Editors' ChoiceObesity

SOX to be fat

Sci. Signal.  22 Mar 2016:
Vol. 9, Issue 420, pp. ec66
DOI: 10.1126/scisignal.aaf7082

Although diet and lifestyle are certainly major factors influencing the development of obesity and metabolic disease, genetic and epigenetic factors also contribute. Low birth weight is associated with the tendency to develop obesity in adult life. Leow et al. isolated mesenchymal stem cells from the umbilical cords of normal- and low-weight neonates, differentiated them into adipocytes in culture, and compared patterns of histone modifications between the two cell types. Histone modifications at the promoter of the gene encoding the transcription factor SOX6 suggested that this gene might be more actively transcribed in adipocytes from low-weight neonates. Indeed, in addition to showing increased expression of several known adipogenic markers, adipocytes derived from low-weight neonates had a greater abundance of SOX6 transcripts and SOX6 protein. In mesenchymal stem cell–derived adipocytes and in several human and mouse adipocyte cell lines, knocking down SOX6 reduced lipid droplet formation and triglyceride content, whereas overexpressing SOX6 increased cellular triglyceride content. Gene expression analyses and chromatin immunoprecipitation assays in wild-type and SOX6-knockdown adipocytes indicated that SOX6 directly stimulated the expression of MEST (mesoderm-specific transcript) and PPARG (peroxisome proliferator–activated receptor γ), both of which promote adipogenesis. The MEST promoter showed reduced CpG methylation in adipocytes derived from low-weight neonates compared with those derived from normal-weight neonates. Mobility shift assays demonstrated that CpG methylation reduced SOX6 binding to the MEST promoter, implying that more SOX6 could bind to the MEST promoter in adipocytes from low-weight neonates. Experiments in cultured adipocytes also suggested that SOX6 may reduce antiadipogenic Wnt signaling. The adipocytes of zebrafish sox6 mutants had fewer lipid droplets than adipocytes of wild-type animals, and knocking down Sox6 in mice reduced the expression of adipogenic markers in white adipose tissue, reduced serum and liver triglycerides, and reduced the abundance of the circulating adipokine leptin. These findings imply that one of the ways that epigenetic changes in infants who are small for their gestational age predispose these individuals to obesity later in life is by increasing the expression of SOX6, which seems to promote adipogenesis through multiple mechanisms.

S. C. Leow, J. Poschmann, P. G. Too, J. Yin, R. Joseph, C. McFarlane, S. Dogra, A. Shabbir, P. W. Ingham, S. Prabhakar, M. K. S. Leow, Y. S. Lee, K. L. Ng, Y. S. Chong, P. D. Gluckman, W. Stünkel, The transcription factor SOX6 contributes to the developmental origins of obesity by promoting adipogenesis. Development 143, 950–961 (2016). [PubMed]