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

ABSTRACT 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. FASEB J. 33, 3731–3745 (2019). www.fasebj.org