Adiponectin plays a key role in the regulation of the whole-body energy homeostasis by modulating glucose and lipid metabolism. Although obesity-induced reduction of adiponectin expression is primarily ascribed to a transcriptional regulation failure, the underlying mechanisms are largely undefined. Here we show that DNA hypermethylation of a particular region of the adiponectin promoter suppresses adiponectin expression through epigenetic control and, in turn, exacerbates metabolic diseases in obesity. Obesity-induced, pro-inflammatory cytokines promote DNMT1 expression and its enzymatic activity. Activated DNMT1 selectively methylates and stimulates compact chromatin structure in the adiponectin promoter, impeding adiponectin expression. Suppressing DNMT1 activity with a DNMT inhibitor resulted in the amelioration of obesity-induced glucose intolerance and insulin resistance in an adiponectin-dependent manner. These findings suggest a critical role of adiponectin gene epigenetic control by DNMT1 in governing energy homeostasis, implying that modulating DNMT1 activity represents a new strategy for the treatment of obesity-related diseases.

Orosomucoid (ORM), also called ␣-1 acid glycoprotein, is an abundant plasma protein that is an immunomodulator induced by stressful conditions such as infections. In this study, we reveal that Orm is induced selectively in the adipose tissue of obese mice to suppress excess inflammation that otherwise disturbs energy homeostasis. Adipose Orm levels were elevated by metabolic signals, including insulin, high glucose, and free fatty acid, as well as by the proinflammatory cytokine tumor necrosis factor-␣, which is found in increased levels in the adipose tissue of morbid obese subjects. In both adipocytes and macrophages, ORM suppressed proinflammatory gene expression and pathways such as NF-B and mitogen-activated protein kinase signalings and reactive oxygen species generation. Concomitantly, ORM relieved hyperglycemia-induced insulin resistance as well as tumor necrosis factor-␣-mediated lipolysis in adipocytes. Accordingly, ORM improved glucose and insulin tolerance in obese and diabetic db/db mice. Taken together, our results suggest that ORM integrates inflammatory and metabolic signals to modulate immune responses to protect adipose tissue from excessive inflammation and thereby from metabolic dysfunction.