Reciprocal Regulation of Hepatic TGF-1 and Foxo1 Controls Gluconeogenesis and Energy Expenditure.
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UNLABELLED: Obesity and insulin resistance are risk factors for the pathogenesis of type 2 diabetes (T2D). Here, we report that hepatic TGF-1 expression positively correlates with obesity and insulin resistance in mice and humans. Hepatic TGF-1 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-1 in the liver exacerbated metabolic dysfunctions in DIO mice. Mechanistically, hepatic TGF-1 and Foxo1 are reciprocally regulated: fasting or insulin resistance caused Foxo1 activation, increasing TGF-1 expression, which, in turn, activated protein kinase A, stimulating Foxo1-S273 phosphorylation to promote Foxo1-mediated gluconeogenesis. Disruption of TGF-1Foxo1TGF-1 looping by deleting TGF-1 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-1Foxo1TGF-1 looping could be a potential therapeutic target for prevention and treatment of obesity and T2D. ARTICLE HIGHLIGHTS: Hepatic TGF-1 levels are increased in obese humans and mice. Hepatic TGF-1 maintains glucose homeostasis in lean mice and causes glucose and energy dysregulations in obese and diabetic mice. Hepatic TGF-1 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-1Foxo1TGF-1 looping in hepatocytes plays a critical role in controlling glucose and energy metabolism in health and disease.
