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

X Prieur, L Dollet, M Takahashi, M Nemani, B Pillot… - Diabetologia, 2013 - Springer
X Prieur, L Dollet, M Takahashi, M Nemani, B Pillot, C Le May, C Mounier…
Diabetologia, 2013Springer
Aims/hypothesis Mutations in BSCL 2/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 …
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.
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