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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 <i>Homeobox A5</i> (<i>HOXA5</i>) in human preadipocytes impaired differentiation in mature adipose cells in vitro. The reduced adipogenesis was accompanied by inappropriate <i>WNT</i>-signaling activation. Importantly, in preadipocytes from FDR individuals, <i>HOXA5</i> expression was attenuated, with hypermethylation of the <i>HOXA5</i> promoter region found responsible for its downregulation, as revealed by luciferase assay. Both <i>HOXA5</i> 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 <i>HOXA5</i> expression negatively correlated with enhanced transcription of the <i>WNT</i> signaling downstream genes <i>NFATC1</i> and <i>WNT2B</i>. In silico evidence indicated that <i>NFATC1</i> and <i>WNT2B</i> were directly controlled by <i>HOXA5</i>. The <i>HOXA5</i> 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, <i>HOXA5</i> controlled adipogenesis in humans by suppressing <i>WNT</i> signaling. Altered DNA methylation of the <i>HOXA5</i> promoter contributed to restricted adipogenesis in the SAT of lean subjects who were FDR of type 2 diabetics and in obese individuals.