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Publication
Macrophage-specific de Novo Synthesis of Ceramide Is Dispensable for
Inflammasome-driven Inflammation and Insulin Resistance in Obesity.
Authors Camell CD, Nguyen KY, Jurczak MJ, Christian BE, Shulman GI, Shadel GS, Dixit VD
Submitted By Submitted Externally on 9/22/2017
Status Published
Journal The Journal of biological chemistry
Year 2015
Date Published 12/4/2015
Volume : Pages 290 : 29402 - 13
PubMed Reference 26438821
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.








Genes
SymbolDescription
Sptlc2serine palmitoyltransferase, long chain base subunit 2
Lyz2lysozyme 2

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