Adipocyte-specific deficiency of de novo sphingolipid biosynthesis leads to lipodystrophy and insulin resistance

Su Yeon Lee; Hui Young Lee; Jae Hwi Song; Goon Tae Kim; Suwon Jeon; Yoo Jeong Song; Jae Sung Lee; Jang Ho Hur; Hyun Hee Oh; Shi Young Park; Soon Mi Shim; Hyun Joo Yoo; Byung Cheon Lee; Xian Cheng Jiang; Cheol Soo Choi; Tae Sik Park

doi:10.2337/db16-1232

Adipocyte-specific deficiency of de novo sphingolipid biosynthesis leads to lipodystrophy and insulin resistance

Su Yeon Lee, Hui Young Lee, Jae Hwi Song, Goon Tae Kim, Suwon Jeon, Yoo Jeong Song, Jae Sung Lee, Jang Ho Hur, Hyun Hee Oh, Shi Young Park, Soon Mi Shim, Hyun Joo Yoo, Byung Cheon Lee, Xian Cheng Jiang, Cheol Soo Choi, Tae Sik Park

Department of Biosystems and Biotechnology

Research output: Contribution to journal › Article › peer-review

45 Citations (Scopus)

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 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.

Original language	English
Pages (from-to)	2596-2609
Number of pages	14
Journal	Diabetes
Volume	66
Issue number	10
DOIs	https://doi.org/10.2337/db16-1232
Publication status	Published - 2017 Oct 1

Bibliographical note

Funding 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.

Publisher Copyright:
© 2017 by the American Diabetes Association.

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism

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10.2337/db16-1232

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Lee, S. Y., Lee, H. Y., Song, J. H., Kim, G. T., Jeon, S., Song, Y. J., Lee, J. S., Hur, J. H., Oh, H. H., Park, S. Y., Shim, S. M., Yoo, H. J., Lee, B. C., Jiang, X. C., Choi, C. S., & Park, T. S. (2017). Adipocyte-specific deficiency of de novo sphingolipid biosynthesis leads to lipodystrophy and insulin resistance. Diabetes, 66(10), 2596-2609. https://doi.org/10.2337/db16-1232

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title = "Adipocyte-specific deficiency of de novo sphingolipid biosynthesis leads to lipodystrophy and insulin resistance",

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 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.",

author = "Lee, {Su Yeon} and Lee, {Hui Young} and Song, {Jae Hwi} and Kim, {Goon Tae} and Suwon Jeon and Song, {Yoo Jeong} and Lee, {Jae Sung} and Hur, {Jang Ho} and Oh, {Hyun Hee} and Park, {Shi Young} and Shim, {Soon Mi} and Yoo, {Hyun Joo} and Lee, {Byung Cheon} and Jiang, {Xian Cheng} and Choi, {Cheol Soo} and Park, {Tae Sik}",

note = "Funding 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. Publisher Copyright: {\textcopyright} 2017 by the American Diabetes Association.",

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doi = "10.2337/db16-1232",

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T1 - Adipocyte-specific deficiency of de novo sphingolipid biosynthesis leads to lipodystrophy and insulin resistance

AU - Lee, Su Yeon

AU - Lee, Hui Young

AU - Song, Jae Hwi

AU - Kim, Goon Tae

AU - Jeon, Suwon

AU - Song, Yoo Jeong

AU - Lee, Jae Sung

AU - Hur, Jang Ho

AU - Oh, Hyun Hee

AU - Park, Shi Young

AU - Shim, Soon Mi

AU - Yoo, Hyun Joo

AU - Lee, Byung Cheon

AU - Jiang, Xian Cheng

AU - Choi, Cheol Soo

AU - Park, Tae Sik

N1 - Funding 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. Publisher Copyright: © 2017 by the American Diabetes Association.

PY - 2017/10/1

Y1 - 2017/10/1

N2 - 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.

AB - 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.

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DO - 10.2337/db16-1232

M3 - Article

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SN - 0012-1797

VL - 66

SP - 2596

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JO - Diabetes

JF - Diabetes

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ER -

Adipocyte-specific deficiency of de novo sphingolipid biosynthesis leads to lipodystrophy and insulin resistance

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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