BFIT, a unique acyl-CoA thioesterase induced in thermogenic brown adipose tissue: cloning, organization of the human gene and assessment of a potential link to obesity

We hypothesized that certain proteins encoded by temperature-responsive gen es in brown adipose tissue (BAT) contribute to the remarkable metabolic shi fts observed in this tissue, thus prompting a differential mRNA expression analysis to identify candidates involved in this process in mouse BAT. An m RNA species corresponding to a novel partial-length gene was found to be in duced 2-3-fold above the control following cold exposure (4 degreesC), and repressed approximate to 70% by warm acclimation (33 degreesC, 3 weeks) com pared with controls (22 degreesC). The gene displayed robust BAT expression (i.e. approximate to 7-100-fold higher than other tissues in controls). Th e full-length murine gene encodes a 594 amino acid (approximate to 67 kDa) open reading frame with significant homology to the human hypothetical acyl -CoA thioesterase KIAA0707. Based on cold-inducibility of the gene and the presence of two acyl-CoA thioesterase domains, we termed the protein brown- fat-inducible thioesterase (BFIT). Subsequent analyses and cloning efforts revealed the presence of a novel splice variant in humans (termed hBFIT2), encoding the orthologue to the murine BAT gene. BFIT was mapped to syntenic regions of chromosomes I (human) and 4 (mouse) associated with body fatnes s and diet-induced obesity, potentially linking a deficit of BFIT activity with exacerbation of these traits. Consistent with this notion, BFIT mRNA w as significantly higher (approximate to1.6-2-fold) in the BAT of obesity-re sistant compared with obesity-prone mice fed a high-fat diet, and was 2.5-f old higher in controls compared with ob/ob mice. Its strong, cold-inducible BAT expression in mice suggests that BFIT supports the transition of this tissue towards increased metabolic activity, probably through alteration of intracellular fatty acyl-CoA concentration.