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

Abstract

BackgroundA functional population of adipocyte precursors, termed adipose-derived stromal/stem cells (ASCs), is crucial for proper adipose tissue (AT) expansion, lipid handling, and prevention of lipotoxicity in response to chronic positive energy balance. We previously showed that obese human subjects contain a dysfunctional pool of ASCs. Elucidation of the mechanisms underlying abnormal ASC function might lead to therapeutic interventions for prevention of lipotoxicity by improving the adipogenic capacity of ASCs.MethodsUsing epigenome-wide association studies, we explored the impact of obesity on the methylation signature of human ASCs and their differentiated counterparts. Mitochondrial phenotyping of lean and obese ASCs was performed. TBX15 loss- and gain-of-function experiments were carried out and western blotting and electron microscopy studies of mitochondria were performed in white AT biopsies from lean and obese individuals.ResultsWe found that DNA methylation in adipocyte precursors is significantly modified by the obese environment, and adipogenesis, inflammation, and immunosuppression were the most affected pathways. Also, we identified TBX15 as one of the most differentially hypomethylated genes in obese ASCs, and genetic experiments revealed that TBX15 is a regulator of mitochondrial mass in obese adipocytes. Accordingly, morphological analysis of AT from obese subjects showed an alteration of the mitochondrial network, with changes in mitochondrial shape and number.ConclusionsWe identified a DNA methylation signature in adipocyte precursors associated with obesity, which has a significant impact on the metabolic phenotype of mature adipocytes.

Osteoporosis- and obesity-risk interrelationships: An epigenetic analysis of GWAS-derived SNPs at the developmental geneTBX15

“…Our analysis of GWAS data highlighting TBX15 as both an osteoporosis-and obesity-related gene harboring risk SNPs is consistent with the importance to bone development of TBX15 (25) and the relationships of this TF to adipose biology (20,22,23,34,66,67). It is also in accord with the interrelationships in the development of bone and adipose tissue (68) and the preferential expression of TBX15 in both adult-derived ostb and SAT.…”

“…It is also preferentially expressed in MSC (which can give rise to ostb) and chond (which are in an alternative pathway to bone formation) (23,66,69). There is also evidence for the involvement of TBX15 in modulating white and brown/brite adipocyte differentiation; mitochondrial function and oxidative or glycolytic metabolism in adipose cells; and cold-adapted adipose metabolism among the Inuit (22,23,34,66,67). In addition, this TF has a well-established role in the embryonic development of many parts of the skeleton (25,26).…”

“…In GWAS of (mostly) individuals of European ancestry (EUR) (13, 21) or of East Asians (6, 11), SNPs linked to TBX15 were identified as significantly associated with BMI, WHRadjBMI or WCadjBMI in mixed sex populations, or separately in women or men (Supplementary Material, Table S1). TBX15 codes for a Tbox transcription factor (TF) that may be involved in various aspects of adipose development and maintenance (22)(23)(24) and is known to be important in formation of the skeletal system (25,26). SNPs in or near TBX15 are significantly associated not only with obesity traits but also with estimated heel bone mineral density (eBMD), a useful indicator of hip and non-spine fractures that is used as a proxy for osteoporosis risk (27).Our study of the relationships in GWAS of TBX15 to both adipose and bone biology provides novel insights into the developmental relationships between two related tissue lineages converging on one gene.…”

Adipose stem cells from patients with Crohn’s disease show a distinctive DNA methylation pattern

“…It is now recognized that, in addition to the expected binary behavior of CpG methylation (either hypo-or hypermethylated), some cytosines show intermediate, yet low, levels of methylation [22]. Thus, we explored potential differences in the segmented methylomes as fully methylated regions (FMRs; > 50% methylated CpGs), low-methylated regions (LMRs; 3.9-50%), and unmethylated regions (UMRs; 1-3.9%), as described [22][23][24][25][26]. The FMR class comprised over 50% of the methylome in all samples (Fig.…”

“…2a (right panel), with the majority located in the open sea region (> 50%). We found that 35% of methylation sites occurred in the promoter region (including TSS 1500, TSS 200, and 5′ UTR), which is related to gene silencing [23,27] (Fig. 2b).…”