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 language | English (US) |
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Pages (from-to) | 1193-1206 |
Number of pages | 14 |
Journal | Diabetes |
Volume | 72 |
Issue number | 9 |
DOIs | |
State | Published - 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