title: Adipose-specific knockout of SEIPIN/BSCL2 results in progressive lipodystrophy.
abstract: 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 knockout (ASKO) mice, which exhibit adipocyte hypertrophy with enlarged lipid droplets, reduced lipolysis, adipose tissue inflammation, progressive loss of 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 peroxisome proliferator-activated receptor-γ (Pparγ) knockout (FKO-γ) 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 PPAR-γ.
authors.affiliation: Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Liu
authors.affiliation: Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Department of Endocrinology, Lu He Teaching Hospital of the Capital Medical University, Beijing, China.
authors.forename: Xuhong
authors.initials: X
authors.lastname: Wang
authors.affiliation: School of Biotechnology and Biomolecular Sciences, the University of New South Wales, Sydney, NSW, Australia.
authors.forename: Yuxi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: School of Biotechnology and Biomolecular Sciences, the University of New South Wales, Sydney, NSW, Australia.
authors.forename: Ruby C Y
authors.initials: RC
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Sin Man
authors.initials: SM
authors.lastname: Lam
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Guanghou
authors.initials: G
authors.lastname: Shui
authors.affiliation: MOE Key Laboratory of Bioinformatics and Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Linkang
authors.initials: L
authors.lastname: Zhou
authors.affiliation: MOE Key Laboratory of Bioinformatics and Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Cui
authors.affiliation: Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Gao
authors.affiliation: Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Lv
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
authors.forename: Guoheng
authors.initials: G
authors.lastname: Xu
authors.affiliation: Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China vangeorgeliu@gmail.com zdoc66@126.com h.rob.yang@unsw.edu.au.
authors.forename: George
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Endocrinology, Lu He Teaching Hospital of the Capital Medical University, Beijing, China vangeorgeliu@gmail.com zdoc66@126.com h.rob.yang@unsw.edu.au.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhao
authors.affiliation: School of Biotechnology and Biomolecular Sciences, the University of New South Wales, Sydney, NSW, Australia vangeorgeliu@gmail.com zdoc66@126.com h.rob.yang@unsw.edu.au.
authors.forename: Hongyuan
authors.initials: H
authors.lastname: Yang
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D002001:Adipose Tissue, Brown / Q000378:metabolism / Q000473:pathology; D000818:Animals; D059305:Diet, High-Fat; D018450:Disease Progression; D044388:GTP-Binding Protein gamma Subunits; D055786:Gene Knockout Techniques; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*; D007333:Insulin Resistance / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics; D008060:Lipodystrophy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000502:physiology
chemical_list: C115783:Bscl2 protein, mouse; D044388:GTP-Binding Protein gamma Subunits; D047495:PPAR gamma; D020962:Heterotrimeric GTP-Binding Proteins