title: Overexpression of the adiponectin receptor AdipoR1 in rat skeletal muscle amplifies local insulin sensitivity.
abstract: Adiponectin is an adipokine whose plasma levels are inversely related to degrees of insulin resistance (IR) or obesity. It enhances glucose disposal and mitochondrial substrate oxidation in skeletal muscle and its actions are mediated through binding to receptors, especially adiponectin receptor 1 (AdipoR1). However, the in vivo significance of adiponectin sensitivity and the molecular mechanisms of muscle insulin sensitization by adiponectin have not been fully established. We used in vivo electrotransfer to overexpress AdipoR1 in single muscles of rats, some of which were fed for 6 wk with chow or high-fat diet (HFD) and then subjected to hyperinsulinemic-euglycemic clamp. After 1 wk, the effects on glucose disposal, signaling, and sphingolipid metabolism were investigated in test vs. contralateral control muscles. AdipoR1 overexpression (OE) increased glucose uptake and glycogen accumulation in the basal and insulin-treated rat muscle and also in the HFD-fed rats, locally ameliorating muscle IR. These effects were associated with increased phosphorylation of insulin receptor substrate-1, Akt, and glycogen synthase kinase-3β. AdipoR1 OE also caused increased phosphorylation of p70S6 kinase, AMP-activated protein kinase, and acetyl-coA carboxylase as well as increased protein levels of adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain, and leucine zipper motif-1 and adiponectin, peroxisome proliferator activated receptor-γ coactivator-1α, and uncoupling protein-3, indicative of increased mitochondrial biogenesis. Although neither HFD feeding nor AdipoR1 OE caused generalized changes in sphingolipids, AdipoR1 OE did reduce levels of sphingosine 1-phosphate, ceramide 18:1, ceramide 20:2, and dihydroceramide 20:0, plus mRNA levels of the ceramide synthetic enzymes serine palmitoyl transferase and sphingolipid Δ-4 desaturase, changes that are associated with increased insulin sensitivity. These data demonstrate that enhancement of local adiponectin sensitivity is sufficient to improve skeletal muscle IR.
authors.affiliation: Department of Comparative Biomedical Sciences, Royal Veterinary College, University of London, United Kingdom.
authors.forename: S A
authors.initials: SA
authors.lastname: Patel
authors.forename: K L
authors.initials: KL
authors.lastname: Hoehn
authors.forename: R T
authors.initials: RT
authors.lastname: Lawrence
authors.forename: L
authors.initials: L
authors.lastname: Sawbridge
authors.forename: N A
authors.initials: NA
authors.lastname: Talbot
authors.forename: J L
authors.initials: JL
authors.lastname: Tomsig
authors.forename: N
authors.initials: N
authors.lastname: Turner
authors.forename: G J
authors.initials: GJ
authors.lastname: Cooney
authors.forename: J P
authors.initials: JP
authors.lastname: Whitehead
authors.forename: E W
authors.initials: EW
authors.lastname: Kraegen
authors.forename: M E
authors.initials: ME
authors.lastname: Cleasby
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D052242:Adiponectin / Q000378:metabolism; D000818:Animals; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D054419:Receptors, Adiponectin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D052242:Adiponectin; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D008246:Lysophospholipids; D054419:Receptors, Adiponectin; C504339:adiponectin receptor 1, rat; C060506:sphingosine 1-phosphate; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D013110:Sphingosine