Constitutive loss of DNMT3A causes morbid obesity through misregulation of adipogenesis.
Ayala TovyJaime M ReyesLinda ZhangYung-Hsin HuangCarina RosasAlexes C DaquinagAnna GuzmanRaghav RamabadranChun-Wei ChenTianpeng GuSinjini GuptaLaura OrtinauDongsu ParkAaron R CoxRachel E RauSean M HartigMikhail G KoloninMargaret A GoodellPublished in: eLife (2022)
DNA Methyltransferase 3 A (DNMT3A) is an important facilitator of differentiation of both embryonic and hematopoietic stem cells. Heterozygous germline mutations in DNMT3A lead to Tatton-Brown-Rahman Syndrome (TBRS), characterized by obesity and excessive height. While DNMT3A is known to impact feeding behavior via the hypothalamus, here we investigated a role in adipocyte progenitors utilizing heterozygous knockout mice that recapitulate cardinal TBRS phenotypes. These mice become morbidly obese due to adipocyte enlargement and tissue expansion. Adipose tissue in these mice exhibited defects in preadipocyte maturation and precocious activation of inflammatory gene networks, including interleukin-6 signaling. Adipocyte progenitor cell lines lacking DNMT3A exhibited aberrant differentiation. Furthermore, mice in which Dnmt3a was specifically ablated in adipocyte progenitors showed enlarged fat depots and increased progenitor numbers, partly recapitulating the TBRS obesity phenotypes. Loss of DNMT3A led to constitutive DNA hypomethylation, such that the DNA methylation landscape of young adipocyte progenitors resemble that of older wild-type mice. Together, our results demonstrate that DNMT3A coordinates both the central and local control of energy storage required to maintain normal weight and prevent inflammatory obesity.
Keyphrases
- high fat diet induced
- insulin resistance
- dna methylation
- adipose tissue
- genome wide
- high fat diet
- metabolic syndrome
- weight loss
- gene expression
- wild type
- type diabetes
- skeletal muscle
- stem cells
- bariatric surgery
- weight gain
- fatty acid
- body mass index
- copy number
- early onset
- oxidative stress
- bone marrow
- physical activity
- obese patients
- single molecule
- cell free
- atomic force microscopy
- mass spectrometry
- cell fate