Reciprocal Regulation of Hepatic TGF-β1 and Foxo1 Controls Gluconeogenesis and Energy Expenditure

Quan Pan, Weiqi Ai, Yunmei Chen, Da Mi Kim, Zheng Shen, Wanbao Yang, Wen Jiang, Yuxiang Sun, Stephen Safe, Shaodong Guo

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

UNLABELLED: Obesity and insulin resistance are risk factors for the pathogenesis of type 2 diabetes (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 levels 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 be a potential therapeutic target for prevention and treatment of obesity and T2D.

ARTICLE HIGHLIGHTS: Hepatic TGF-β1 levels are increased in obese humans and mice. Hepatic TGF-β1 maintains glucose homeostasis in lean mice and causes glucose and energy dysregulations in obese and diabetic mice. Hepatic TGF-β1 exerts an autocrine effect to promote hepatic gluconeogenesis via cAMP-dependent protein kinase-mediated Foxo1 phosphorylation at serine 273, endocrine effects on brown adipose tissue action, and inguinal white adipose tissue browning (beige fat), causing energy imbalance in obese and insulin-resistant mice. TGF-β1→Foxo1→TGF-β1 looping in hepatocytes plays a critical role in controlling glucose and energy metabolism in health and disease.

Original languageEnglish (US)
Pages (from-to)1193-1206
Number of pages14
JournalDiabetes
Volume72
Issue number9
DOIs
StatePublished - Sep 1 2023

Keywords

  • Animals
  • Mice
  • Diabetes Mellitus, Experimental/metabolism
  • Diabetes Mellitus, Type 2/metabolism
  • Energy Metabolism/genetics
  • Forkhead Box Protein O1/genetics
  • Gluconeogenesis/genetics
  • Glucose/metabolism
  • Insulin Resistance
  • Liver/metabolism
  • Mice, Inbred C57BL
  • Obesity/metabolism
  • Transforming Growth Factor beta1/pharmacology

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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