Yoon Jeong Park^a,b,c, Sangseon Lee^d,1, Sangsoo Lim^d,1, Hahn Nahmgoong^a,b,c, Yul Ji^a,b,c, Jin Young Huh^a,b,c, Assim A. Alfadda^e, Sun Kim^d,f,g, and Jae Bum Kim^a,b,c,2

^aNational Creative Research Initiatives Center for Adipocyte Structure and Function, Seoul National University, Seoul 08826, South Korea; ^bInstitute of Molecular Biology and Genetics, Seoul National University, Seoul 08826, South Korea; ^cSchool of Biological Sciences, Seoul National University, Seoul 08826, South Korea; ^dBioinformatics Institute, Seoul National University, Seoul 08826, South Korea; ^e
Obesity Research Center, College of Medicine, King Saud University, Riyadh, 11461, Saudi Arabia; ^fDepartment of Computer Science and Engineering, Institute of Engineering Research, Seoul National University, Seoul 08826, South Korea; and ^gInterdisciplinary Program in Bioinformatics, Seoul National University, Seoul 08826, South Korea

¹S. Lee and S. Lim contributed equally to this work.
²To whom correspondence may be addressed.

White adipose tissue (WAT) is a key regulator of systemic energy metabolism, and impaired WAT plasticity characterized by enlargement of preexisting adipocytes associates with WAT dysfunction, obesity, and metabolic complications. However, the mechanisms that retain proper adipose tissue plasticity required for metabolic fitness are unclear. Here, we comprehensively showed that adipocyte-specific DNA methylation, manifested in enhancers and CTCF sites, directs distal enhancer-mediated transcriptomic features required to conserve metabolic functions of white adipocytes. Particularly, genetic ablation of adipocyte Dnmt1, the major methylation writer, led to increased adiposity characterized by increased adipocyte hypertrophy along with reduced expansion of adipocyte precursors (APs). These effects of Dnmt1 deficiency provoked systemic hyperlipidemia and impaired energy metabolism both in lean and obese mice. Mechanistically, Dnmt1 deficiency abrogated mitochondrial bioenergetics by inhibiting mitochondrial fission and promoted aberrant lipid metabolism in adipocytes, rendering adipocyte hypertrophy and WAT dysfunction. Dnmt1-dependent DNA methylation prevented aberrant CTCF binding and, in turn, sustained the proper chromosome architecture to permit interactions between enhancer and dynamin-1–like protein gene Dnm1l (Drp1) in adipocytes. Also, adipose DNMT1 expression inversely correlated with adiposity and markers of metabolic health but positively correlated with AP-specific markers in obese human subjects. Thus, these findings support strategies utilizing Dnmt1 action on mitochondrial bioenergetics in adipocytes to combat obesity and related metabolic pathology.

mitochondria, adiposity, DNA methylation, chromosome structure, metabolic disease