ACBP in brown adipose tissue acts as a negative regulator of adaptive thermogenesis

The defective activity of brown adipose tissue (BAT) is linked to obesity and cardiometabolic diseases. While there is extensive knowledge about the biological signals that trigger BAT thermogenesis, information regarding active repressors that may contribute to the pathological impairment of BAT function is quite limited. Acyl CoA-Binding Protein (ACBP), also known as Diazepam Binding Inhibitor (DBI), is a protein with intracellular functions related to lipid metabolism. It can also be secreted and act as a circulating regulatory factor that affects multiple tissues and organs. We discovered that ACBP expression and release in BAT are suppressed by noradrenergic, cAMP-dependent signals that stimulate thermogenesis. This regulation occurs through mechanisms involving gene expression and autophagy-related processes. Mice with targeted ablation of the Acbp gene in brown adipocytes exhibit enhanced BAT thermogenic activity and protection against obesity and glucose intolerance induced by a high-fat diet. This is associated with a remodeling of the BAT transcriptome, characterized by the induction of genes related to BAT thermogenesis. Treatment of brown adipocytes with exogenous ACBP suppressed oxidative activity, lipolysis, and the expression of genes associated with thermogenesis. ACBP inhibits the noradrenergic-induced phosphorylation of p38 MAP kinase and CREB, major intracellular mediators of brown adipocyte thermogenesis. Our findings identify the ACBP system as a crucial auto-regulatory repressor of BAT thermogenesis, which responds reciprocally to the noradrenergic induction of BAT activity.