title: Fatty acid nitroalkenes ameliorate glucose intolerance and pulmonary hypertension in high-fat diet-induced obesity.
abstract: OBJECTIVE
  Obesity is a risk factor for diabetes and cardiovascular diseases, with the incidence of these disorders becoming epidemic. Pathogenic responses to obesity have been ascribed to adipose tissue (AT) dysfunction that promotes bioactive mediator secretion from visceral AT and the initiation of pro-inflammatory events that induce oxidative stress and tissue dysfunction. Current understanding supports that suppressing pro-inflammatory and oxidative events promotes improved metabolic and cardiovascular function. In this regard, electrophilic nitro-fatty acids display pleiotropic anti-inflammatory signalling actions.
  
  
  RESULTS
  It was hypothesized that high-fat diet (HFD)-induced inflammatory and metabolic responses, manifested by loss of glucose tolerance and vascular dysfunction, would be attenuated by systemic administration of nitrooctadecenoic acid (OA-NO2). Male C57BL/6j mice subjected to a HFD for 20 weeks displayed increased adiposity, fasting glucose, and insulin levels, which led to glucose intolerance and pulmonary hypertension, characterized by increased right ventricular (RV) end-systolic pressure (RVESP) and pulmonary vascular resistance (PVR). This was associated with increased lung xanthine oxidoreductase (XO) activity, macrophage infiltration, and enhanced expression of pro-inflammatory cytokines. Left ventricular (LV) end-diastolic pressure remained unaltered, indicating that the HFD produces pulmonary vascular remodelling, rather than LV dysfunction and pulmonary venous hypertension. Administration of OA-NO2 for the final 6.5 weeks of HFD improved glucose tolerance and significantly attenuated HFD-induced RVESP, PVR, RV hypertrophy, lung XO activity, oxidative stress, and pro-inflammatory pulmonary cytokine levels.
  
  
  CONCLUSIONS
  These observations support that the pleiotropic signalling actions of electrophilic fatty acids represent a therapeutic strategy for limiting the complex pathogenic responses instigated by obesity.
authors.affiliation: Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Kelley
authors.forename: Jeff
authors.initials: J
authors.lastname: Baust
authors.forename: Gustavo
authors.initials: G
authors.lastname: Bonacci
authors.forename: Franca
authors.initials: F
authors.lastname: Golin-Bisello
authors.forename: Jason E
authors.initials: JE
authors.lastname: Devlin
authors.forename: Claudette M
authors.initials: CM
authors.lastname: St Croix
authors.forename: Simon C
authors.initials: SC
authors.lastname: Watkins
authors.forename: Sonia
authors.initials: S
authors.lastname: Gor
authors.forename: Nadiezhda
authors.initials: N
authors.lastname: Cantu-Medellin
authors.forename: Eric R
authors.initials: ER
authors.lastname: Weidert
authors.forename: Jefferson C
authors.initials: JC
authors.lastname: Frisbee
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
authors.forename: Hunter C
authors.initials: HC
authors.lastname: Champion
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Freeman
authors.forename: Nicholas K H
authors.initials: NK
authors.lastname: Khoo
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D001835:Body Weight / Q000502:physiology; D059305:Diet, High-Fat / Q000009:adverse effects*; D005227:Fatty Acids / Q000378:metabolism*; D018149:Glucose Intolerance / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000150:complications / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D005227:Fatty Acids; D007328:Insulin
keywords: Inflammation; Nitro-fatty acid signalling; Obesity; Pulmonary hypertension; Xanthine Oxidase