Macrophage alternative activation in obesity and metabolic syndrome

Complex interplay between T helper (Th) cells and macrophages contributes to the formation and progression of chronic inflammatory diseases. While Th1 cytokines promote inflammatory activation of macrophages, Th2 cytokines attenuate macrophage-mediated inflammation and enhance reparative functions. In spite of its biologic importance, the biochemical and molecular basis of how Th2 cytokines promote maturation of anti-inflammatory macrophages is not understood. Using both gain- and loss-of-function approaches, we demonstrate that in response to interleukin-4 (IL-4), signal transducer and activator of transcription 6 (STAT6) and PPARgamma-coactivator-1beta (PGC-1beta) induce macrophage programs for oxidative metabolism and mitochondrial biogenesis necessary for expression of the alternative phenotype.; Obesity and insulin resistance, cardinal features of metabolic syndrome, are driven by low-grade inflammation. In adipose tissue, chronic overnutrition leads to macrophage infiltration and activation, resulting in local inflammation that potentiates insulin resistance. Because macrophages actively participate in the resolution of inflammation, we postulated that macrophage activation programs that attenuate inflammation might ameliorate obesity-induced insulin resistance. Using mice with macrophage-specific deletion of peroxisome proliferator activated receptor (PPAR)-gamma, we show here that PPARgamma is required for maturation of alternatively activated macrophages. Disruption of PPARgamma in myeloid cells impairs alternative macrophage activation, thereby predisposing these animals to development of diet-induced obesity, insulin resistance, and glucose intolerance.; While inflammatory activation of resident hepatic macrophages potentiates insulin resistance, the functions of alternatively activated Kupffer cells in metabolic disease remain unknown. In response to IL-4, PPARdelta directs expression of the alternative phenotype in Kupffer cells of lean and obese mice. Importantly, adoptive transfer of PPARdelta-/- bone marrow into wild type mice diminishes alternative activation of hepatic macrophages, causing hepatic dysfunction and insulin resistance. Suppression of hepatic oxidative metabolism is recapitulated by co-culturing hepatocytes with PPARdelta -/- macrophages, indicating direct involvement of Kupffer cells in controlling liver lipid metabolism.; Together, these findings demonstrate coordinate metabolic and immunologic control of macrophage alternative activation and that macrophages resident in WAT and liver thus activated have beneficial roles in regulating nutrient homeostasis. These findings suggest that macrophage polarization towards the alternative state might be a useful strategy for treating metabolic syndrome and other chronic inflammatory diseases.