Abstract
Along with insulin resistance and increased risk of type 2 diabetes (T2D), lean first-degree relatives of T2D subjects (FDR) feature impaired adipogenesis in subcutaneous adipose tissue (SAT) and subcutaneous adipocyte hypertrophy well before diabetes onset. The molecular mechanisms linking these events have only partially been clarified. In the present report, we show that silencing of the transcription factor Homeobox A5 (HOXA5) in human preadipocytes impaired differentiation in mature adipose cells in vitro. The reduced adipogenesis was accompanied by inappropriate WNT-signaling activation. Importantly, in preadipocytes from FDR individuals, HOXA5 expression was attenuated, with hypermethylation of the HOXA5 promoter region found responsible for its downregulation, as revealed by luciferase assay. Both HOXA5 gene expression and DNA methylation were significantly correlated with SAT adipose cell hypertrophy in FDR, whose increased adipocyte size marks impaired adipogenesis. In preadipocytes from FDR, the low HOXA5 expression negatively correlated with enhanced transcription of the WNT signaling downstream genes NFATC1 and WNT2B. In silico evidence indicated that NFATC1 and WNT2B were directly controlled by HOXA5. The HOXA5 promoter region also was hypermethylated in peripheral blood leukocytes from these same FDR individuals, which was further revealed in peripheral blood leukocytes from an independent group of obese subjects. Thus, HOXA5 controlled adipogenesis in humans by suppressing WNT signaling. Altered DNA methylation of the HOXA5 promoter contributed to restricted adipogenesis in the SAT of lean subjects who were FDR of type 2 diabetics and in obese individuals.
Highlights
In humans, the expansion of adipose tissue may include increased adipose cell size; i.e., hypertrophy and/or de novo formation of lipid-storing adipocytes from resident adipocyteprecursor cells; i.e., hyperplasia
To further investigate whether Homeobox A5 (HOXA5) is required for the expression of adipogenesis-related genes, total mRNA was collected at different time points after induction of differentiation, and GLUT4, FABP4, and ADIPONECTIN
These data suggested that a loss of HOXA5 function can lead to an impaired expression of other genes enabling a repression of adipocyte differentiation
Summary
The expansion of adipose tissue may include increased adipose cell size; i.e., hypertrophy and/or de novo formation of lipid-storing adipocytes from resident adipocyteprecursor cells; i.e., hyperplasia. An elevated ratio of hypertrophic vs hyperplastic adipose tissue has been reported in different metabolically unhealthy states, including type 2 diabetes (T2D), obesity accompanied by increased risk of T2D, and first-degree relatives of T2D individuals, even when lean and healthy [1]. These observations led to the interpretation that, at least in the subcutaneous adipose tissue (SAT), differentiation of novel adipocytes is of major importance in determining a healthy, as opposed to unhealthy, adipose tissue generation. The molecular mechanisms favoring healthy accumulation of adipose tissue, rather than excessive adipocyte hypertrophy, have been only in part elucidated
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