Regulatory mechanisms underlying interleukin-6 expression in murine brown adipocytes

Three types of adipocytes, white, brown, and beige, regulate the systemic energy balance through the storage and expenditure of chemical energy. In addition, adipocytes produce various bioactive molecules known as adipokines. In contrast to white adipocyte-derived molecules, less information is available on the adipokines produced by brown adipocytes (batokine). This study explored the regulatory expression of interleukin (IL)-6 in cell culture studies. Norepinephrine or a nonselective beta-adrenergic receptor agonist increased the expression of IL-6 in primary brown adipocytes and HB2 brown adipocytes. Treatment with forskolin (Fsk), an activator of the cAMP-dependent protein kinase (PKA) pathway (downstream signaling of the beta-adrenergic receptor), efficiently stimulated IL-6 expression in brown adipocytes and myotubes. Phosphorylated CREB and phosphorylated p38 MAP kinase levels were increased in Fsk-treated brown adipocytes within 5 min. In contrast, a long-term (similar to 60 min and similar to 4 h) treatment with Fsk was required for increase in STAT3 phosphorylation and C/EBP beta expression, respectively. The PKA, p38 MAP kinase, STAT3, and C/EBP beta pathways are required for the maximal IL-6 expression induced by Fsk, which were verified by use of various inhibitors of these signal pathways. Vitamin C enhanced Fsk-induced IL-6 expression through the extracellular signal-regulated kinase activity. The present study provides basic information on the regulatory expression of IL-6 in activated brown adipocytes. White adipocytes accumulate excess energy as fat, whereas brown adipocytes consume the chemical energy of fat and carbohydrates as heat. Adipocytes also secrete bioactive molecules called adipokine. Interleukin-6 (IL-6) is produced not only in white adipocytes but also brown adipocytes, but the regulation of IL-6 expression in brown adipocytes is unclear. We explored the mechanisms underlying IL-6 gene induction in activated brown adipocytes. Forskolin increased IL-6 expression in brown adipocytes through stimulated phosphorylation of CREB, p38 MAP kinase, and STAT3. In addition, C/EBP beta induction was required for the enhancement of IL-6 induction. Vitamin C also promoted forskolin-induced IL-6 expression. The present study provides basic information on the regulatory expression of IL-6 in activated brown adipocytes.