Identification of a loss-of-function mutation in ube2l6 associated with obesity resistance

Genevieve Marcelin, Shun Mei Liu, Gary J. Schwartz, Streamson C. Chua, Jr.

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2784-2795
Number of pages12
JournalDiabetes
Volume62
Issue number8
DOIs
StatePublished - Aug 2013

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Adipocytes
Chromosomes, Human, Pair 2
Obesity
Mutation
Adipogenesis
Alleles
Lipase
Ubiquitin-Conjugating Enzymes
Congenic Mice
Quantitative Trait Loci
Genetic Association Studies
Leptin
Hypertrophy
Hyperplasia
Single Nucleotide Polymorphism
Half-Life
Adipose Tissue
Triglycerides
Fats
Genes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

Cite this

Identification of a loss-of-function mutation in ube2l6 associated with obesity resistance. / Marcelin, Genevieve; Liu, Shun Mei; Schwartz, Gary J.; Chua, Jr., Streamson C.

In: Diabetes, Vol. 62, No. 8, 08.2013, p. 2784-2795.

Research output: Contribution to journalArticle

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