title: 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.
abstract: We hypothesized that certain proteins encoded by temperature-responsive genes in brown adipose tissue (BAT) contribute to the remarkable metabolic shifts observed in this tissue, thus prompting a differential mRNA expression analysis to identify candidates involved in this process in mouse BAT. An mRNA species corresponding to a novel partial-length gene was found to be induced 2-3-fold above the control following cold exposure (4 degrees C), and repressed approximately 70% by warm acclimation (33 degrees C, 3 weeks) compared with controls (22 degrees C). The gene displayed robust BAT expression (i.e. approximately 7-100-fold higher than other tissues in controls). The full-length murine gene encodes a 594 amino acid ( approximately 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 1 (human) and 4 (mouse) associated with body fatness and diet-induced obesity, potentially linking a deficit of BFIT activity with exacerbation of these traits. Consistent with this notion, BFIT mRNA was significantly higher ( approximately 1.6-2-fold) in the BAT of obesity-resistant compared with obesity-prone mice fed a high-fat diet, and was 2.5-fold 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.
authors.affiliation: Department of Endocrinology, Genentech, Inc., South San Francisco, CA 94080, USA. sean.adams@pharma.novartis.com
authors.forename: S H
authors.initials: SH
authors.lastname: Adams
authors.forename: C
authors.initials: C
authors.lastname: Chui
authors.forename: S L
authors.initials: SL
authors.lastname: Schilbach
authors.forename: X X
authors.initials: XX
authors.lastname: Yu
authors.forename: A D
authors.initials: AD
authors.lastname: Goddard
authors.forename: J C
authors.initials: JC
authors.lastname: Grimaldi
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.forename: P
authors.initials: P
authors.lastname: Dowd
authors.forename: S
authors.initials: S
authors.lastname: Colman
authors.forename: D A
authors.initials: DA
authors.lastname: Lewin
mesh_terms: D000273:Adipose Tissue / Q000201:enzymology*; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D003001:Cloning, Molecular; D003080:Cold Temperature; D018076:DNA, Complementary / Q000378:metabolism; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009765:Obesity / Q000235:genetics*; D016366:Open Reading Frames; D010170:Palmitoyl-CoA Hydrolase / Q000096:biosynthesis* / Q000737:chemistry* / Q000235:genetics*; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D021101:Radiation Hybrid Mapping; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D013696:Temperature; D014018:Tissue Distribution
chemical_list: D000596:Amino Acids; D018076:DNA, Complementary; D012333:RNA, Messenger; C499088:ACOT11 protein, human; C441288:Thea protein, mouse; D010170:Palmitoyl-CoA Hydrolase