title: eNOS phosphorylation on serine 1176 affects insulin sensitivity and adiposity.
abstract: Phosphorylation of endothelial nitric oxide synthase (eNOS) is an important regulator of its enzymatic activity. We generated knockin mice expressing phosphomimetic (SD) and unphosphorylatable (SA) eNOS mutations at S1176 to study the role of eNOS phosphorylation. The single amino acid SA mutation is associated with hypertension and decreased vascular reactivity, while the SD mutation results in increased basal and stimulated endothelial NO production. In addition to these vascular effects, modulation of the S1176 phosphorylation site resulted in unanticipated effects on metabolism. The eNOS SA mutation results in insulin resistance, hyperinsulinemia, adiposity, and increased weight gain on high fat. In contrast, the eNOS SD mutation is associated with decreased insulin levels and resistance to high fat-induced weight gain. These results demonstrate the importance of eNOS in regulation of insulin sensitivity, energy metabolism, and bodyweight regulation, and suggest eNOS phosphorylation as a novel target for the treatment of obesity and insulin resistance.
authors.affiliation: Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kashiwagi
authors.forename: Dmitriy N
authors.initials: DN
authors.lastname: Atochin
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Michael
authors.initials: M
authors.lastname: Schleicher
authors.forename: Terrence
authors.initials: T
authors.lastname: Pong
authors.forename: William C
authors.initials: WC
authors.lastname: Sessa
authors.forename: Paul L
authors.initials: PL
authors.lastname: Huang
mesh_terms: D050154:Adiposity / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001794:Blood Pressure; D055879:Gene Knock-In Techniques; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009569:Nitric Oxide / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D012694:Serine / Q000235:genetics / Q000378:metabolism*; D014655:Vascular Resistance; D015430:Weight Gain / Q000235:genetics
chemical_list: D009569:Nitric Oxide; D012694:Serine; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D005947:Glucose