title: AMPK Activation by Metformin Suppresses Abnormal Extracellular Matrix Remodeling in Adipose Tissue and Ameliorates Insulin Resistance in Obesity.
abstract: Fibrosis is emerging as a hallmark of metabolically dysregulated white adipose tissue (WAT) in obesity. Although adipose tissue fibrosis impairs adipocyte plasticity, little is known about how aberrant extracellular matrix (ECM) remodeling of WAT is initiated during the development of obesity. Here we show that treatment with the antidiabetic drug metformin inhibits excessive ECM deposition in WAT of ob/ob mice and mice with diet-induced obesity, as evidenced by decreased collagen deposition surrounding adipocytes and expression of fibrotic genes including the collagen cross-linking regulator LOX Inhibition of interstitial fibrosis by metformin is likely attributable to the activation of AMPK and the suppression of transforming growth factor-β1 (TGF-β1)/Smad3 signaling, leading to enhanced systemic insulin sensitivity. The ability of metformin to repress TGF-β1-induced fibrogenesis is abolished by the dominant negative AMPK in primary cells from the stromal vascular fraction. TGF-β1-induced insulin resistance is suppressed by AMPK agonists and the constitutively active AMPK in 3T3L1 adipocytes. In omental fat depots of obese humans, interstitial fibrosis is also associated with AMPK inactivation, TGF-β1/Smad3 induction, aberrant ECM production, myofibroblast activation, and adipocyte apoptosis. Collectively, integrated AMPK activation and TGF-β1/Smad3 inhibition may provide a potential therapeutic approach to maintain ECM flexibility and combat chronically uncontrolled adipose tissue expansion in obesity.
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Luo
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA.
authors.forename: Allison
authors.initials: A
authors.lastname: Nocon
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Fry
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA.
authors.forename: Alex
authors.initials: A
authors.lastname: Sherban
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA.
authors.forename: Xianliang
authors.initials: X
authors.lastname: Rui
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA.
authors.forename: Bingbing
authors.initials: B
authors.lastname: Jiang
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA.
authors.forename: X Julia
authors.initials: XJ
authors.lastname: Xu
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA.
authors.forename: Jingyan
authors.initials: J
authors.lastname: Han
authors.affiliation: Division of Endocrinology, Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City, Kansas City, MO.
authors.forename: Yun
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Medicine, Physiology and Biophysics, Center for Diabetes Research and Treatment and Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, CA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Qifu
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA Barshop Institute for Longevity and Aging Studies, Center for Healthy Aging, The University of Texas Health Science Center, San Antonio, TX Department of Molecular Medicine, The University of Texas Health Science Center, San Antonio, TX Geriatric Research, Education and Clinical Center, Audie L. Murphy VA Hospital, South Texas Veterans Health Care System, San Antonio, TX zang@uthscsa.edu.
authors.forename: Mengwei
authors.initials: M
authors.lastname: Zang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D066298:In Vitro Techniques; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D053773:Transforming Growth Factor beta1
chemical_list: D007004:Hypoglycemic Agents; D053773:Transforming Growth Factor beta1; D003094:Collagen; D008687:Metformin; D055372:AMP-Activated Protein Kinases