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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE285403 | GEO | 2025/05/08

REPOSITORIES: GEO

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Project description:Brown adipose tissue (BAT) is a major site of nonshivering thermogenesis (NST) in mammals and might play an important role in human obesity and energy homeostasis. Recent single-cell/nucleus RNA-sequencing studies have revealed heterogeneity in thermogenesis among brown adipocytes, such as the findings of low thermogenesis and regulated thermogenesis in brown adipocytes. Activating and enhancing function adipocytes (BAC) has acquired attention as a possible therapeutic intervention for metabolic diseases. Nuclear factor-erythroid 2-related factor 1 (NFE2L1, also known as Nrf1), a CNC-bZIP protein, is a master regulator of multiple cellular functions and responds to various stress in many cells and tissues. NFE2L1 acts as a guardian role in BAC function providing increased proteometabolic quality control for adapting to cold or obesity. Our previous studies demonstrated that NFE2L1-dependent lipolytic activity is crucial for white adipose tissue (WAT) plasticity and lipid homeostasis. To further clarify the role of NFE2L1 in adipocytes, we focused on the phenotype and gene expression profiling of BAT in adipocyte-specific Nfe2l1-knockout [Nfe2l1(f)-KO] mice. We found that deletion of Nfe2l1 decreased core body temperature and cold intolerance under cold exposure. Compared with floxed mice, the BAT of Nfe2l1(f)-KO mice expressed substantially lower levels of many genes related to lipolysis, thermogenesis, oxidative capacity of mitochondria, cellular respiration while higher genes related to inflammation, pyroptosis. By snRNA-seq, we found that Nfe2l1-knockout resulted in increased antigen processing and presentation (APP), necroptosis and NOD-like receptor signal pathway (NOD) signaling pathways in most subpopulations of BAC, with devastating effects on a normal subpopulation of BAC with low thermogenesis and high necroptosis genes expression. Absent of Nfe2l1 impairs the function of BAC, causing a morphological “whitening” phenotype with adipocyte hypertrophy and severe inflammation. Moreover, the adipose inflammation and pyroptosis in Nfe2l1(f)-KO mice could be mitigated by cold exposure or β3-agonist treatment. These findings provided a deeper insight into the function of NFE2L1 in the metabolic programming of brown adipocytes.

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

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