Global Tudor-SN transgenic mice are protected from obesity-induced hepatic steatosis and insulin resistance.

In the current study, we explored the impact of Tudor-staphylococcal nuclease (SN) on obesity induced by a high-fat diet (HFD) in mice, because the functional involvement of Tudor-SN in lipid metabolism in vivo is unknown. HFD-transgenic (Tg) mice exhibited reductions in hepatic steatosis and systemic insulin resistance. There was no difference in hepatic lipid accumulation between chow-fed wild-type (WT) and chow-fed Tg mice; consistently, no difference in activation of the lipogenic pathway was detected. Overactivation of hepatic nuclear sterol regulatory element-binding protein (nSrebp2)-2, the central regulator of cholesterol metabolic proteins, was observed in HFD-Tg livers along with improved cholesterol homeostasis, but no such changes were observed in HFD-WT livers. Consistent results were observed in vitro in α-mouse liver 12 cells treated with palmitate mimicking the HFD state. In addition, global gene analysis indicated that various downstream targets of nSrebp2, were up-regulated in HFD-Tg livers. Moreover, HFD-WT mice displayed islet hypertrophy and suppression of glucose-induced insulin secretion from islets, whereas HFD-Tg mice had normal pancreatic islets. This finding suggests that the improved pancreatic metabolism of HFD-Tg mice is related to the systemic effect of insulin resistance, not to the autonomous influence of pancreatic cells. Tudor-SN is likely to be a key regulator for ameliorating HFD-induced hepatic steatosis and systemic insulin resistance in vivo.-Wang, X., Xin, L., Duan, Z., Zuo, Z., Wang, Y., Ren, Y., Zhang, W., Sun, X., Liu, X., Ge, L., Yang, X., Yao, Z., Yang, J. Global Tudor-SN transgenic mice are protected from obesity-induced hepatic steatosis and insulin resistance.