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Experiment

Sptlc2fl/fl LysMcre/- HFD clamps

Summary

Data Summary

Investigator	Dixit, Vishwa
Description	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. Applicable research area(s): Diabetes, Obesity, Metabolism, Cardiovascular
Status	Completed
Public Release	6/28/2018
Data Collected?	Data will not be collected for this catalog item
Animal Age	Measured In: week(s) post-natal (w)
Flags

Data Analysis

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Type	Count
Animals	15
Experimental Conditions	2
Catalog Items	1
Curation Info (# flags)	3
Phenotype Assays	13
Phenotype Measurements	195
Histology Images	0
Publications	0

Animals

Strain Name	Common Name	Females	Males	Unknown
C57BL/6	C57BL/6	0	7	0
B6.Cg-Sptlc2^tm1Jia Lyz2^tm1(cre)Ifo	C57BL/6-Sptlc2^tm1Jia Lyz2^tm1(cre)Ifo	0	8	0

Animals/Strains

Experimental Factors

	Categorical Values
	Name / Abbreviation	Description
	Experimental Factor: Experimental Group
	Control	This animal belongs to the control group for the experiment.
	Experiment	This animal belongs to experimental group that is homozygous for gene manipulations.
	Experimental Factor: Mouse Diet
	Research Diets - D12492	Rodent Diet with 34% Fat, 60% kcal from Fat

Experimental Factor (Units)
Experimental Group
Mouse Diet

Experimental Factor Values

Phenotype Assays Add / Edit

Name	Abbreviation
glucose uptake	glucose uptake
average clamp glucose	average clamp glucose
fat body mass	fat body mass
lean body mass	lean body mass
total body weight	total body weight
glucose, basal	glucose, basal
hepatic glucose production, basal	hepatic glucose production, basal
glucose synthesis	glucose synthesis
glucose turnover, whole body	glucose turnover, whole body
glycogen/lipid synthesis, whole body	glycogen/lipid synthesis, whole body
glycolysis, whole body	glycolysis, whole body
glycogen synthesis	glycogen synthesis
glycolysis	glycolysis

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