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KDM4B protects against obesity and metabolic dysfunction

Significance Obesity has become a major epidemic around the globe, with fatal comorbidities such as type 2 diabetes, heart disease, and cancer that have led to alarming health concerns in modern medicine. Although excess adipose tissue is associated with negative metabolic outcomes, the physiological functions of epigenetic regulators in adipose tissue and metabolism are unclear. Here we show that KDM4B in adipose tissues epigenetically controls energy expenditure, oxidation, lipolysis, and thermogenesis. Loss of Kdm4b impairs energy expenditure, adaptive thermogenesis, and adipose tissue lipolysis, resulting in obesity and associated metabolic dysfunction. Our results provide insights into control of obesity and suggest that modulation of KDM4B levels or activity may be a potential therapeutic target for human obesity. Although significant progress has been made in understanding epigenetic regulation of in vitro adipogenesis, the physiological functions of epigenetic regulators in metabolism and their roles in obesity remain largely elusive. Here, we report that KDM4B (lysine demethylase 4B) in adipose tissues plays a critical role in energy balance, oxidation, lipolysis, and thermogenesis. Loss of KDM4B in mice resulted in obesity associated with reduced energy expenditure and impaired adaptive thermogenesis. Obesity in KDM4B-deficient mice was accompanied by hyperlipidemia, insulin resistance, and pathological changes in the liver and pancreas. Adipocyte-specific deletion of Kdm4b revealed that the adipose tissues were the main sites for KDM4B antiobesity effects. KDM4B directly controlled the expression of multiple metabolic genes, including Ppargc1a and Ppara. Collectively, our studies identify KDM4B as an essential epigenetic factor for the regulation of metabolic health and maintaining normal body weight in mice. KDM4B may provide a therapeutic target for treatment of obesity.