SUCLA2失调控介导的琥珀酸代谢异常促进巨噬细胞炎性活化及肥胖发生

肥胖是一种炎性疾病，其进程中伴随脂肪组织巨噬细胞炎性活化加剧，该现象与巨噬细胞代谢改变密切相关，其中琥珀酸累积是重要特征。研究表明，催化琥珀酸生成的琥珀酰辅酶A合成酶β亚基（SUCLA2）的单核苷酸多样性（SNP）与代谢紊乱相关，但其自身活性调节及意义尚不清楚。申请人在巨噬细胞特异性敲除AMPK小鼠中发现巨噬细胞琥珀酸代谢紊乱及下游HIF1α通路激活，且高脂诱导后脂肪组织巨噬细胞炎性活化和肥胖加剧。结合免疫共沉淀技术，发现SUCLA2与AMPK互作并被磷酸化，影响琥珀酸代谢。据此，我们提出科学假设：SUCLA2受AMPK磷酸化并负调控其活性，控制琥珀酸生成及下游HIF1α通路激活，影响巨噬细胞炎性活化及肥胖发生。同时，SUCLA2的SNP干扰AMPK对其磷酸化调控，导致琥珀酸代谢紊乱。通过本项目研究，将为靶向调节琥珀酸代谢改善巨噬细胞炎性活化导致的肥胖提供科学依据，为肥胖治疗提供新的靶点。

Obesity is an inflammatory disease, accompanied by increased inflammatory activation of macrophages in adipose tissue. Inflammatory activation of macrophage is closely related to the metabolic changes, among which the main characteristic is succinate accumulation. It has been reported that the single nucleotide diversity (SNP) of succinyl-CoA synthetase β subunit (SUCLA2) that catalyzes succinate was related to metabolic dysfunction, but the underlying mechanism and significance of its activity regulation is still unclear. In macrophage isolated from macrophage AMPK-specific knockout mice, we found the disorder of cellular succinate metabolism and the activation of its downstream HIF1α signaling pathway. Following high-fat diet feeding, the induction of the inflammatory activation of macrophage in adipose tissue and the aggravation of obesity were observed in macrophage AMPK-specific knockout mice. Then, we confirmed that SUCLA2 interacted and with AMPK and was phosphorylated by AMPK through immunoprecipitation, affecting succinate metabolism. Thus, we hypothesized that SUCLA2 was negatively regulated by AMPK phosphorylation, controlling the production of succinate and the activation of the downstream HIF1α signaling pathway, then affecting the inflammatory activation of macrophages and the occurrence of obesity. Meanwhile, the SNP of SUCLA2 affected its phosphorylation and activity regulation by AMPK, resulting in succinate metabolic disorder. Our study provides a scientific basis for targeting the regulation of succinate metabolism to improve obesity induced by inflammatory activation of macrophages and also provides a new target for the treatment of obesity.