small molecule agonists of AdipoRs, we studied apigenin and apigenin-6C-glucopyranose (isovitexin) that induced osteoblast differentiation. In-silico, in vitro and omics-based studies were performed. Molecular docking using the crystal structures of AdipoRs showed different interaction profiles of isovitexin and apigenin. In osteoblasts, isovitexin but not apigenin rapidly phosphorylated AMP-activated protein kinase (pAMPK) which is downstream of AdipoRs and a master regulator of cellular energy metabolism, and upregulated expression of AdipoRs. Blocking AMPK abolished the osteogenic effect of isovitexin and its effect on AdipoR expression. Isovitexin upregulated the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha), the mitochondrial biogenesis factor in osteoblasts, and the effect was blocked by AMPK inhibition. Upregulation of PGC-1alpha by isovitexin was accompanied by increased mitochondrial membrane proteins and mitochondrial DNA (mtDNA). Isovitexin via AdipoRs and PGC-1alpha induced oxidative phosphorylation (OxPhos) and ATP synthesis that resulted in osteoblast differentiation. Isovitexin had no agonistic/antagonistic activity and stimulatory/inhibitory effect in screening platforms for G protein-coupled receptors and kinases, respectively. In vivo, isovitexin upregulated AdipoRs and osteogenic genes, and increased mtDNA in rat calvarium. We conclude that isovitexin selectively via AdipoRs induced osteoblast differentiation that was fuelled by mitochondrial respiration. CI - Copyright (c) 2021 Elsevier B.V. All rights reserved. FAU - Pal, Subhashis AU - Pal S AD - Division of Endocrinology, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow, 226031, India. FAU - Singh, Maninder AU - Singh M AD - Division of Molecular and Structural Biology, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow, 226031, India. FAU - Porwal, Konica AU - Porwal K AD - Division of Endocrinology, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow, 226031, India. FAU - Rajak, Sangam AU - Rajak S AD - Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, India. FAU - Das, Nabanita AU - Das N AD - Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow, 226031, India. FAU - Rajput, Swati AU - Rajput S AD - Division of Endocrinology, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow, 226031, India. FAU - Trivedi, Arun K AU - Trivedi AK AD - Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow, 226031, India. FAU - Maurya, Rakesh AU - Maurya R AD - Division of Medicinal & Process Chemistry, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow, 226031, India. FAU - Sinha, Rohit A AU - Sinha RA AD - Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, India. FAU - Siddiqi, Mohammad I AU - Siddiqi MI AD - Division of Molecular and Structural Biology, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow, 226031, India. FAU - Sanyal, Sabyasachi AU - Sanyal S AD - Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow, 226031, India. FAU - Chattopadhyay, Naibedya AU - Chattopadhyay N AD - Division of Endocrinology, CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Lucknow, 226031, India. Electronic address: n_chattopadhyay@cdri.res.in. LA - eng PT - Journal Article DEP - 20211114 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 0 (Receptors, Adiponectin) RN - 0 (adiponectin receptor 1, mouse) RN - 0 (adiponectin receptor 2, mouse) RN - 7V515PI7F6 (Apigenin) RN - 8L70Q75FXE (Adenosine Triphosphate) RN - KTQ9R9MS0Q (isovitexin) SB - IM MH - Adenosine Triphosphate/metabolism MH - Animals MH - Animals, Newborn MH - Apigenin/*pharmacology MH - Cell Differentiation/drug effects MH - Cells, Cultured MH - Energy Metabolism/drug effects MH - Mice MH - Mitochondria/drug effects/metabolism MH - Osteoblasts/*drug effects/metabolism MH - Osteogenesis/*drug effects MH - Oxidative Phosphorylation/drug effects MH - Primary Cell Culture MH - Receptors, Adiponectin/*agonists/metabolism MH - Up-Regulation/drug effects OTO - NOTNLM OT - Adiponectin receptor OT - Mitochondrial biogenesis OT - Osteoblast OT - Osteoblast differentiation OT - Osteogenic EDAT- 2021/11/18 06:00 MHDA- 2022/03/08 06:00 CRDT- 2021/11/17 05:50 PHST- 2021/08/15 00:00 [received] PHST- 2021/10/29 00:00 [revised] PHST- 2021/11/11 00:00 [accepted] PHST- 2021/11/18 06:00 [pubmed] PHST- 2022/03/08 06:00 [medline] PHST- 2021/11/17 05:50 [entrez] AID - S0014-2999(21)00790-1 [pii] AID - 10.1016/j.ejphar.2021.174634 [doi] PST - ppublish SO - Eur J Pharmacol. 2021 Dec 15;913:174634. doi: 10.1016/j.ejphar.2021.174634. Epub 2021 Nov 14.