title: Osteopontin deficiency protects against obesity-induced hepatic steatosis and attenuates glucose production in mice.
abstract: OBJECTIVE
  Obesity is strongly associated with the development of non-alcoholic fatty liver disease (NAFLD). The cytokine osteopontin (OPN) was recently shown to be involved in obesity-induced adipose tissue inflammation and reduced insulin response. Accumulating evidence links OPN to the pathogenesis of NAFLD. Here we aimed to identify the role of OPN in obesity-associated hepatic steatosis and impaired hepatic glucose metabolism.
  
  
  METHODS
  Wild-type (WT) and Opn (also known as Spp1) knockout (Opn (-/-)) mice were fed a high-fat or low-fat diet to study OPN effects in obesity-driven hepatic alterations.
  
  
  RESULTS
  We show that genetic OPN deficiency protected from obesity-induced hepatic steatosis, at least in part, by downregulating hepatic triacylglycerol synthesis. Conversely, absence of OPN promoted fat storage in adipose tissue thereby preventing the obesity-induced shift to ectopic fat accumulation in the liver. Euglycaemic-hyperinsulinaemic clamp studies revealed that insulin resistance and excess hepatic glucose production in obesity were significantly attenuated in Opn (-/-) mice. OPN deficiency markedly improved hepatic insulin signalling as shown by enhanced insulin receptor substrate-2 phosphorylation and prevented upregulation of the major hepatic transcription factor Forkhead box O1 and its gluconeogenic target genes. In addition, obesity-driven hepatic inflammation and macrophage accumulation was blocked by OPN deficiency.
  
  
  CONCLUSIONS
  Our data strongly emphasise OPN as mediator of obesity-associated hepatic alterations including steatosis, inflammation, insulin resistance and excess gluconeogenesis. Targeting OPN action could therefore provide a novel therapeutic strategy to prevent obesity-related complications such as NAFLD and type 2 diabetes.
authors.affiliation: Department of Medicine III, Clinical Division of Endocrinology and Metabolism, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.
authors.forename: F W
authors.initials: FW
authors.lastname: Kiefer
authors.forename: S
authors.initials: S
authors.lastname: Neschen
authors.forename: B
authors.initials: B
authors.lastname: Pfau
authors.forename: B
authors.initials: B
authors.lastname: Legerer
authors.forename: A
authors.initials: A
authors.lastname: Neuhofer
authors.forename: M
authors.initials: M
authors.lastname: Kahle
authors.forename: M
authors.initials: M
authors.lastname: Hrabé de Angelis
authors.forename: M
authors.initials: M
authors.lastname: Schlederer
authors.forename: M
authors.initials: M
authors.lastname: Mair
authors.forename: L
authors.initials: L
authors.lastname: Kenner
authors.forename: J
authors.initials: J
authors.lastname: Plutzky
authors.forename: M
authors.initials: M
authors.lastname: Zeyda
authors.forename: T M
authors.initials: TM
authors.lastname: Stulnig
mesh_terms: D000818:Animals; D005234:Fatty Liver / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D053495:Osteopontin / Q000172:deficiency* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014280:Triglycerides / Q000378:metabolism
chemical_list: D014280:Triglycerides; D053495:Osteopontin; D005947:Glucose