Department of Pharmacology and.
Department of Cell Systems & Anatomy, University of Texas Health at San Antonio, San Antonio, Texas, USA.
J Clin Invest. 2021 Dec 15;131(24). doi: 10.1172/JCI148545.
Dysregulation in adipokine biosynthesis and function contributes to obesity-induced metabolic diseases. However, the identities and functions of many of the obesity-induced secretory molecules remain unknown. Here, we report the identification of leucine-rich alpha-2-glycoprotein 1 (LRG1) as an obesity-associated adipokine that exacerbates high fat diet-induced hepatosteatosis and insulin resistance. Serum levels of LRG1 were markedly elevated in obese humans and mice compared with their respective controls. LRG1 deficiency in mice greatly alleviated diet-induced hepatosteatosis, obesity, and insulin resistance. Mechanistically, LRG1 bound with high selectivity to the liver and promoted hepatosteatosis by increasing de novo lipogenesis and suppressing fatty acid β-oxidation. LRG1 also inhibited hepatic insulin signaling by downregulating insulin receptor substrates 1 and 2. Our study identified LRG1 as a key molecule that mediates the crosstalk between adipocytes and hepatocytes in diet-induced hepatosteatosis and insulin resistance. Suppressing LRG1 expression and function may be a promising strategy for the treatment of obesity-related metabolic diseases.
脂肪因子生物合成和功能失调导致肥胖引起的代谢性疾病。然而，许多肥胖诱导的分泌分子的身份和功能仍然未知。在这里，我们报告了富含亮氨酸的α-2-糖蛋白 1（LRG1）作为一种与肥胖相关的脂肪因子的鉴定，它可加剧高脂肪饮食诱导的肝脂肪变性和胰岛素抵抗。与各自的对照相比，肥胖人群和小鼠的血清 LRG1 水平明显升高。LRG1 缺陷小鼠极大地缓解了饮食诱导的肝脂肪变性、肥胖和胰岛素抵抗。从机制上讲，LRG1 与肝脏具有高选择性结合，并通过增加从头脂肪生成和抑制脂肪酸β氧化来促进肝脂肪变性。LRG1 还通过下调胰岛素受体底物 1 和 2 抑制肝胰岛素信号。我们的研究确定 LRG1 是一种关键分子，它介导了饮食诱导的肝脂肪变性和胰岛素抵抗中脂肪细胞和肝细胞之间的串扰。抑制 LRG1 的表达和功能可能是治疗肥胖相关代谢性疾病的一种有前途的策略。
