Abstract：
Thermogenesis in beige/brown adipose tissues can be leveraged to combat metabolic disorders such as type 2 diabetes and obesity. The complement system plays pleiotropic roles in metabolic homeostasis and organismal energy balance with canonical effects on immune cells and noncanonical effects on nonimmune cells. The adipsin/C3a/C3a receptor 1 (C3aR1) pathway stimulates insulin secretion and sustains pancreatic β cell mass. However, its role in adipose thermogenesis has not been defined. Here, we show that male Adipsin/Cfd-knockout mice exhibited increased energy expenditure and white adipose tissue (WAT) browning. In addition, male adipocyte-specific C3aR1-knockout mice exhibited enhanced WAT thermogenesis and increased respiration. In stark contrast, female adipocyte-specific C3aR1-knockout mice displayed decreased brown fat thermogenesis and were cold intolerant. Female mice expressed lower levels of Adipsin in thermogenic adipocytes and adipose tissues than males. C3aR1 was also lower in female subcutaneous adipose tissue than in males. Collectively, these results reveal sexual dimorphism in the adipsin/C3a/C3aR1 axis in regulating adipose thermogenesis and defense against cold stress. Our findings establish a potentially new role of the alternative complement pathway in adaptive thermogenesis and highlight sex-specific considerations in potential therapeutic targets for metabolic diseases.
摘要：
米色/棕色脂肪组织中的产热可用于对抗代谢紊乱，如2型糖尿病和肥胖症。补体系统在代谢稳态和机体能量平衡中起多效作用，对免疫细胞具有规范作用，对非免疫细胞具有非规范作用。脂肪素/C3a/C3aR1途径刺激胰岛素分泌并维持胰腺β细胞量。然而,其在脂肪产热中的作用尚未确定。这里,我们显示雄性Adipsin/Cfd基因敲除小鼠表现出增加的能量消耗和白色脂肪组织（WAT）褐变。此外,雄性脂肪细胞特异性C3aR1敲除小鼠表现出增强的WAT产热和增加的呼吸。与之形成鲜明对比的是,雌性脂肪细胞特异性C3aR1敲除小鼠表现出减少的棕色脂肪产热，并且不耐受冷。雌性小鼠在产热脂肪细胞和脂肪组织中表达的Adipsin水平低于雄性。C3aR1在女性皮下脂肪组织中也低于男性。总的来说，这些结果揭示了脂肪素/C3a/C3aR1轴在调节脂肪产热和防御冷应激方面的性二态性。我们的发现建立了新发现的替代补体途径在适应性产热中的作用，并强调了在代谢性疾病的潜在治疗靶标中的性别特异性考虑。
