Intracellular ATP in balance of pro- and anti-inflammatory cytokines in adipose tissue with and without tissue expansion.

OBJECTIVES: To understand the mechanism of white fat expansion in the presence of inflammation, we examined the balance of pro- and anti-inflammatory cytokines in epididymal fat during weight gain in diet-induced obese mice.

METHODS: The pro- and anti-inflammatory cytokines were examined in white fat of diet-induced obese mice and lean mice. The mechanism of gene expression was investigated with a focus on intracellular ATP (iATP). ATP activity was tested in cellular and non-cellular systems in activation of serine kinases (IKKβ, JNK and ERK).

RESULTS: The pro- (tumor necrosis factor-α (TNF-α), interleukin-1 beta (IL-1β), IL-6, monocyte chemoattractant protein 1, interferon gamma and osteopontin) and the anti-inflammatory cytokines (IL-10, IL-1Ra, IL-13, soluble TNF receptor 2, pigment epithelium-derived factor and adiponectin) were increased at the same time during the weight gain. The balance was observed even in the absence of tissue expansion upon feeding in lean and obese mice. The iATP levels were positively associated with the cytokine elevation in the adipose tissue. In macrophages, induction of iATP with lauric acid stimulated the expression. Inhibition of iATP with β-oxidation inhibitor (Etomoxir) or mitochondrial uncoupler (2,4-dinitrophenol, DNP) suppressed the expression. ATP exhibited an activity in the activation of inflammatory kinases (IKKβ, JNK and ERK) in the living cells and cell lysate. The kinase activation was blocked in the cells by ATP inhibition.

CONCLUSIONS: The data suggest that the pro- and anti-inflammatory cytokines are dynamically balanced in the white adipose tissue by iATP.