Cystathionine γ-lyase deficiency aggravates obesity-related insulin resistance via FoxO1-dependent hepatic gluconeogenesis.

Hepatic gluconeogenesis makes a significant contribution to the pathogenesis of obesity and its related insulin resistance. Cystathionine γ-lyase (CSE; also cystathionase), a principal hydrogen sulfide (H2S)-synthesizing enzyme in the liver, is involved in glucose and lipid metabolism disorders. However, the roles and precise mechanisms of CSE/H2S in obesity and its related insulin resistance remain obscure. Here we show that CSE knockout exacerbated high-fat diet-induced mouse obesity as well as its related insulin resistance. Further study elucidated that the inhibition of insulin and AMPK signaling pathways by CSE deficiency resulted in nuclear accumulation of Forkhead box protein O1 and subsequently promoted hepatic gluconeogenesis. These phenomena can be reversed by NaHS supplementation. However, in wild-type mice, NaHS treatment ameliorates high fat diet-induced obesity and metabolism disorders, indicating that maintaining an appropriate level of H2S is critical for its mutual change of positive and negative effects of obesity-associated insulin resistance. Our study reveals a double-edged sword effect and a novel mechanism for CSE/H2S in obesity associated with insulin resistance and provides evidence for CSE/H2S as a promising therapeutic potential target for obesity-related insulin resistance.-Guo, W., Li, D., You, Y., Li, W., Hu, B., Zhang, S., Miao, L., Xian, M., Zhu, Y., Shen, X. Cystathionine γ-lyase deficiency aggravates obesity-related insulin resistance via FoxO1-dependent hepatic gluconeogenesis.