Blasco-Roset Albert, Quesada-López Tania, Mestres-Arenas Alberto, Villarroya Joan, Godoy-Nieto Francisco J, Cereijo Rubén, Rupérez Celia, Neess Ditte, Færgeman Nils J, Giralt Marta, Planavila Anna, Villarroya Francesc
Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain; Institut de Recerca de Sant Joan de Déu, 08028 Barcelona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, 28029 Madrid, Spain.
Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain; Institut de Recerca de Sant Joan de Déu, 08028 Barcelona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, 28029 Madrid, Spain; Institut d'Investigació Biomèdica Sant Pau (IIB-SANT PAU), Barcelona, Spain; Department of Infectious Diseases, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain.
Mol Metab. 2025 Jun;96:102153. doi: 10.1016/j.molmet.2025.102153. Epub 2025 Apr 11.
Defective activity of brown adipose tissue (BAT) is linked to obesity and cardiometabolic diseases. While much is known regarding the biological signals that trigger BAT thermogenesis, relatively little is known about the repressors that may impair BAT function in physiological and pathological settings. Acyl CoA-binding protein (ACBP; also known as diazepam binding inhibitor, DBI) has intracellular functions related to lipid metabolism and can be secreted to act as a circulating regulatory factor that affects multiple organs. Our objective was to determine the role of ACBP in BAT function.
Experimental models based on the targeted inactivation of the Acbp gene in brown adipocytes, both in vitro and in vivo, as well as brown adipocytes treated with recombinant ACBP, were developed and analyzed for transcriptomic and metabolic changes.
ACBP expression and release in BAT are suppressed by noradrenergic cAMP-dependent signals that stimulate thermogenesis. This regulation occurs through gene expression modulation and autophagy-related processes. Mice with targeted ablation of Acbp in brown adipocytes exhibit enhanced BAT thermogenic activity and protection against high-fat diet-induced obesity and glucose intolerance; this is associated with BAT transcriptome changes, including upregulation of BAT thermogenesis-related genes. Treatment of brown adipocytes with exogenous ACBP suppresses oxidative activity, lipolysis, and thermogenesis-related gene expression. ACBP treatment inhibits the noradrenergic-induced phosphorylation of p38 MAP-kinase and CREB, which are major intracellular mediators of brown adipocyte thermogenesis.
The ACBP system acts as a crucial auto regulatory repressor of BAT thermogenesis that responds reciprocally to the noradrenergic induction of BAT activity.
棕色脂肪组织（BAT）活性缺陷与肥胖及心脏代谢疾病相关。虽然我们对触发BAT产热的生物信号了解颇多，但对于在生理和病理环境中可能损害BAT功能的抑制因子却知之甚少。酰基辅酶A结合蛋白（ACBP；也称为地西泮结合抑制剂，DBI）具有与脂质代谢相关的细胞内功能，并且可以分泌出来作为一种循环调节因子，影响多个器官。我们的目的是确定ACBP在BAT功能中的作用。
建立了基于体外和体内棕色脂肪细胞中Acbp基因靶向失活的实验模型，以及用重组ACBP处理的棕色脂肪细胞，并对其转录组和代谢变化进行分析。
刺激产热的去甲肾上腺素能cAMP依赖性信号可抑制BAT中ACBP的表达和释放。这种调节通过基因表达调控和自噬相关过程发生。棕色脂肪细胞中Acbp基因靶向缺失的小鼠表现出增强的BAT产热活性，并对高脂饮食诱导的肥胖和葡萄糖不耐受具有保护作用；这与BAT转录组变化有关，包括BAT产热相关基因的上调。用外源性ACBP处理棕色脂肪细胞可抑制氧化活性、脂解作用和产热相关基因的表达。ACBP处理可抑制去甲肾上腺素能诱导的p38丝裂原活化蛋白激酶和CREB的磷酸化，而p38丝裂原活化蛋白激酶和CREB是棕色脂肪细胞产热的主要细胞内介质。
ACBP系统作为BAT产热的关键自动调节抑制因子，对BAT活性的去甲肾上腺素能诱导做出反向反应。
