Adipocyte-secreted IL-6 sensitizes macrophages to IL-4 signaling

Complex bidirectional crosstalk between adipocytes and adipose tissue immune cells plays an important role in regulating adipose function, inflammation, and insulin responsiveness. Adipocytes secrete the pleiotropic cytokine IL-6 in response to both inflammatory and catabolic stimuli. Previous studies suggest that IL-6 secretion from adipocytes in obesity may promote adipose tissue inflammation. Here we investigated catabolic stimulation of adipocyte IL-6 secretion and its impact on adipose tissue immune cells. In obesity, catecholamine resistance reduces cAMP-driven adipocyte IL-6 secretion in response to catabolic signals. By restoring adipocyte catecholamine sensitivity in obese adipocytes, amlexanox stimulates adipocyte-specific IL-6 secretion. Here we report that in this context, adipocyte secreted IL-6 activates local macrophage STAT3 to promote Il4ra expression, thereby sensitizing them to IL-4 signaling, and promoting an anti-inflammatory gene expression pattern. Supporting a paracrine adipocyte to macrophage mechanism, these effects could be recapitulated using adipocyte conditioned media to pretreat bone marrow derived macrophages prior to polarization with IL-4. The effects of IL-6 signaling in the adipose tissue are complex and context specific. These results suggest that cAMP driven IL-6 secretion from adipocytes sensitizes adipose tissue macrophages to IL-4 signaling.</p

Additional file 1 of Xanthine oxidase inhibitor urate-lowering therapy titration to target decreases serum free fatty acids in gout and suppresses lipolysis by adipocytes

Additional file 1: Supplementary Figure 1. PLS-DA and RF analysis of serum metabolomic profiling at time zero. PLS-DA and RF analysis at time zero resulted in a good discrimination and prediction of the samples per BMI (A), but not per number of flares (B), or hyperuricemia (HU) > 8 mg/dL (C), or presence of tophi (D). Supplementary Figure 2. XOI-based ULT effects on serum metabolomic profiling. (A) PCA examining samples at time zero as well as at 12 and 24 weeks ULT titration to target. (B) Hierarchical clustering analysis at three time points. (C) Random Forest (RF) analysis using metabolite data derived from sera collected at baseline, or at 12 and 24 weeks ULT titration to target. (D) Top metabolites generated by RF analysis resulted in predictive accuracy of 52% (compared to 33% expected by random chance alone). Supplementary Figure 3. Validation of XOI-based ULT effects on xanthine and purine metabolism by serum metabolomic profiling. (A) Levels of ULT drugs included in the treatment and in metabolites related to purine and xanthine metabolism were significantly elevated in samples collected at 12- and 24-weeks treatment. Green: indicates significant difference (p≤0.05) between the groups shown, metabolite ratio of < 1.00. Light Green: narrowly missed statistical cutoff for significance 0.0

Additional file 3 of Xanthine oxidase inhibitor urate-lowering therapy titration to target decreases serum free fatty acids in gout and suppresses lipolysis by adipocytes

Additional file 3. Supplementary methods

Additional file 2 of Xanthine oxidase inhibitor urate-lowering therapy titration to target decreases serum free fatty acids in gout and suppresses lipolysis by adipocytes

Additional file 2: Supplementary Table 1. Included the 1105 compounds of known identity from the Metabolon platform. Supplementary Table 2. Relative levels of fatty acids identified in the UCSD cohort. Supplementary Table 3. Fatty acids identified in the Omaha cohort. Concentrations are reported in pmol/mL of plasma