Hsu Julia Chu-Ning, Chiu Kuan-Ting, Chen Chia-Hui, Wang Chih-Hsien, Shyue Song-Kun, Lee Tzong-Shyuan
Department of Veterinary Medicine, College of Veterinary Medicine, National Chung Hsing University, 145, Xingda Road, South District, Taichung 402202, Taiwan.
Department of Physiology, School of Medicine, National Yang-Ming University, 155, Sec. 2, Linong Street, Beitou District, Taipei 112304, Taiwan.
Int J Mol Sci. 2025 Apr 29;26(9):4222. doi: 10.3390/ijms26094222.
High-mobility group box 1 (HMGB1) is a nuclear protein that can be secreted or released into the extracellular environment during cellular stress, functioning as a damage-associated molecular pattern molecule. This study investigates the role of HMGB1 in adipocyte development and metabolism, explicitly examining its interaction with β3-adrenergic receptor-mediated lipolysis and caveolin-1 (CAV1) regulation, which may influence cardiovascular risk factors. Using 3T3-L1 preadipocytes and mouse embryonic fibroblasts, we demonstrated that HMGB1 expression increases progressively during adipogenesis, reaching peak levels in mature adipocytes. While exogenous HMGB1 treatment did not affect preadipocyte proliferation or differentiation, it inhibited lipolysis in mature adipocytes. Mechanistically, HMGB1 suppressed β3-adrenergic receptor agonist CL-316,243-induced hormone-sensitive lipase activation by reducing protein kinase A-mediated phosphorylation and attenuating extracellular signal-regulated kinase signaling without affecting upstream cyclic AMP levels. We discovered a novel regulatory mechanism wherein CAV1 physically interacts with HMGB1 in mature adipocytes, with c-Src-dependent CAV1 phosphorylation functioning as a negative regulator of HMGB1 secretion. This finding was confirmed in CAV1-deficient models, which displayed increased HMGB1 secretion and diminished lipolytic activity both in vitro and in vivo. Furthermore, administering HMGB1-neutralizing antibodies to wild-type mice enhanced fasting-induced lipolysis, establishing circulating HMGB1 as a crucial antilipolytic factor. These findings reveal HMGB1's previously uncharacterized role in adipose tissue metabolism as a negative regulator of lipolysis through CAV1-dependent mechanisms. This work provides new insights into adipose tissue metabolism regulation and identifies potential therapeutic targets for obesity-related metabolic disorders and cardiovascular diseases.
高迁移率族蛋白B1（HMGB1）是一种核蛋白，在细胞应激期间可分泌或释放到细胞外环境中，作为一种损伤相关分子模式分子发挥作用。本研究调查了HMGB1在脂肪细胞发育和代谢中的作用，明确研究了其与β3-肾上腺素能受体介导的脂解作用和小窝蛋白-1（CAV1）调节的相互作用，这可能会影响心血管危险因素。使用3T3-L1前脂肪细胞和小鼠胚胎成纤维细胞，我们证明HMGB1表达在脂肪生成过程中逐渐增加，在成熟脂肪细胞中达到峰值水平。虽然外源性HMGB1处理不影响前脂肪细胞的增殖或分化，但它抑制成熟脂肪细胞中的脂解作用。从机制上讲，HMGB1通过减少蛋白激酶A介导的磷酸化并减弱细胞外信号调节激酶信号传导而不影响上游环磷酸腺苷水平，从而抑制β3-肾上腺素能受体激动剂CL-316,243诱导的激素敏感性脂肪酶激活。我们发现了一种新的调节机制，其中CAV1在成熟脂肪细胞中与HMGB1发生物理相互作用，c-Src依赖性CAV1磷酸化作为HMGB1分泌的负调节剂。这一发现在CAV1缺陷模型中得到证实，该模型在体外和体内均显示出HMGB1分泌增加和脂解活性降低。此外，向野生型小鼠施用HMGB1中和抗体可增强禁食诱导的脂解作用，确立循环HMGB1作为一种关键的抗脂解因子。这些发现揭示了HMGB1在脂肪组织代谢中以前未被描述的作用，即通过依赖CAV1的机制作为脂解的负调节剂。这项工作为脂肪组织代谢调节提供了新的见解，并确定了肥胖相关代谢紊乱和心血管疾病的潜在治疗靶点。
