White adipose tissue (WAT) expands by increasing adipocyte number (hyperplasia) and size (hypertrophy). Their relative importance differs between individuals resulting in alternate adipose morphologies. Hypertrophic WAT is the pernicious morphology, which is associated with dyslipidemia, insulin resistance, and T2D. Kerr and colleagues tested whether WAT morphology is epigenetically regulated and performed CpG-methylome profiling on abdominal subcutaneous adipocytes from a large cohort of women. Their results support the notion that differential CpG-methylation in adipocytes is linked to hypertrophic WAT morphology predisposing to T2D.
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In 1975, Arion and colleagues discovered that hepatocytes release glucose into the bloodstream in response to hypoglycaemia using the glucose-6-phosphatase (G6Pase) system. This system is in the endoplasmic reticulum (ER) and is composed of two functionally linked proteins, a G6P transporter subunit (G6PT) and a catalytic subunit called G6P phosphatase (G6Pase). The G6PT subunit promotes the storage of G6P inside the ER, while G6Pase, which has its catalytic domain in the reticular lumen, hydrolyses G6P to yield free glucose + phosphate. The free glucose stored in the reticular lumen can be transported to the cytosol and from there to the extracellular space in hypoglycaemic conditions by a direct mechanism that has not yet been established, but eventually by glucose transporters (GLUTs).
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Epigenetic regulation of diabetogenic adipose morphology
Objective: Hypertrophic white adipose tissue (WAT) morphology is associated with insulin resistance and type 2 diabetes. The mechanisms governing hyperplastic versus hypertrophic WAT expansion are poorly understood. We assessed if epigenetic modifications in adipocytes are associated with hypertrophic adipose morphology. A subset of genes with differentially methylated CpG-sites (DMS) in the promoters was taken forward for functional evaluation.
Methods: The study included 126 women who underwent abdominal subcutaneous biopsy to determine adipose morphology. Global transcriptome profiling was performed on WAT from 113 of the women, and CpG methylome profiling on isolated adipocytes from 78 women. Small interfering RNAs (siRNA) knockdown in human mesenchymal stem cells (hMSCs) was used to assess influence of specific genes on lipid storage.
Results: A higher proportion of CpG-sites were methylated in hypertrophic compared to hyperplastic WAT. Methylation at 35,138 CpG-sites was found to correlate to adipose morphology. 2,102 of these CpG-sites were also differentially methylated in T2D; 98% showed directionally consistent change in methylation in WAT hypertrophy and T2D. We identified 2,508 DMS in 638 adipose morphology-associated genes where methylation correlated with gene expression. These genes were over-represented in gene sets relevant to WAT hypertrophy, such as insulin resistance, lipolysis, extracellular matrix organization, and innate immunity. siRNA knockdown of ADH1B, AZGP1, C14orf180, GYG2, HADH, PRKAR2B, PFKFB3, and AQP7 influenced lipid storage and metabolism.
Conclusions: CpG methylation could be influential in determining adipose morphology and thereby constitute a novel antidiabetic target. We identified C14orf180 as a novel regulator of adipocyte lipid storage and possibly differentiation.