Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) is the most severe form of human lipodystrophy, characterized by an almost complete loss of adipose tissue and severe insulin resistance. BSCL2 is caused by loss-of-function mutations in the BSCL2/SEIPIN gene, which is upregulated during adipogenesis and abundantly expressed in the adipose tissue. The physiological function of SEIPIN in mature adipocytes, however, remains to be elucidated. Here, we generated adipose-specific Seipin knock-out mice (ASKO mice), which exhibit adipocyte hypertrophy with enlarged lipid droplets, reduced lipolysis, adipose tissue inflammation, progressive loss of both white and brown adipose tissue, insulin resistance and hepatic steatosis. Lipidomic and microarray analyses revealed accumulation/imbalance of lipid species including ceramides in ASKO adipose tissue, as well as increased endoplasmic reticulum stress. Interestingly, the ASKO mice almost completely phenocopy the fat-specific Pparγ knock-out (FKOγ) mice. Rosiglitazone treatment significantly improved a number of metabolic parameters of the ASKO mice, including insulin sensitivity. Our results therefore demonstrate a critical role of SEIPIN in maintaining lipid homeostasis and function of adipocytes, and reveal an intimate relationship between SEIPIN and PPARγ.
a L.L., Q. J. and X.W. contributed equally to this work.
- Received May 7, 2013.
- Accepted March 8, 2014.
- © 2014 by the American Diabetes Association.
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