Adipsin and Adipocyte-derived C3aR1 Regulate Thermogenic Fat in a Sex-dependent Fashion.

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 non-canonical effects on non-immune cells. The adipsin/C3a/C3aR1 pathway stimulates insulin secretion and sustains pancreatic beta cell mass. However, its role in adipose thermogenesis has not been defined. Here, we show that male Adipsin/Cfd knockout mice exhibit increased energy expenditure and white adipose tissue (WAT) browning. In addition, male adipocyte-specific C3aR1 knockout mice exhibit enhanced WAT thermogenesis and increased respiration. In stark contrast, female adipocyte-specific C3aR1 knockout mice display decreased brown fat thermogenesis and are cold intolerant. Female mice express lower levels of Adipsin in thermogenic adipocytes and adipose tissues than males. C3aR1 is also lower in female subcutaneous adipose tissue than 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 newly discovered role of the alternative complement pathway in adaptive thermogenesis and highlight sex-specific considerations in potential therapeutic targets for metabolic diseases.

米色/棕色脂肪组织中的产热作用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发挥多效性作用，对免疫细胞有典型作用，对非免疫细胞有非典型作用。脂联素/C3a/C3aR1通路刺激胰岛素分泌并维持胰腺β细胞数量。然而，其在脂肪产热中的作用尚未明确。在此，我们发现雄性脂联素/补体因子D（Adipsin/Cfd）敲除小鼠表现出能量消耗增加和白色脂肪组织（WAT）褐变。此外，雄性脂肪细胞特异性C3aR1敲除小鼠表现出WAT产热增强和呼吸增加。形成鲜明对比的是，雌性脂肪细胞特异性C3aR1敲除小鼠棕色脂肪产热减少且不耐寒。雌性小鼠在产热脂肪细胞和脂肪组织中脂联素的表达水平低于雄性。雌性皮下脂肪组织中C3aR1的水平也低于雄性。总之，这些结果揭示了脂联素/C3a/C3aR1轴在调节脂肪产热和抵御寒冷应激方面的性别二态性。我们的研究结果确立了替代补体途径在适应性产热中的新发现的作用，并强调了在代谢疾病潜在治疗靶点中考虑性别特异性的重要性。