Dai, LinglingBhargava, PrernaStanya, Kristopher J.Alexander, RyanLiou, Yae-HueiJacobi, DavidKnudsen, NelsonHyde, AlexanderGangl, Matthew R.Liu, SihaoLee, Chih-Hao2017-12-062017Dai, L., P. Bhargava, K. J. Stanya, R. K. Alexander, Y. Liou, D. Jacobi, N. H. Knudsen, et al. 2017. “Macrophage alternative activation confers protection against lipotoxicity-induced cell death.” Molecular Metabolism 6 (10): 1186-1197. doi:10.1016/j.molmet.2017.08.001. http://dx.doi.org/10.1016/j.molmet.2017.08.001.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34492463Objective: Alternative activation (M2) of adipose tissue resident macrophage (ATM) inhibits obesity-induced metabolic inflammation. The underlying mechanisms remain unclear. Recent studies have shown that dysregulated lipid homeostasis caused by increased lipolysis in white adipose tissue (WAT) in the obese state is a trigger of inflammatory responses. We investigated the role of M2 macrophages in lipotoxicity-induced inflammation. Methods: We used microarray experiments to profile macrophage gene expression regulated by two M2 inducers, interleukin-4 (Il-4), and peroxisome proliferator-activated receptor delta/gamma (Pparδ/Pparγ) agonists. Functional validation studies were performed in bone marrow-derived macrophages and mice deprived of the signal transducer and activator of transcription 6 gene (Stat6; downstream effector of Il-4) or Pparδ/Pparγ genes (downstream effectors of Stat6). Palmitic acid (PA) and β-adrenergic agonist were employed to induce macrophage lipid loading in vitro and in vivo, respectively. Results: Profiling of genes regulated by Il-4 or Pparδ/Pparγ agonists reveals that alternative activation promotes the cell survival program, while inhibiting that of inflammation-related cell death. Deletion of Stat6 or Pparδ/Pparγ increases the susceptibility of macrophages to PA-induced cell death. NLR family pyrin domain containing 3 (Nlrp3) inflammasome activation by PA in the presence of lipopolysaccharide is also increased in Stat6−/− macrophages and to a lesser extent, in Pparδ/γ−/− macrophages. In concert, β-adrenergic agonist-induced lipolysis results in higher levels of cell death and inflammatory markers in ATMs derived from myeloid-specific Pparδ/γ−/− or Stat6−/− mice. Conclusions: Our data suggest that ATM cell death is closely linked to metabolic inflammation. Within WAT where concentrations of free fatty acids fluctuate, M2 polarization regulated by the Stat6-Ppar axis enhances ATM's tolerance to lipid-mediated stress, thereby maintaining the homeostatic state.en-USObesityAdipose tissue macrophageAlternative activationLipotoxicityMeta-inflammationM2, alternative activation of macrophageM1, classic activation of macrophageWAT, white adipose tissueATM, adipose tissue resident macrophagePpar, peroxisome proliferator-activated receptorStat6, signal transducer and activator of transcription 6PA, palmitic acidNlrp3, NLR family pyrin domain containing 3BMDM, bone marrow derived macrophageILC2, type 2 innate lymphoid cellSVF, stromal vascular fractionOCR, oxygen consumption rateAngptl4, angiopoietin-like 4Sgms1, sphingomyelin synthase 1Plin2, perilipin 2Acadvl, acyl-CoA dehydrogenase, very long chainSlc25a20, solute carrier family 25 member 20Mogat1, monoacylglycerol O-acyltransferase 1Mgl1, macrophage galactose-type lectin-1Arg1, arginase 1Bcl2, B-cell lymphoma 2H2-Eb1, histocompatibility 2, class II antigen E betaJournal Article2017-12-0610.1016/j.molmet.2017.08.001