Department of Endocrinology, Tongji Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, 200092, China.
Department of Breast and Thyroid Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China.
Adv Sci (Weinh). 2024 Nov;11(42):e2407789. doi: 10.1002/advs.202407789. Epub 2024 Sep 9.
Intermittent fasting (IF) plays a critical role in mitigating obesity, yet the precise biological mechanisms require further elucidation. Here Orosomucoid 2 (Orm2) is identified as an IF-induced hepatokine that stimulates adipose browning. IF induced Orm2 expression and secretion from the liver through peroxisome proliferator-activated receptor alpha (PPARα). In adipose tissue, Orm2 bound to glycoprotein 130/interleukin 23 receptor (GP130/IL23R) and promoted adipose browning through the activation of p38 mitogen-activated protein kinases (p38-MAPK). In obese mice, Orm2 led to a significant induction of adipose tissue browning and subsequent weight loss, an effect that is not replicated by a mutant variant of Orm2 deficient in GP130/IL23R binding capability. Crucially, genetic association studies in humans identified an obesity-associated Orm2 variant (D178E), which shows decreased GP130/IL23R binding and impaired browning capacity in mice. Overall, the research identifies Orm2 as a promising therapeutic target for obesity, mediating adipose browning through the GP130/IL23R-p38 signalling pathway.
间歇性禁食（IF）在减轻肥胖方面起着关键作用，但确切的生物学机制仍需进一步阐明。本研究鉴定出 Orosomucoid 2（Orm2）是一种 IF 诱导的肝因子，可刺激脂肪棕色化。IF 通过过氧化物酶体增殖物激活受体α（PPARα）诱导 Orm2 在肝脏中的表达和分泌。在脂肪组织中，Orm2 与糖蛋白 130/白细胞介素 23 受体（GP130/IL23R）结合，并通过激活 p38 丝裂原活化蛋白激酶（p38-MAPK）促进脂肪棕色化。在肥胖小鼠中，Orm2 导致脂肪组织棕色化的显著诱导和随后的体重减轻，而缺乏与 GP130/IL23R 结合能力的 Orm2 突变体则不能复制这种效果。至关重要的是，人类的遗传关联研究鉴定出一种与肥胖相关的 Orm2 变体（D178E），该变体在小鼠中显示出与 GP130/IL23R 结合能力降低和棕色化能力受损相关。总之，该研究确定 Orm2 是肥胖症的一个有前途的治疗靶点，通过 GP130/IL23R-p38 信号通路介导脂肪棕色化。
