title: Loss of AMP-activated protein kinase-α2 impairs the insulin-sensitizing effect of calorie restriction in skeletal muscle.
abstract: Whether the well-known metabolic switch AMP-activated protein kinase (AMPK) is involved in the insulin-sensitizing effect of calorie restriction (CR) is unclear. In this study, we investigated the role of AMPK in the insulin-sensitizing effect of CR in skeletal muscle. Wild-type (WT) and AMPK-α2(-/-) mice received ad libitum (AL) or CR (8 weeks at 60% of AL) feeding. CR increased the protein level of AMPK-α2 and phosphorylation of AMPK-α2. In WT and AMPK-α2(-/-) mice, CR induced comparable changes of body weight, fat pad weight, serum triglycerides, serum nonesterified fatty acids, and serum leptin levels. However, decreasing levels of fasting/fed insulin and fed glucose were observed in WT mice but not in AMPK-α2(-/-) mice. Moreover, CR-induced improvements of whole-body insulin sensitivity (evidenced by glucose tolerance test/insulin tolerance test assays) and glucose uptake in skeletal muscle tissues were abolished in AMPK-α2(-/-) mice. Furthermore, CR-induced activation of Akt-TBC1D1/TBC1D4 signaling, inhibition of mammalian target of rapamycin-S6K1-insulin receptor substrate-1 pathway, and induction of nicotinamide phosphoribosyltransferase-NAD(+)-sirtuin-1 cascade were remarkably impaired in AMPK-α2(-/-) mice. CR serum increased stability of AMPK-α2 protein via inhibiting the X chromosome-linked ubiquitin-specific protease 9-mediated ubiquitylation of AMPK-α2. Our results suggest that AMPK may be modulated by CR in a ubiquitylation-dependent manner and acts as a chief dictator for the insulin-sensitizing effects of CR in skeletal muscle.
authors.affiliation: Department of Pharmacology, Second Military Medical University, Shanghai, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Wang
authors.forename: Ruo-Yu
authors.initials: RY
authors.lastname: Zhang
authors.forename: Jie
authors.initials: J
authors.lastname: Song
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: Guan
authors.forename: Tian-Ying
authors.initials: TY
authors.lastname: Xu
authors.forename: Hui
authors.initials: H
authors.lastname: Du
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Chao-Yu
authors.initials: CY
authors.lastname: Miao
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D031204:Caloric Restriction; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D054409:Nicotinamide Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D015431:Weight Loss
chemical_list: D016207:Cytokines; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D012333:RNA, Messenger; D054409:Nicotinamide Phosphoribosyltransferase; C495867:nicotinamide phosphoribosyltransferase, mouse; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1