Identification of a loss-of-function mutation in Ube2l6 associated with obesity resistance
- 1Department of Medicine and
- 2Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461
- Corresponding author: Streamson Chua, .
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 ATGL (adipocyte triglyceride lipase)-mediated triglyceride breakdown and prolongation of ATGL half-life in adipose tissue. In addition, BALB/c alleles on chr.2 exerted a cell autonomous role in restraining the adipogenic potential of pre-adipocytes. Within a 9.8-Mb critical interval, we identified a non-synonymous coding SNP 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 knock-down 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 chr.2 obesity QTL.
- Received August 3, 2012.
- Accepted March 27, 2013.
- © 2013 by the American Diabetes Association.
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