1. Adipocyte-Specific Deficiency of De Novo Sphingolipid Biosynthesis Leads to Lipodystrophy and Insulin Resistance
- Author
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Cheol Soo Choi, Jang Ho Hur, Jae Hwi Song, Hyun Joo Yoo, Hui-Young Lee, Hyun Hee Oh, Soon Mi Shim, Suwon Jeon, Goon Tae Kim, Xian-Cheng Jiang, Su Yeon Lee, Shi Young Park, Byung Cheon Lee, Jae Sung Lee, Yoo Jeong Song, and Tae Sik Park
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Lipodystrophy ,Endocrinology, Diabetes and Metabolism ,Serine C-Palmitoyltransferase ,Adipose tissue ,030209 endocrinology & metabolism ,Biology ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Downregulation and upregulation ,Sphingosine ,Internal medicine ,Adipocyte ,Adipocytes ,Internal Medicine ,medicine ,Animals ,Cell Proliferation ,Mice, Knockout ,Adipogenesis ,Serine C-palmitoyltransferase ,Cell Differentiation ,medicine.disease ,Sphingolipid ,030104 developmental biology ,Endocrinology ,Adipose Tissue ,chemistry ,lipids (amino acids, peptides, and proteins) ,Insulin Resistance ,Lysophospholipids ,Sterol Regulatory Element Binding Protein 1 ,Obesity Studies - 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.
- Published
- 2017