title: Formononetin, an isoflavone, activates AMP-activated protein kinase/β-catenin signalling to inhibit adipogenesis and rescues C57BL/6 mice from high-fat diet-induced obesity and bone loss.
abstract: Balance between adipocyte and osteoblast differentiation is the key link of disease progression in obesity and osteoporosis. We have previously reported that formononetin (FNT), an isoflavone extracted from Butea monosperma, stimulates osteoblast formation and protects against postmenopausal bone loss. The inverse relationship between osteoblasts and adipocytes prompted us to analyse the effect of FNT on adipogenesis and in vivo bone loss, triggered by high-fat diet (HFD)-induced obesity. The anti-obesity effect and mechanism of action of FNT was determined in 3T3-L1 cells and HFD-induced obese male mice. Our findings show that FNT suppresses the adipogenic differentiation of 3T3-L1 fibroblasts, through down-regulation of key adipogenic markers such as PPARγ, CCAAT/enhancer-binding protein alpha (C/EBPα) and sterol regulatory element-binding protein (SREBP) and inhibits intracellular TAG accumulation. Increased intracellular reactive oxygen species levels and AMP-activated protein kinase (AMPK) activation accompanied by stabilisation of β-catenin were attributed to the anti-adipogenic action of FNT. In vivo, 12 weeks of FNT treatment inhibited the development of obesity in mice by attenuating HFD-induced body weight gain and visceral fat accumulation. The anti-obesity effect of FNT results from increased energy expenditure. FNT also protects against HFD-induced dyslipidaemia and rescues deterioration of trabecular bone volume by increasing bone formation and decreasing bone resorbtion caused by HFD. FNT's rescuing action against obesity-induced osteoporosis commenced at the level of progenitors, as bone marrow progenitor cells, obtained from the HFD mice group supplemented with FNT, showed increased osteogenic and decreased adipogenic potentials. Our findings suggest that FNT inhibits adipogenesis through AMPK/β-catenin signal transduction pathways and protects against HFD-induced obesity and bone loss.
authors.affiliation: 1Endocrinology Division,CSIR-Central Drug Research Institute,Lucknow 226031,India.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Gautam
authors.affiliation: 1Endocrinology Division,CSIR-Central Drug Research Institute,Lucknow 226031,India.
authors.forename: Vikram
authors.initials: V
authors.lastname: Khedgikar
authors.affiliation: 1Endocrinology Division,CSIR-Central Drug Research Institute,Lucknow 226031,India.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Kushwaha
authors.affiliation: 1Endocrinology Division,CSIR-Central Drug Research Institute,Lucknow 226031,India.
authors.forename: Dharmendra
authors.initials: D
authors.lastname: Choudhary
authors.affiliation: 1Endocrinology Division,CSIR-Central Drug Research Institute,Lucknow 226031,India.
authors.forename: Geet Kumar
authors.initials: GK
authors.lastname: Nagar
authors.affiliation: 2Medicinal and Process Chemistry Division,CSIR-Central Drug Research Institute,Lucknow 226031,India.
authors.forename: Kapil
authors.initials: K
authors.lastname: Dev
authors.affiliation: 2Medicinal and Process Chemistry Division,CSIR-Central Drug Research Institute,Lucknow 226031,India.
authors.forename: Preety
authors.initials: P
authors.lastname: Dixit
authors.affiliation: 2Medicinal and Process Chemistry Division,CSIR-Central Drug Research Institute,Lucknow 226031,India.
authors.forename: Divya
authors.initials: D
authors.lastname: Singh
authors.affiliation: 2Medicinal and Process Chemistry Division,CSIR-Central Drug Research Institute,Lucknow 226031,India.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Maurya
authors.affiliation: 1Endocrinology Division,CSIR-Central Drug Research Institute,Lucknow 226031,India.
authors.forename: Ritu
authors.initials: R
authors.lastname: Trivedi
mesh_terms: D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D001862:Bone Resorption / Q000188:drug therapy; D002454:Cell Differentiation / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects; D007529:Isoflavones / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000209:etiology / Q000517:prevention & control*; D010024:Osteoporosis / Q000209:etiology / Q000517:prevention & control*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071256:Uncoupling Protein 1 / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D007529:Isoflavones; D017382:Reactive Oxygen Species; D000071256:Uncoupling Protein 1; D051176:beta Catenin; C007768:formononetin; D055372:AMP-Activated Protein Kinases
keywords:  AMPK AMP-activated protein kinase;  BAT brown adipose tissue;  BMSC bone marrow stromal cell;  C/EBP CCAAT/enhancer-binding protein;  DMEM Dulbecco’s modified Eagle medium;  FBS fetal bovine serum;  FNT formononetin;  GSK-3 glycogen synthase kinase-3;  HFD high-fat diet;  OCN osteocalcin;  ROS reactive oxygen species;  RUNX2 runt-related transcription factor 2;  SREBP sterol regulatory element-binding protein;  UCP1 uncoupling protein 1;  Wnt-10b wingless-related integration site-10b; AMP-activated protein kinase; Bone loss; Isoflavones; Micro-computed tomography; Obesity; TNFα
              