Adipocyte-Derived Th2 Cytokines and Myeloid PPARδ Regulate Macrophage Polarization and Insulin Sensitivity

Abstract

The polarization of adipose tissue-resident macrophages toward the alternatively activated, anti-inflammatory M2 phenotype is believed to improve insulin sensitivity. However, the mechanisms controlling tissue macrophage activation remain unclear. Here we show that adipocytes are a source of Th2 cytokines, including IL-13 and to a lesser extent IL-4, which induce macrophage PPARdelta/beta (Ppard/b) expression through a STAT6 binding site on its promoter to activate alternative activation. Coculture studies indicate that Ppard ablation renders macrophages incapable of transition to the M2 phenotype, which in turns causes inflammation and metabolic derangement in adipocytes. Remarkably, a similar regulatory mechanism by hepatocyte-derived Th2 cytokines and macrophage PPARdelta is found to control hepatic lipid metabolism. The physiological relevance of this paracrine pathway is demonstrated in myeloid-specific PPARdelta(-/-) mice, which develop insulin resistance and show increased adipocyte lipolysis and severe hepatosteatosis. These findings provide a molecular basis to modulate tissue-resident macrophage activation and insulin sensitivity.

Pathological Role of Adipose Tissue Dysfunction in Cardio-Metabolic Disorders

“…There is evidence that inflammation of WAT, which is characterized by infiltration of inflammatory cells and increased production of pro-inflammatory cytokines by these immune cells or resident senescent cells, induces systemic insulin resistance and accelerates the development of diabetes. 9,34,42,43) Excessive energy intake results in the hypertrophy of adipocytes by increasing the influx of fatty acids into these cells and promotes a pro-inflammatory phenotype in adipose tissue. These changes up-regulate the production of various chemoattractants, including chemokine (C-C motif) ligand 2 (CCL2), which is also known as monocyte chemoattractant protein-1 (MCP-1).…”

Adipose tissue inflammation and ectopic lipid accumulation [Review]

“…Indeed, deficiency of Toll-like receptor 4 (TLR4) or TLR4 signaling protects against obesity-induced M1 macrophage polarization and adipose tissue inflammation in vivo [25][26][27][28]. On the other hand, peroxisome proliferatoractivated receptor γ (PPARγ) and PPARδ stimulate M2 polarization of adipose tissue macrophages and thus improve systemic insulin sensitivity [29][30][31]. Indeed, activation of PPARγ by pioglitazone, a thiazolidinedione class of insulin sensitizer, improves the unbalanced M1/M2 phenotype of adipose tissue macrophages in diet-induced obese mice [32].…”

Recent Advances in the Study on Resveratrol

“…These phenotypic changes act to dampen inflammation and maintain homeostasis, avoiding metabolic problems such as insulin resistance. 40,41) Furthermore, prostacyclin analogues have been reported as ligands for PPARβ/δ. 42) Vaticanol C, a resveratrol tetramer, activates PPARα and PPARβ/δ in vitro (5 μM) and in vivo (0.04% of diet for 8 weeks), but has no effect on SIRT1 activation.…”