Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuoku, Kumamoto, Japan.
Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan.
Nat Commun. 2024 Nov 12;15(1):9585. doi: 10.1038/s41467-024-53835-9.
Lipodystrophy and obesity are associated with insulin resistance and metabolic syndrome accompanied by fat tissue dysregulation. Here, we show that serine protease inhibitor A1 (SerpinA1) expression in the liver is increased during recovery from lipodystrophy caused by the adipocyte-specific loss of insulin signaling in mice. SerpinA1 induces the proliferation of white and brown preadipocytes and increases the expression of uncoupling protein 1 (UCP1) to promote mitochondrial activation in mature white and brown adipocytes. Liver-specific SerpinA1 transgenic mice exhibit increased browning of adipose tissues, leading to increased energy expenditure, reduced adiposity and improved glucose tolerance. Conversely, SerpinA1 knockout mice exhibit decreased adipocyte mitochondrial function, impaired thermogenesis, obesity, and systemic insulin resistance. SerpinA1 forms a complex with the Eph receptor B2 and regulates its downstream signaling in adipocytes. These results demonstrate that SerpinA1 is an important hepatokine that improves obesity, energy expenditure and glucose metabolism by promoting preadipocyte proliferation and activating mitochondrial UCP1 expression in adipocytes.
脂肪营养不良和肥胖与胰岛素抵抗和代谢综合征有关，同时伴随着脂肪组织失调。在这里，我们表明，在小鼠脂肪细胞特异性胰岛素信号缺失引起的脂肪营养不良恢复期间，肝脏中丝氨酸蛋白酶抑制剂 A1（SerpinA1）的表达增加。SerpinA1 诱导白色和棕色前体脂肪细胞的增殖，并增加解偶联蛋白 1（UCP1）的表达，以促进成熟白色和棕色脂肪细胞中线粒体的激活。肝脏特异性 SerpinA1 转基因小鼠表现出脂肪组织的棕色化增加，导致能量消耗增加、脂肪减少和葡萄糖耐量改善。相反，SerpinA1 敲除小鼠表现出脂肪细胞线粒体功能下降、产热受损、肥胖和全身胰岛素抵抗。SerpinA1 与 Eph 受体 B2 形成复合物，并在脂肪细胞中调节其下游信号。这些结果表明，SerpinA1 是一种重要的肝因子，通过促进前体脂肪细胞的增殖和激活脂肪细胞中线粒体 UCP1 的表达，改善肥胖、能量消耗和葡萄糖代谢。
