Inflammation induced by RAW macrophages suppresses UCP1 mRNA induction via ERK activation in 10T1/2 adipocytes.

Recently, it has been demonstrated that uncoupling protein-1 (UCP1)-expressing white adipocytes (brown-like adipocytes) are important for energy expenditure in white adipose tissue (WAT), in which energy expenditure decreases under obese conditions. However, the relationship between the induction of brown-like adipocytes and the decrease in energy expenditure in obese WAT remains to be elucidated. Here, we show that proinflammatory cytokines derived from activated macrophages suppress the induction of UCP1 promoter activity and mRNA expression via an extracellular signal-related kinase (ERK) in white adipocytes. The coculture with RAW264.7 (RAW) macrophages suppressed the induction of UCP1 mRNA expression by isoproterenol (ISO), a typical β-adrenergic receptor agonist, in C3H10T1/2 (10T1/2) adipocytes. A conditioned medium derived from lipopolysaccharide (LPS)-activated macrophages and tumor necrosis factor-α (TNF-α) also suppressed the induction of UCP1 mRNA but did not affect its mRNA stability. By using a luciferase reporter assay system, the conditioned medium and TNF-α also suppressed the activity of the UCP1 promoter and transcriptional factors binding to the cAMP response element (CRE). Importantly, PD98059, an ERK inhibitor, partially abrogated the suppression of UCP1 promoter activation and mRNA induction. These results indicate that ERK is an important factor in the suppression of UCP1 transcriptional activation in the interaction between white adipocytes and activated macrophages. This report suggests a possible mechanism of the UCP1 transcriptional suppression in white adipocytes associated with obese and diabetic conditions.