OR30-01 Brown Adipose Tissue as an Endocrine Organ: Multiple-omics Analysis Identifies ACBP as a Novel Brown Adipokine Secreted in Response to Brown Fat Inactivation

Abstract A. Blasco-Roset: None. T.P. Quesada-López: None. F.J. Godoy-Nieto: None. C. Garcia-Beltran: None. M. Peyrou: None. C. Rupérez: None. A. Mestres-Arenas: None. J. Villarroya: None. M. Giralt: None. L. Ibáñez: None. A. Planavila: None. F. Villarroya: None. Brown adipose tissue (BAT) activity protects against obesity and related metabolic pathologies such as diabetes and cardiovascular disease. In addition to its thermogenic activity, the endocrine role of BAT (secretion of brown adipokines or “batokines”) is suspected to be key for the health effects of active BAT. In order to identify brown adipokines, we used multiomics approaches based on cold-induced BAT stimulation in rodent models: a) bioinformatic prediction of secretability of BAT transcriptome (RNAseq), b) analysis in proteome changes in serum using non-biased proteomics, c) arterio-venous differential proteomics in blood across the interscapular BAT depot. We also analyzed samples from a cohort of one-year old children, the age in which the BAT size/body weight ratio is the highest in humans and therefore the impact of BAT secretory activity on systemic levels of putative batokines is expected to be the highest. Parallel assessment of BAT activity and potential blood batokine candidates (non-biased proteomics analysis) and further correlation analysis allowed us to validate in humans the batokine candidates identified in rodent models. A new identified batokine was Acyl-CoA Binding Protein (ACBP), also known as Diazepam Binding-Inhibitor (DBI). ACBP is expressed in BAT inversely to its degree of thermogenic activation. Systemic plasma ACPB levels as well as ACBP secretion by BAT (arterio-venous ACBP levels across interscapular BAT) were reduced in mice with activated BAT (cold-exposed), and increased after deacclimation from cold to a warmer temperature. Treatment of brown adipocytes with thermogenic stimuli (norepinephrine, cAMP) reduced the expression and secretion of ACBP in vitro. Activation of autophagy, concomitant with thermogenic inactivation of BAT, is involved in ACBP secretion by brown adipocytes. The role of BAT-specific ACBP expression and secretion on high fat diet-induced obesity and thermal adaptations was confirmed in mice specifically deficient of ACBP in BAT (CRE/Lox-based targeted ACBP gene invalidation under the control of the BAT-specific UCP1 promoter). Our data indicate that the expression and secretion of ACBP by BAT may have local effects of repression of the thermogenic activity and possibly systemic effects on other tissues involved in metabolic regulation. Our findings support the importance of BAT and its secretory capacity in the control of systemic metabolic dysfunction. Saturday, June 1, 2024