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Reciprocal regulation of hepatic TGF-β1 and Foxo1 controls gluconeogenesis and energy expenditure

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posted on 2023-06-21, 21:03 authored by Quan Pan, Weiqi Ai, Yunmei Chen, Da Mi Kim, Zheng Shen, Wanbao Yang, Wen Jiang, Yuxiang Sun, Stephen Safe, Shaodong Guo

  

Obesity and insulin resistance are risk factors for the pathogenesis of T2D. Here we report that hepatic TGF-β1 expression positively correlates with obesity and insulin resistance in mice and humans. Hepatic TGF-β1 deficiency decreased blood glucose in lean mice, and improved glucose and energy dysregulations in diet-induced obese (DIO) mice and diabetic mice. Conversely, overexpression of TGF-β1 in the liver exacerbated metabolic dysfunctions in DIO mice. Mechanistically, hepatic TGF-β1 and Foxo1 are reciprocally regulated: fasting or insulin resistance caused Foxo1 activation, increasing TGF-β1 expression, which in turn activated protein kinase A, stimulating Foxo1-S273 phosphorylation to promote Foxo1-mediated gluconeogenesis. Disruption of TGF-β1→Foxo1→TGF-β1 looping by deleting TGF-β1 receptor II in the liver or by blocking Foxo1-S273 phosphorylation ameliorated hyperglycemia and improved energy metabolism in adipose tissues. Taken together, our studies reveal that hepatic TGF-β1→Foxo1→TGF-β1 looping could serve as a potential therapeutic target for prevention and treatment of obesity and T2D.

Funding

This work was supported by National Institutes of Health grants (R01DK095118, R01 DK120968, and R01DK124588), American Diabetes Association Career Development Award (1-15-CD-09), Faculty Start-up funds from Texas A&M University Health Science Center and AgriLife Research, and USDA National Institute of Food and Agriculture grant (Hatch 1010958) to S.G (PI). Dr. S. G. is recipient of the 2015 American Diabetes Association Research Excellence Thomas R. Lee Award and the 2021 Presidential Impact Fellow Award of Texas A&M University. This work was also partially supported by NIH R01DK118334 and R01AG064869 to YS (PI) and SG (Co-I).

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