Journal
DIABETOLOGIA
Volume 56, Issue 8, Pages 1813-1825Publisher
SPRINGER
DOI: 10.1007/s00125-013-2926-9
Keywords
Adipocyte differentiation; BSCL; Insulin resistance; Lipodystrophy; Lipolysis; Liver steatosis; Lipoprotein clearance; Seipin; Thiazolidinedione; Triacylglycerol
Categories
Funding
- Institut National de la Sante et de la Recherche Medicale (Inserm)
- French Ministere de la Recherche et de la Technologie (MRT)
- French association (Aide aux Jeunes Diabetiques [AJD])
- French association (Fondation de France)
- French association (Fondation GenaVie)
- French association (Association de Langue Francaise pour l'Etude du Diabete et des Maladies Metaboliques [ALFEDIAM]/Societe Francophone du Diabete [SFD])
- MRT
- Region Ile-de-France
- AJD
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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. Bscl2 (-/-) mice were generated and phenotyped. Mouse embryonic fibroblasts (MEFs) were used as a model of adipocyte differentiation. 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. 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.
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