Thiazolidinediones partially reverse the metabolic disturbances observed in Bscl2/seipin-deficient mice

X. Prieur, L. Dollet, M. Takahashi, M. Nemani, B. Pillot, C. Le May, C. Mounier, H. Takigawa-Imamura, D. Zelenika, F. Matsuda, B. Fève, J. Capeau, M. Lathrop, P. Costet, B. Cariou, J. Magré

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Abstract

Aims/hypothesis: Mutations in BSCL2/seipin cause Berardinelli-Seip congenital lipodystrophy (BSCL), a rare recessive disorder characterised by near absence of adipose tissue and severe insulin resistance. We aimed to determine how seipin deficiency alters glucose and lipid homeostasis and whether thiazolidinediones can rescue the phenotype. Methods: Bscl2 -/- mice were generated and phenotyped. Mouse embryonic fibroblasts (MEFs) were used as a model of adipocyte differentiation. Results: As observed in humans, Bscl2 -/- mice displayed an early depletion of adipose tissue, with insulin resistance and severe hepatic steatosis. However, Bscl2 -/- mice exhibited an unexpected hypotriglyceridaemia due to increased clearance of triacylglycerol-rich lipoproteins (TRL) and uptake of fatty acids by the liver, with reduced basal energy expenditure. In vitro experiments with MEFs demonstrated that seipin deficiency led to impaired late adipocyte differentiation and increased basal lipolysis. Thiazolidinediones were able to rescue the adipogenesis impairment but not the alteration in lipolysis in Bscl2 -/- MEFs. In vivo treatment of Bscl2 -/- mice with pioglitazone for 9 weeks increased residual inguinal and mesenteric fat pads as well as plasma leptin and adiponectin concentrations. Pioglitazone treatment increased energy expenditure and improved insulin resistance, hypotriglyceridaemia and liver steatosis in these mice. Conclusions/ interpretation: Seipin plays a key role in the differentiation and storage capacity of adipocytes, and affects glucose and lipid homeostasis. The hypotriglyceridaemia observed in Bscl2 -/- mice is linked to increased uptake of TRL by the liver, offering a new model of liver steatosis. The demonstration that the metabolic complications associated with BSCL can be partially rescued with pioglitazone treatment opens an interesting therapeutic perspective for BSCL patients.

Original languageEnglish
Pages (from-to)1813-1825
Number of pages13
JournalDiabetologia
Volume56
Issue number8
DOIs
Publication statusPublished - Aug 1 2013

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Prieur, X., Dollet, L., Takahashi, M., Nemani, M., Pillot, B., Le May, C., Mounier, C., Takigawa-Imamura, H., Zelenika, D., Matsuda, F., Fève, B., Capeau, J., Lathrop, M., Costet, P., Cariou, B., & Magré, J. (2013). Thiazolidinediones partially reverse the metabolic disturbances observed in Bscl2/seipin-deficient mice. Diabetologia, 56(8), 1813-1825. https://doi.org/10.1007/s00125-013-2926-9