Cisd2 modulates the differentiation and functioning of adipocytes by regulating intracellular Ca2+ homeostasis.
CISD2 is a causative gene associated with Wolfram syndrome (WFS). However, it remains a mystery as to how the loss of CISD2 causes metabolic defects in patients with WFS. Investigation on the role played by Cisd2 in specific cell types may help us to resolve these underlying mechanisms. White adipose tissue (WAT) is central to the maintenance of energy metabolism and glucose homeostasis in humans. In this study, adipocyte-specific Cisd2 knockout (KO) mice showed impairment in the development of epididymal WAT (eWAT) in the cell autonomous manner. A lack of Cisd2 caused defects in the biogenesis and function of mitochondria during differentiation of adipocytes in vitro. Insulin-stimulated glucose uptake and secretion of adiponectin by the Cisd2 KO adipocytes were decreased. Moreover, Cisd2 deficiency increased the cytosolic level of Ca(2+) and induced Ca(2+)-calcineurin-dependent signaling that inhibited adipogenesis. Importantly, Cisd2 was found to interact with Gimap5 on the mitochondrial and ER membranes and thereby modulate mitochondrial Ca(2+) uptake associated with the maintenance of intracellular Ca(2+) homeostasis in adipocytes. Thus, it would seem that Cisd2 plays an important role in intracellular Ca(2+) homeostasis, which is required for the differentiation and functioning of adipocytes as well as the regulation of glucose homeostasis in mice.
Institute of Biochemistry and Molecular Biology.
Chih-Hao
CH
Wang
Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County 350, Taiwan Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan.
Yi-Fan
YF
Chen
Department of Life Sciences and Institute of Genome Sciences.
Chia-Yu
CY
Wu
Department of Life Sciences and Institute of Genome Sciences Brain Research Center.
Pei-Chun
PC
Wu
Department of Life Sciences and Institute of Genome Sciences.
Yi-Long
YL
Huang
Center of General Education, Chang Gung University, Taoyuan 333, Taiwan.
Cheng-Heng
CH
Kao
Department of Life Sciences and Institute of Genome Sciences.
Chao-Hsiung
CH
Lin
Department of Life Sciences and Institute of Genome Sciences Brain Research Center.
Lung-Sen
LS
Kao
Department of Life Sciences and Institute of Genome Sciences Brain Research Center Aging and Health Research Center, National Yang-Ming University, Taipei 112, Taiwan Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County 350, Taiwan joeman@ym.edu.tw joeman@mmc.edu.tw tftsai@ym.edu.tw.
Ting-Fen
TF
Tsai
Institute of Biochemistry and Molecular Biology Department of Medicine, Mackay Medical College, Sanzhi, New Taipei City 252, Taiwan joeman@ym.edu.tw joeman@mmc.edu.tw tftsai@ym.edu.tw.
Yau-Huei
YH
Wei
D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism*; D052242:Adiponectin / Q000378:metabolism; D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D000071183:Autophagy-Related Proteins; D002118:Calcium / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D003600:Cytosol / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D019204:GTP-Binding Proteins; D005947:Glucose / Q000378:metabolism; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*
D052242:Adiponectin; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; C534135:Gimap5 protein, mouse; D009419:Nerve Tissue Proteins; C515811:Noxp70 protein, mouse; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D005947:Glucose; D002118:Calcium