Format

Send to

Choose Destination
Diabetes. 2017 Oct;66(10):2596-2609. doi: 10.2337/db16-1232. Epub 2017 Jul 11.

Adipocyte-Specific Deficiency of De Novo Sphingolipid Biosynthesis Leads to Lipodystrophy and Insulin Resistance.

Author information

1
Department of Life Science, Gachon University, Sungnam, Korea.
2
Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University School of Medicine, Incheon, Korea.
3
Department of Food Science and Technology, Sejong University, Seoul, Korea.
4
Biomedical Research Center, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Korea.
5
College of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
6
Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York.
7
Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University School of Medicine, Incheon, Korea tspark@gachon.ac.kr cschoi@gachon.ac.kr.
8
Endocrinology, Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea.
9
Department of Life Science, Gachon University, Sungnam, Korea tspark@gachon.ac.kr cschoi@gachon.ac.kr.

Abstract

Sphingolipids have been implicated in the etiology of chronic metabolic diseases. Here, we investigated whether sphingolipid biosynthesis is associated with the development of adipose tissues and metabolic diseases. SPTLC2, a subunit of serine palmitoyltransferase, was transcriptionally upregulated in the adipose tissues of obese mice and in differentiating adipocytes. Adipocyte-specific SPTLC2-deficient (aSPTLC2 KO) mice had markedly reduced adipose tissue mass. Fatty acids that were destined for the adipose tissue were instead shunted to liver and caused hepatosteatosis. This impaired fat distribution caused systemic insulin resistance and hyperglycemia, indicating severe lipodystrophy. Mechanistically, sphingosine 1-phosphate (S1P) was reduced in the adipose tissues of aSPTLC2 KO mice, and this inhibited adipocyte proliferation and differentiation via the downregulation of S1P receptor 1 and decreased activity of the peroxisome proliferator-activator receptor γ. In addition, downregulation of SREBP (sterol regulatory element-binding protein)-1c prevented adipogenesis of aSPTLC2 KO adipocytes. Collectively, our observations suggest that the tight regulation of de novo sphingolipid biosynthesis and S1P signaling plays an important role in adipogenesis and hepatosteatosis.

PMID:
28698261
DOI:
10.2337/db16-1232
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center