Ceramide Synthase 5 Is Essential to Maintain C16:0-Ceramide Pools and Contributes to the Development of Diet-induced Obesity

Ceramides are bioactive sphingolipids, which are composed of sphingoid bases carrying acyl chains of various lengths. Ceramides are synthesized by a family of six ceramide synthases (CerS) in mammals, which produce ceramides with different N-linked acyl chains. Increased ceramide levels are known to...

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Bibliographic Details
Published in:The Journal of biological chemistry 2016-03, Vol.291 (13), p.6989-7003
Main Authors: Gosejacob, Dominic, Jäger, Philipp S., vom Dorp, Katharina, Frejno, Martin, Carstensen, Anne C., Köhnke, Monika, Degen, Joachim, Dörmann, Peter, Hoch, Michael
Format: Article
Language:English
Subjects:
adipose tissue metabolism
Adipose Tissue, White - enzymology
Adipose Tissue, White - pathology
Animals
Blood Glucose - metabolism
ceramide
ceramide synthase
Ceramides - biosynthesis
diabetes
Diet, High-Fat
Dietary Fats - adverse effects
Gene Expression
gene knockout
Glucose Tolerance Test
insulin resistance
Insulin Resistance - genetics
Isoenzymes - deficiency
Isoenzymes - genetics
lipid metabolism
Lipids
Liver - enzymology
Liver - pathology
Lung - enzymology
Lung - pathology
Male
metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Muscle, Skeletal - enzymology
Muscle, Skeletal - pathology
obesity
Obesity - enzymology
Obesity - etiology
Obesity - genetics
Obesity - pathology
sphingolipid
Sphingosine N-Acyltransferase - deficiency
Sphingosine N-Acyltransferase - genetics
Spleen - enzymology
Spleen - pathology
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Summary:Ceramides are bioactive sphingolipids, which are composed of sphingoid bases carrying acyl chains of various lengths. Ceramides are synthesized by a family of six ceramide synthases (CerS) in mammals, which produce ceramides with different N-linked acyl chains. Increased ceramide levels are known to contribute to the development of obesity and insulin resistance. Recently, it has been demonstrated that the ceramide acylation pattern is of particular importance for an organism to maintain energy homeostasis. However, which of the CerS family members are involved in this process is not yet completely known. Using newly developed CerS5 knock-out mice, we show here that CerS5 is essential to maintain cellular C16:0 sphingolipid pools in lung, spleen, muscle, liver, and white adipose tissue. Glycerophospholipid levels in CerS5-deficient mice were not altered. We found a strong impact of CerS5-dependent ceramide synthesis in white adipose tissue after high fat diet feeding. In skeletal muscle, liver, and spleen, C16:0-ceramide levels were altered independent of feeding conditions. The loss of CerS5 is associated with reduced weight gain and improved systemic health, including maintenance of glucose homeostasis and reduced white adipose tissue inflammation after high fat diet challenge. Our findings indicate that reduction of endogenous C16:0-ceramide by genetic inhibition of CerS5 is sufficient to ameliorate obesity and its comorbidities.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M115.691212