Diabetologia, 2011, Vol.54(8), pp.2132-2142
Byline: F. W. Kiefer (1), S. Neschen (2), B. Pfau (1), B. Legerer (1), A. Neuhofer (1), M. Kahle (2), M. Hrabe de Angelis (2), M. Schlederer (3), M. Mair (3), L. Kenner (3), J. Plutzky (4), M. Zeyda (1), T. M. Stulnig (1) Keywords: Gluconeogenesis; High-fat diet; Inflammation; Insulin resistance; Non-alcoholic fatty liver disease Abstract: Aims/hypothesis 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 .sup.-/-) 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 .sup.-/- 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/interpretation 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. Author Affiliation: (1) Department of Medicine III, Clinical Division of Endocrinology and Metabolism, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria (2) Institute of Experimental Genetics, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany (3) Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria (4) Department of Medicine, Brigham and Women's Hospital Boston, Cardiovascular Division, Harvard Medical School, Boston, MA, USA Article History: Registration Date: 19/04/2011 Received Date: 19/12/2010 Accepted Date: 04/04/2011 Online Date: 12/05/2011 Article note: Electronic supplementary material The online version of this article (doi: 10.1007/s00125-011-2170-0) contains supplementary material, which is available to authorised users.
Gluconeogenesis ; High-fat diet ; Inflammation ; Insulin resistance ; Non-alcoholic fatty liver disease
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