DNMT3A mutations contribute to obesity through inflammation and adipogenesis

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Adipogenesis and inflammation contribute to obesity, but how they converge to preserve metabolic homeostasis remains elusive. Somatic mutations in the DNA methyltransferase DNMT3A occur frequently in hematopoietic stem-cells (HSCs), often leading to malignancy. Germline mutations cause overgrowth syndrome and obesity, suggesting a new role for DNMT3A in regulating metabolism. Since obesity triggers an inflammatory response, and inflammation is known to perturb the hematopoietic system, modeling DNMT3A patient mutations may offer insight into the interplay between inflammation, hematopoiesis, and metabolism.

Here, we demonstrate that Dnmt3a-mutant mice become obese with dysregulated adipogenesis caused by their inability to balance glycolysis, fat storage, and breakage. Mutant mice display a substantial increase in fat tissue (~50% of body weight) and adipose tissue hypertrophy with increase in activation and level of macrophages, suggesting a role for inflammation in these obese mice. Interestingly, transplanting wildtype (WT) bone marrow into mutant mice decreased weight gain. Single cell analysis revealed a unique monocyte-like population with a pro-inflammatory gene signature, such as IL6, in Dnmt3a-mutant but not WT-HSCs. Overall, these studies suggest DNMT3A mutations induce an inflammatory response, which is further amplified by defects in mutant adipose tissue. Our work provides insight into the role of DNMT3A in predisposing to obesity through dysregulated adipogenesis and increased inflammation. It also suggests that targeting the abnormal inflammatory signaling present in DNMT3A-mutant cells could be used as an early intervention to prevent DNMT3A-assicaited disease.