SLC25A24 as a novel susceptibility gene for low fat mass in humans and mice.

CONTEXT

Genetic factors contribute to the development of obesity.

OBJECTIVE

The aim of this study was to identify novel genes that regulate body fat mass.

DESIGN

We performed a search for single nucleotide polymorphisms (SNPs) associated with body fat percentage using SNP arrays and undertook a replication study and animal study.

SETTING AND PATIENTS

Baseline examinations were conducted in 251 (first-stage analysis), 499 (second-stage analysis), and 732 (additional analyses) Japanese postmenopausal women. The mean age (mean ± SD) of the subjects was 66.5 ± 9.4 years. We also analyzed the fat-related phenotypes of a candidate gene in knockout mice.

RESULTS

In the analysis of total body fat, we focused on an SNP of SLC25A24 that showed the lowest significant P value obtained from multiple comparison tests among Japanese postmenopausal women. A significant association was also found between SLC25A24 SNPs and body mass index in the 1482 Japanese postmenopausal women examined in the study. The SLC25A24 SNPs affected the mRNA expression of SLC25A24 in human preadipocytes. Compared with wild-type mice, Slc25a24-KO mice had significantly lower body weights and white adipose tissue weights. Adipocyte differentiation was inhibited in Slc25a24-KO adipose tissues and Slc25a24-knockdown adipocytes.

CONCLUSIONS

Genetic analyses in human and mouse models revealed the importance of SLC25A24/Slc25a24 in the regulation of body fat mass and adipogenesis.