title: Macrophage-specific de Novo Synthesis of Ceramide Is Dispensable for Inflammasome-driven Inflammation and Insulin Resistance in Obesity.
abstract: Dietary lipid overload and calorie excess during obesity is a low grade chronic inflammatory state with diminished ability to appropriately metabolize glucose or lipids. Macrophages are critical in maintaining adipose tissue homeostasis, in part by regulating lipid metabolism, energy homeostasis, and tissue remodeling. During high fat diet-induced obesity, macrophages are activated by lipid derived "danger signals" such as ceramides and palmitate and promote the adipose tissue inflammation in an Nlrp3 inflammasome-dependent manner. Given that the metabolic fate of fatty acids in macrophages is not entirely elucidated, we have hypothesized that de novo synthesis of ceramide, through the rate-limiting enzyme serine palmitoyltransferase long chain (Sptlc)-2, is required for saturated fatty acid-driven Nlrp3 inflammasome activation in macrophages. Here we report that mitochondrial targeted overexpression of catalase, which is established to mitigate oxidative stress, controls ceramide-induced Nlrp3 inflammasome activation but does not affect the ATP-mediated caspase-1 cleavage. Surprisingly, myeloid cell-specific deletion of Sptlc2 is not required for palmitate-driven Nlrp3 inflammasome activation. Furthermore, the ablation of Sptlc2 in macrophages did not impact macrophage polarization or obesity-induced adipose tissue leukocytosis. Consistent with these data, investigation of insulin resistance using hyperinsulinemic-euglycemic clamps revealed no significant differences in obese mice lacking ceramide de novo synthesis machinery in macrophages. These data suggest that alternate metabolic pathways control fatty acid-derived ceramide synthesis in macrophage and the Nlrp3 inflammasome activation in obesity.
authors.affiliation: From the Section of Comparative Medicine and Department of Immunobiology.
authors.forename: Christina D
authors.initials: CD
authors.lastname: Camell
authors.affiliation: From the Section of Comparative Medicine and Department of Immunobiology.
authors.forename: Kim Y
authors.initials: KY
authors.lastname: Nguyen
authors.affiliation: Departments of Internal Medicine.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Jurczak
authors.affiliation: Pathology, and.
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Christian
authors.affiliation: Departments of Internal Medicine.
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
authors.affiliation: Departments of Internal Medicine, Genetics, Yale School of Medicine, New Haven, Connectitcut 06520.
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Shadel
authors.affiliation: From the Section of Comparative Medicine and Department of Immunobiology, Vishwa.Dixit@yale.edu.
authors.forename: Vishwa Deep
authors.initials: VD
authors.lastname: Dixit
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002352:Carrier Proteins / Q000235:genetics*; D002518:Ceramides / Q000378:metabolism*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000737:chemistry; D005260:Female; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D007333:Insulin Resistance; D008055:Lipids / Q000737:chemistry; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000473:pathology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009765:Obesity / Q000378:metabolism*; D018384:Oxidative Stress; D051102:Serine C-Palmitoyltransferase / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D002518:Ceramides; D005227:Fatty Acids; D058847:Inflammasomes; D008055:Lipids; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D051102:Serine C-Palmitoyltransferase; C495090:Sptlc2 protein, mouse
keywords: adipose tissue; ceramide synthesis; inflammasome; insulin resistance; macrophage; obesity; saturated fat