Liver-specific suppressor of cytokine signaling-3 deletion in mice enhances hepatic insulin sensitivity and lipogenesis resulting in fatty liver and obesity1

Abstract

Obesity is associated with chronic inflammation and contributes to the development of insulin resistance and nonalcoholic fatty liver disease. The suppressor of cytokine signaling-3 (SOCS3) protein is increased in inflammation and is thought to contribute to the pathogenesis of insulin resistance by inhibiting insulin and leptin signaling. Therefore, we studied the metabolic effects of liver-specific SOCS3 deletion in vivo. We fed wild-type (WT) and liver-specific SOCS3 knockout (SOCS3 LKO) mice either a control diet or a high-fat diet (HFD) for 6 weeks and examined their metabolic phenotype. We isolated hepatocytes from WT and SOCS3 LKO mice and examined the effects of tumor necrosis factor a and insulin on Akt phosphorylation and fatty acid metabolism and lipogenic gene expression. Hepatocytes from control-fed SOCS3 LKO mice were protected from developing tumor necrosis factor a-induced insulin resistance but also had increased lipogenesis and expression of sterol response element-binding protein-1c target genes. Lean SOCS3 LKO mice fed a control diet had enhanced hepatic insulin sensitivity; however, when fed an HFD, SOCS3 LKO mice had increased liver fat, inflammation, and whole-body insulin resistance. SOCS3 LKO mice fed an HFD also had elevated hypothalamic SOCS3 and fatty acid synthase expression and developed greater obesity due to increased food intake and reduced energy expenditure. Conclusion: Deletion of SOCS3 in the liver increases liver insulin sensitivity in mice fed a control diet but paradoxically promotes lipogenesis, leading to the development of nonalcoholic fatty liver disease, inflammation, and obesity. (HEPATOLOGY 2010;52:1632-1642

Depletion of suppressor of cytokine signaling-1a causes hepatic steatosis and insulin resistance in zebrafish

“…At 90 dpf, liver steatosis was observed in socs1a-deficient fish (Fig. 4, E-H, and Table 2), as could also be observed in SOCS1-, SOCS2-, and SOCS3-deficient mice only in the presence of HFD (12,37,42). Moreover, significantly increased plasma insulin levels were observed in socs1a-null fish, and the mutant fish did not exhibit improved plasma glucose clearance compared with the control fish (Fig.…”

“…SOCS2 deletion in mice can protect against hepatic steatosis but only worsens insulin resistance with HFD feeding (42). Notably, the phenotype observed in socs1a-deficient zebrafish is clearly different from the SOCS1-, SOCS2-, and SOCS3-knockout mouse phenotypes (12,37,40,42), with enhanced liver steatosis and impaired insulin sensitivity under normal feeding conditions suggesting the differences in the regulation of hepatic metabolism between these two vertebrate models.…”

Aryl Hydrocarbon Receptor Plays Protective Roles against High Fat Diet (HFD)-induced Hepatic Steatosis and the Subsequent Lipotoxicity via Direct Transcriptional Regulation of Socs3 Gene Expression

“…Lane 8 was run using a cell extract prepared from Socs3 expression vector-transfected RAW264. AhR LKO mice, liver-specific Socs3 KO mice fed a HFD showed the severe hepatic steatosis associated with increased de novo lipogenesis and inflammation (40). The mechanism involves HFD-dependent increase of Srebp-1c expression (40).…”

“…AhR LKO mice, liver-specific Socs3 KO mice fed a HFD showed the severe hepatic steatosis associated with increased de novo lipogenesis and inflammation (40). The mechanism involves HFD-dependent increase of Srebp-1c expression (40). A recent study revealed that SOCS3 acts as an inhibitor of the JAK/ STAT5a pathway and disturbs lipogenesis by decreasing Srebp-1c expression (43).…”

Leptin signal transduction underlies the differential metabolic response of LEW and WKY rats to cafeteria diet

“…Furthermore, the effect of diet on the peripheral regulation of leptin signalling was also strain-specific, and the impairment of central leptin signalling in CAF-fed LEW rats was also observed in the liver by the significant upregulation of LepRb transcription and the downregulation of Socs3, a phenomenon that is associated with an increase in liver insulin sensitivity and with the promotion of the lipogenesis-induced inflammatory response and the obesity (Sachithanandan et al 2010). Nonetheless, in CAF-fed WKY rats, LepRb gene expression was downregulated by the diet, whereas Socs3 expression was slightly but not significantly decreased.…”