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 g. 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.
Bibliographical noteFunding Information:
Acknowledgments. The authors thank Derek Erion (Takeda Pharmaceutical Company, Boston, MA) for critical review of the manuscript. Funding. This research was supported by the Bio & Medical Technology Development Program through the National Research Foundation of Korea (NRF), funded by the Korean government (MSIP) (NRF-2014M3A9B6069338) to T.-S.P. and NRF-2014M3A9D5A01073886 to C.S.C.). Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. S.-Y.L. and H.-Y.L. performed the experiments and wrote the manuscript. J.-H.S., S.J., Y.-J.S., G.-T.K., and B.C.L. performed the experiments for protein expression and cell culture. J.S.L., J.-H.H., and S.-Y.P. performed clamp studies and the metabolic cage experiment. S.-M.S., H.H.O., and H.J.Y. analyzed sphingolipids. X.-C.J. provided SPT2 floxed mice and performed the experiments. C.S.C. and T.-S.P. designed and supervised the studies, analyzed and interpreted data, finalized the manuscript, and obtained funding. T.-S.P. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
© 2017 by the American Diabetes Association.
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism