title: Specific Sirt1 Activator-mediated Improvement in Glucose Homeostasis Requires Sirt1-Independent Activation of AMPK.
abstract: The specific Sirt1 activator SRT1720 increases mitochondrial function in skeletal muscle, presumably by activating Sirt1. However, Sirt1 gain of function does not increase mitochondrial function, which raises a question about the central role of Sirt1 in SRT1720 action. Moreover, it is believed that the metabolic effects of SRT1720 occur independently of AMP-activated protein kinase (AMPK), an important metabolic regulator that increases mitochondrial function. Here, we show that SRT1720 activates AMPK in a Sirt1-independent manner and SRT1720 activates AMPK by inhibiting a cAMP degrading phosphodiesterase (PDE) in a competitive manner. Inhibiting the cAMP effector protein Epac prevents SRT1720 from activating AMPK or Sirt1 in myotubes. Moreover, SRT1720 does not increase mitochondrial function or improve glucose tolerance in AMPKα2 knockout mice. Interestingly, weight loss induced by SRT1720 is not sufficient to improve glucose tolerance. Therefore, contrary to current belief, the metabolic effects produced by SRT1720 require AMPK, which can be activated independently of Sirt1.
authors.affiliation: Laboratory of Obesity and Aging Research, Genetics and Developmental Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Sung-Jun
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Translational Medicine Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Faiyaz
authors.initials: F
authors.lastname: Ahmad
authors.affiliation: Laboratory of Obesity and Aging Research, Genetics and Developmental Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jee-Hyun
authors.initials: JH
authors.lastname: Um
authors.affiliation: Laboratory of Obesity and Aging Research, Genetics and Developmental Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Brown
authors.affiliation: Laboratory of Obesity and Aging Research, Genetics and Developmental Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Xihui
authors.initials: X
authors.lastname: Xu
authors.affiliation: Laboratory of Obesity and Aging Research, Genetics and Developmental Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Hyeog
authors.initials: H
authors.lastname: Kang
authors.affiliation: Department of Biochemistry and Biophysics, The University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Hengming
authors.initials: H
authors.lastname: Ke
authors.affiliation: Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Feng
authors.affiliation: Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: James
authors.initials: J
authors.lastname: Ryall
authors.affiliation: School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Philp
authors.affiliation: Department of Orthopedic Surgery, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Schenk
authors.affiliation: Laboratory of Obesity and Aging Research, Genetics and Developmental Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Myung K
authors.initials: MK
authors.lastname: Kim
authors.affiliation: Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Sartorelli
authors.affiliation: Laboratory of Obesity and Aging Research, Genetics and Developmental Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: chungj@nhlbi.nih.gov.
authors.forename: Jay H
authors.initials: JH
authors.lastname: Chung
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D018149:Glucose Intolerance; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D006576:Heterocyclic Compounds, 4 or More Rings; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C116122:RAPGEF3 protein, human; D034741:RNA, Small Interfering; C525422:SRT1720; D000242:Cyclic AMP; C534978:Prkaa2 protein, mouse; D055372:AMP-Activated Protein Kinases; D010727:Phosphoric Diester Hydrolases; D056564:Sirtuin 1; D005947:Glucose
keywords: AMPK; Aging; Epac; Mitochondria; Obesity; Phosphodiesterases; SRT1720; Sirt1; Type 2 diabetes; cAMP