title: Cold-induced PGC-1alpha expression modulates muscle glucose uptake through an insulin receptor/Akt-independent, AMPK-dependent pathway.
abstract: Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) participates in control of expression of genes involved in adaptive thermogenesis, muscle fiber type differentiation, and fuel homeostasis. The objective of the present study was to evaluate the participation of cold-induced PGC-1alpha expression in muscle fiber type-specific activity of proteins that belong to the insulin-signaling pathway. Rats were exposed to 4 degrees C for 4 days and acutely treated with insulin in the presence or absence of an antisense oligonucleotide to PGC-1alpha. Cold exposure promoted a significant increase of PGC-1alpha and uncoupling protein-3 protein expression in type I and type II fibers of gastrocnemius muscle. In addition, cold exposure led to higher glucose uptake during a hyperinsulinemic clamp, which was accompanied by higher expression and membrane localization of GLUT4 in both muscle fiber types. Cold exposure promoted significantly lower insulin-induced tyrosine phosphorylation of the insulin receptor (IR) and Ser473 phosphorylation of acute transforming retrovirus thymoma (Akt) and an insulin-independent increase of Thr172 phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK). Inhibition of PGC-1alpha expression in cold-exposed rats by antisense oligonucleotide treatment diminished glucose clearance rates during a hyperinsulinemic clamp and reduced expression and membrane localization of GLUT4. Reduction of PGC-1alpha expression resulted in no modification of insulin-induced tyrosine phosphorylation of the IR and Ser473 phosphorylation of Akt. Finally, reduction of PGC-1alpha resulted in lower Thr172 phosphorylation of AMPK. Thus cold-induced hyperexpression of PGC-1alpha participates in control of skeletal muscle glucose uptake through a mechanism that controls GLUT4 expression and subcellular localization independent of the IR and Akt activities but dependent on AMPK.
authors.affiliation: Department of Internal Medicine, State University of Campinas, SP 13083-970, Brazil.
authors.forename: Rachel L G S
authors.initials: RL
authors.lastname: Oliveira
authors.forename: Mirian
authors.initials: M
authors.lastname: Ueno
authors.forename: Cláudio T
authors.initials: CT
authors.lastname: de Souza
authors.forename: Márcio
authors.initials: M
authors.lastname: Pereira-da-Silva
authors.forename: Alessandra L
authors.initials: AL
authors.lastname: Gasparetti
authors.forename: Rosangela M N
authors.initials: RM
authors.lastname: Bezzera
authors.forename: Luciane C
authors.initials: LC
authors.lastname: Alberici
authors.forename: Aníbal E
authors.initials: AE
authors.lastname: Vercesi
authors.forename: Mario J A
authors.initials: MJ
authors.lastname: Saad
authors.forename: Lício A
authors.initials: LA
authors.lastname: Velloso
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D003080:Cold Temperature; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D003847:Deoxyglucose / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D006728:Hormones / Q000097:blood; D007328:Insulin / Q000494:pharmacology; D007473:Ion Channels; D008297:Male; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D018656:Muscle Fibers, Fast-Twitch / Q000378:metabolism; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D051058:Oncogene Protein v-akt; D010101:Oxygen Consumption / Q000187:drug effects; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D011972:Receptor, Insulin / Q000502:physiology*; D015682:Retroviridae Proteins, Oncogenic / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis*; D000071247:Uncoupling Protein 3
chemical_list: D000963:Antimetabolites; D002352:Carrier Proteins; D051275:Glucose Transporter Type 4; D006360:Heat-Shock Proteins; D006728:Hormones; D007328:Insulin; D007473:Ion Channels; D024101:Mitochondrial Proteins; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D016376:Oligonucleotides, Antisense; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015682:Retroviridae Proteins, Oncogenic; C495694:Slc2a4 protein, rat; D014157:Transcription Factors; C000604392:UCP3 protein, human; C000604394:Ucp3 protein, rat; D000071247:Uncoupling Protein 3; D003847:Deoxyglucose; D011972:Receptor, Insulin; D051058:Oncogene Protein v-akt; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose