福克斯O1
内分泌学
胰岛素抵抗
内科学
糖异生
胰岛素受体
白色脂肪组织
脂肪组织
胰岛素
生物
葡萄糖稳态
脂肪肝
医学
信号转导
新陈代谢
蛋白激酶B
细胞生物学
疾病
作者
Quan Pan,Weiqi Ai,Yunmei Chen,Da Mi Kim,James Zheng Shen,Wanbao Yang,Jinyu Wen,Yuxiang Sun,Stephen Safe,Shaodong Guo
出处
期刊:Diabetes
[American Diabetes Association]
日期:2023-06-21
卷期号:72 (9): 1193-1206
被引量:2
摘要
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.
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