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Downregulation of Adiponectin /Adipor2 Is Associated with Hepatic Inflammation and Steatosis in Obese Mice
Yanhua Peng2,3, Drew a. Rideout*1,2, Steven S. Rakita2,1, Mini Sajan2,3, Robert Farese2,3, Min You3, Michel M. Murr1,2
1Department of Surgery, University of South Florida, Tampa, FL; 2Department of Surgery and Research, James A. Haley Veterans Affairs Medical Center, Tampa, FL; 3Department of Molecular Medicine, University of South Florida, Tampa, FL
Background: Non-alcoholic fatty liver disease (NAFLD) is a common manifestation of obesity and is linked to the metabolic syndrome through a complex interplay of hepatic glucose and lipid metabolism. Adiponectin regulates fat storage, lipid oxidation, energy expenditure and inflammation. We propose that high fat diet reduces adiponectin and induces steatosis and hepatic inflammation.
Methods: 4 week-old C57BL mice were fed high fat diet (n=8) or regular chow (control; n=6) for 7 weeks to induce obesity. Body weight, liver weight and serum adiponectin were measured. Liver sections were stained with H&E and Oil Red for fat content. Liver homogenates were used to measure protein (immunoblotting) and mRNA (RT-PCR) of TLR4, TNF-α, SREBP-1, Adiponectin receptors (AdipoR1 and AdipoR2) in addition to nuclear phorsphorylated p65NF-κB. Gels were quantified using densitometry; t-test was used, p<0.05 was significant.
Results: High fat diet increased body and liver weight by 50% and 33%, respectively. Serum adiponectin decreased in mice fed a high fat diet (2,500±20 vs. 6,500±30; p<0.001 vs. control). In liver sections, high fat diet increased fat content in hepatocytes (10,280±120 vs. 1,542±12 fat droplets; p<0.001, vs. control) and hepatocyte ballooning (8,900±50 vs. 1,523±23 cells; p<0.001 vs. control). Liver AdipoR2 decreased with high fat diet (protein: 1,308±10 vs. 3,045±18; mRNA: 1,981±15 vs. 4,738±20; all p<0.001 vs. control); however, AdipoR1 was not changed. High fat diet increased hepatic levels of TLR4, TNF-α and SREBP-1 protein (TLR4: 4,678±35 vs. 2,675±15; TNF-α: 4,429±35 vs. 2,390±25, SREBP1: 4,543±37 vs. 2,574±26, all p<0.001 vs. control) and mRNA (TLR4: 6,789±35 vs. 3,458±29; TNF-α: 3,200±24 vs. 1,301±25; SREBP1: 3,456±23 vs. 1,528±10; all p<0.001 vs. control). Additionally, high fat diet increased activation of phorsphorylated p65NF-κB (5,438±30 vs. 2,560±21; p<0.01 vs. control).
Conclusions: High fat diet induces obesity, increases body and liver weight as well as hepatocyte fat content. Liver steatosis induced by high fat diet is associated with upregulation of hepatic SREBP-1 that promotes lipogenesis and fat storage. In addition, high fat diet is associated with upregulation of pro-inflammatory transcription factors and cytokines and downregulation of AdipoR2 that has anti-inflammatory properties. Moreover, obesity-induced reduction in serum adiponectin suggests that adiponectin signaling may be the crosslink between high fat diet, inflammation and NAFLD.
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