Identification of a loss-of-function mutation in Ube2l6 associated with obesity resistance

  1. Streamson Chua1,2
  1. 1Department of Medicine and
  2. 2Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461
  1. Corresponding author: Streamson Chua, streamson.chua{at}einstein.yu.edu.

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 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.

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