ACSL1 Is Associated With Fetal Programming of Insulin Sensitivity and Cellular Lipid Content

Abstract

Individuals who are born small for gestational age (SGA) have a risk to develop various metabolic diseases during their life course. The biological memory of the prenatal state of growth restricted individuals may be reflected in epigenetic alterations in stem cell populations. Mesenchymal stem cells (MSCs) from the Wharton's jelly of umbilical cord tissue are multipotent, and we generated primary umbilical cord MSC isolates from SGA and normal neonates, which were subsequently differentiated into adipocytes. We established chromatin state maps for histone marks H3K27 acetylation and H3K27 trimethylation and tested whether enrichment of these marks was associated with gene expression changes. After validating gene expression levels for 10 significant chromatin immunoprecipitation sequencing candidate genes, we selected acyl-coenzyme A synthetase 1 (ACSL1) for further investigations due to its key roles in lipid metabolism. The ACSL1 gene was found to be highly associated with histone acetylation in adipocytes differentiated from MSCs with SGA background. In SGA-derived adipocytes, the ACSL1 expression level was also found to be associated with increased lipid loading as well as higher insulin sensitivity. ACSL1 depletion led to changes in expression of candidate genes such as proinflammatory chemokines and down-regulated both, the amount of cellular lipids and glucose uptake. Increased ACSL1, as well as modulated downstream candidate gene expression, may reflect the obese state, as detected in mice fed a high-fat diet. In summary, we believe that ACSL1 is a programmable mediator of insulin sensitivity and cellular lipid content and adipocytes differentiated from Wharton's jelly MSCs recapitulate important physiological characteristics of SGA individuals.

The transcription factor SOX6 contributes to the developmental origins of obesity by promoting adipogenesis

“…Similar observations were made for known adipogenic genes, such as those encoding PPARγ, C/EBPα, FABP4 and FASN (Fig. S1C), in line with our published observations of a higher adipogenic potential for differentiated MSCs derived from the SGA group (Joseph et al, 2015). Western blots showing the protein levels of SOX6 in the adipocytes (Fig.…”

“…We previously published observations of significant molecular changes in Wharton's jelly-derived MSCs from SGA infants prior to (Sukarieh et al, 2014) and post (Joseph et al, 2015) adipocyte differentiation. Given its evolutionary importance and demonstration in multiple species (Hanson and Gluckman, 2014), it seems probable that multiple molecular pathways operate to predispose individuals with a history of suboptimal early-life conditions to later increased metabolic disease risk.…”

“…In our previous study, histone ChIP-seq using preadipocytes (cycle 0), intermediate adipocytes (cycle 3) and mature differentiated adipocytes (cycle 6) from two representative cell lines of SGA (MSC-01) and control group (MSC-44) of human neonates revealed notably different enrichment of H3K27 acetylation sites in adipocytes derived from the SGA background (Joseph et al, 2015). SOX6 was among the most significant genes with promoterassociated H3K27 acetylation along with lower levels of H3K27 trimethylation in adipocytes derived from the MSC-01 SGA compared with the MSC-44 control isolate (Fig.…”

“…Fetal growth characteristics were assessed by published methods (Sukarieh et al, 2014;Joseph et al, 2015). Briefly, the SGA condition was diagnosed by ultrasonography and determined as growth between the fifth and tenth percentile when compared with a control reference population.…”

“…To explore molecular mechanisms that might be important in this relationship, we previously reported the use of multipotent mesenchymal stem cells (MSCs) from the Wharton's jelly of umbilical cord (UC) tissue to generate primary UC-MSC isolates from small for gestational age (SGA) and normal neonates (Sukarieh et al, 2014). Chromatin immunoprecipitation-sequencing (ChIP-seq) studies from adipocytes differentiated from MSCs revealed candidate genes that were found to be associated with histone hyperacetylation and increased gene expression in the SGA group (Joseph et al, 2015). One gene of uncertain functional importance found in that study is SOX6 [SRY (sex determining region Y)-box 6].…”