Osteopontin deficiency protects against obesity-induced hepatic steatosis and attenuates glucose production in mice

Abstract

Aims/hypothesisObesity 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.MethodsWild-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.ResultsWe 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/interpretationOur 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-011-2170-0) contains supplementary material, which is available to authorised users.

Metformin Supports the Antidiabetic Effect of a Sodium Glucose Cotransporter 2 Inhibitor by Suppressing Endogenous Glucose Production in Diabetic Mice

“…Catheter ends were connected to syringes in CMA402 pumps (Axel Semrau, Sprockhoevel, Germany). After 110 min of primed continuous H]glucose infusion (1.85 kBq/min), we collected a basal blood sample to determine plasma insulin, glucose, and [3- ]deoxyglucose-6-phosphate was extracted, and glucose uptake rates (R g ) were calculated as previously described (18 Ultima-Gold scintillation-cocktail, radioisotopes, and a Tri-Carb2910TR were from Perkin Elmer (Germany).…”

Wogonin suppresses osteopontin expression in adipocytes by activating PPARα

“…In this study, we demonstrate an inhibitory effect of wogonin on OPN expression in adipocytes in vivo and in vitro (Figure 1 and 2). Given that OPN is responsible for the severe inflammation and insulin resistance in insulin target tissues [6][7][8][9] , our results present a novel explanation for the anti-diabetic properties of wogonin.…”

“…In cultured rat aortic smooth muscle cells, high glucose has been shown to stimulate OPN expression [30] . In contrast, OPN deficiency prevented glucose production and hyperglycemia in HFD mice [6,9] . These studies suggest that the interplay between OPN and hyperglycemia may form a vicious cycle, leading to the development of diabetes.…”

“…Currently, OPN has been implicated in the pathogenesis of insulin resistance, obesity, and diabetes [5] . The pharmacological and genetic inhibition of OPN has mitigated hepatic and adipose tissue inflammation, improved obesityinduced insulin resistance in hepatic and adipose tissue, attenuated hepatic steatosis, and prevented the upregulation of gluconeogenic genes in the liver [6][7][8][9] , suggesting that OPN is an important player in the development of insulin resistance and diabetes.…”

“…A high level of OPN is associated with fat storage in adipose tissue, accumulation of adipose tissue macrophages, adipose tissue inflammation, and adipocyte hypertrophy [6][7][8][9] . In addition, adipocytes can synthesize OPN.…”