Epigenetic Dysregulation of the Homeobox A5 (HOXA5) Gene Associates with Subcutaneous Adipocyte Hypertrophy in Human Obesity

• 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. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)

Nyckelord

Adipocyte hypertrophy

Adipose tissue

DNA methylation

Epigenetic marks

Gene expression

Human adipogenesis

Obesity

Preadipocyte

T2D familiarity

Transcription factors

adiponectin

fatty acid binding protein 4

glucose transporter 4

homeobox protein Hox-A5

transcription factor

transcription factor NFAT

unclassified drug

vinculin

Wnt2 protein

adipocyte

adipogenesis

Article

bisulfite sequencing

cell differentiation

cell isolation

controlled study

differential gene expression

epigenetics

first-degree relative

gene

gene silencing

genetic transcription

HOXA5 gene

human

human cell

hypertrophy

in vitro study

leukocyte

luciferase assay

mRNA expression level

non insulin dependent diabetes mellitus

proadipocyte

protein expression level

real time polymerase chain reaction

subcutaneous adipocyte hypertrophy

Western blotting

Wnt signaling

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)