title: Control of muscle mitochondria by insulin entails activation of Akt2-mtNOS pathway: implications for the metabolic syndrome.
abstract: BACKGROUND
  In the metabolic syndrome with hyperinsulinemia, mitochondrial inhibition facilitates muscle fat and glycogen accumulation and accelerates its progression. In the last decade, nitric oxide (NO) emerged as a typical mitochondrial modulator by reversibly inhibiting citochrome oxidase and oxygen utilization. We wondered whether insulin-operated signaling pathways modulate mitochondrial respiration via NO, to alternatively release complete glucose oxidation to CO(2) and H(2)O or to drive glucose storage to glycogen.
  
  
  RESULTS
  We illustrate here that NO produced by translocated nNOS (mtNOS) is the insulin-signaling molecule that controls mitochondrial oxygen utilization. We evoke a hyperinsulinemic-normoglycemic non-invasive clamp by subcutaneously injecting adult male rats with long-lasting human insulin glargine that remains stable in plasma by several hours. At a precise concentration, insulin increased phospho-Akt2 that translocates to mitochondria and determines in situ phosphorylation and substantial cooperative mtNOS activation (+4-8 fold, P<.05), high NO, and a lowering of mitochondrial oxygen uptake and resting metabolic rate (-25 to -60%, P<.05). Comparing in vivo insulin metabolic effects on gastrocnemius muscles by direct electroporation of siRNA nNOS or empty vector in the two legs of the same animal, confirmed that in the silenced muscles disrupted mtNOS allows higher oxygen uptake and complete (U-(14)C)-glucose utilization respect to normal mtNOS in the vector-treated ones (respectively 37+/-3 vs 10+/-1 micromolO(2)/h.g tissue and 13+/-1 vs 7.2+/-1 micromol (3)H(2)O/h.g tissue, P<.05), which reciprocally restricted glycogen-synthesis by a half.
  
  
  CONCLUSIONS
  These evidences show that after energy replenishment, insulin depresses mitochondrial respiration in skeletal muscle via NO which permits substrates to be deposited as macromolecules; at discrete hyperinsulinemia, persistent mtNOS activation could contribute to mitochondrial dysfunction with insulin resistance and obesity and therefore, to the progression of the metabolic syndrome.
authors.affiliation: Laboratory of Oxygen Metabolism, University Hospital, Buenos Aires, Argentina.
authors.forename: Paola
authors.initials: P
authors.lastname: Finocchietto
authors.forename: Fernando
authors.initials: F
authors.lastname: Barreyro
authors.forename: Silvia
authors.initials: S
authors.lastname: Holod
authors.forename: Jorge
authors.initials: J
authors.lastname: Peralta
authors.forename: María C
authors.initials: MC
authors.lastname: Franco
authors.forename: Carlos
authors.initials: C
authors.lastname: Méndez
authors.forename: Daniela P
authors.initials: DP
authors.lastname: Converso
authors.forename: Alvaro
authors.initials: A
authors.lastname: Estévez
authors.forename: Maria C
authors.initials: MC
authors.lastname: Carreras
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Poderoso
mesh_terms: D004789:Enzyme Activation; D006801:Humans; D007328:Insulin / Q000502:physiology*; D024821:Metabolic Syndrome / Q000201:enzymology / Q000378:metabolism*; D008931:Mitochondria, Muscle / Q000201:enzymology / Q000502:physiology*; D018482:Muscle, Skeletal / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D007328:Insulin; D019001:Nitric Oxide Synthase; D019869:Phosphatidylinositol 3-Kinases; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt