ISSN 1662-4009 (Online)

ESPE Yearbook of Paediatric Endocrinology (2019) 16 11.6 | DOI: 10.1530/ey.16.11.6

Adipose tissue mitochondrial dysfunction in human obesity is linked to a specific DNA methylation signature in adipose-derived stem cells

Ejarque M, Ceperuelo-Mallafré V, Serena C, Maymo-Masip E, Duran X, Díaz-Ramos A, Millan-Scheiding M, Núñez-Álvarez Y, Núñez-Roa C, Gama P, Garcia-Roves PM, Peinado MA, Gimble JM, Zorzano A, Vendrell J & Fernández-Veledo S


Hospital Universitari de Tarragona Joan XXIII-Institut d’Investigació Sanitària Pere Virgili-Universitat Rovira i Virgili, Tarragona, Spain, sonia.fernandezveledo@gmail.com


To read the full abstract: Int J Obes (Lond). 2019;43(6):1256–1268

This epigenome-wide association study in stromal/stem cells (ASCs), derived from subcutaneous adipose tissue samples of lean and obese subjects, revealed a specific DNA methylation signature in adipocyte precursors associated with obesity, which has a significant impact on the metabolic phenotype and the mitochondrial function of mature adipocytes.

These authors hypothesized that an obesogenic environment influences the methylation status of genes in human adipose-derived stem cells (hASCs), which might contribute to the contrasting differentiation and functional capacities of adult adipocytes to promote dysfunctional white adipose tissue. First, they conducted an epigenome-wide association study in DNA from subcutaneous adipose tissue of healthy lean (n=6) and obese (n=6; mean BMI 30 kg/m2) adults, and separately considered methylation levels in hASC and adipocytes. In hASC they observed 650 differently methylated sites between lean and obese subjects. Interestingly, this methylation signature was similar in hASCs and adipocytes. They looked closer at the 10 genes with the largest methylation changes between lean and obese subjects. Of these, 5 genes (TBX15, PRDM16, ACLY, GLI2, LSP1) showed an inverse relationship between DNA methylation intensity and mRNA expression. TBX15 was examined in more detail since it was highly regulated at epigenetic level. TBX15 is a transcription factor that is essential for many developmental processes. In TBX15-silenced obese ASCs, expression levels were decreased for genes involved in fatty acid transport, oxidation, glucose uptake, glycolysis and TCA cycle. This suggests a potential role for TBX15 in the mitochondrial and/or metabolic phenotype of mature adipocytes in an obesity context.

The strength of the study lies in the fact that the authors not only describe differences in the DNA methylation profile in ASCs derived from lean and obese subjects. But they went further by testing the relevance of DNA methylation to gene expression, and then performed experimental modulation of the gene (TBX15) with the greatest methylation difference. One limitation is that the authors examined only the effect of relatively mild obesity on mitochondrial and/or metabolic phenotype. Further studies on extreme obesity would be desirable.