title: Identification of a loss-of-function mutation in Ube2l6 associated with obesity resistance.
abstract: We previously mapped a locus on BALB/c chromosome 2 associated with protection from leptin-deficiency-induced obesity. Here, we generated the corresponding congenic mouse strain by introgression of a segment of C57BL/6J chromosome 2 to the BALB/c background to confirm the genotype-phenotype associations. We found that the BALB/c alleles decreased fat mass expansion by limiting adipocyte hyperplasia and adipocyte hypertrophy. This was concomitant to an increase in adipocyte triglyceride lipase (ATGL)-mediated triglyceride breakdown and prolongation of ATGL half-life in adipose tissue. In addition, BALB/c alleles on chromosome 2 exerted a cell-autonomous role in restraining the adipogenic potential of preadipocytes. Within a 9.8-Mb critical interval, we identified a nonsynonymous coding single nucleotide polymorphism in the gene coding for the ubiquitin-conjugating enzyme E2L6 (Ube2l6, also known as Ubch8) and showed that the BALB/c allele of Ube2l6 is a hypomorph leading to the lack of UBE2L6 protein expression. Ube2l6 knockdown in 3T3-L1 adipocytes repressed adipogenesis. Thus, altered adipogenic potential caused by Ube2l6 knockdown is likely critically involved in BALB/c obesity resistance by inhibiting adipogenesis and reducing adipocyte numbers. Overall, we have identified a loss-of-function mutation in Ube2l6 that contributes to the chromosome 2 obesity quantitative trait locus.
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Marcelin
authors.forename: Shun-Mei
authors.initials: SM
authors.lastname: Liu
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Schwartz
authors.forename: Streamson C
authors.initials: SC
authors.lastname: Chua
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D050156:Adipogenesis / Q000235:genetics*; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism*; D000483:Alleles; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002454:Cell Differentiation; D004734:Energy Metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D040641:Quantitative Trait Loci; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics* / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D044763:Ubiquitin-Conjugating Enzymes
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