RT Journal Article SR Electronic T1 Loss of AMP-Activated Protein Kinase-α2 Impairs the Insulin-Sensitizing Effect of Calorie Restriction in Skeletal Muscle JF Diabetes JO Diabetes FD American Diabetes Association SP 1051 OP 1061 DO 10.2337/db11-1180 VO 61 IS 5 A1 Wang, Pei A1 Zhang, Ruo-Yu A1 Song, Jie A1 Guan, Yun-Feng A1 Xu, Tian-Ying A1 Du, Hui A1 Viollet, Benoit A1 Miao, Chao-Yu YR 2012 UL http://diabetes.diabetesjournals.org/content/61/5/1051.abstract AB 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.