Calreticulin inhibits commitment to adipocyte differentiation.
Calreticulin, an endoplasmic reticulum (ER) resident protein, affects many critical cellular functions, including protein folding and calcium homeostasis. Using embryonic stem cells and 3T3-L1 preadipocytes, we show that calreticulin modulates adipogenesis. We find that calreticulin-deficient cells show increased potency for adipogenesis when compared with wild-type or calreticulin-overexpressing cells. In the highly adipogenic crt(-/-) cells, the ER lumenal calcium concentration was reduced. Increasing the ER lumenal calcium concentration led to a decrease in adipogenesis. In calreticulin-deficient cells, the calmodulin-Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) pathway was up-regulated, and inhibition of CaMKII reduced adipogenesis. Calreticulin inhibits adipogenesis via a negative feedback mechanism whereby the expression of calreticulin is initially up-regulated by peroxisome proliferator-activated receptor gamma (PPAR gamma). This abundance of calreticulin subsequently negatively regulates the expression of PPAR gamma, lipoprotein lipase, CCAAT enhancer-binding protein alpha, and aP2. Thus, calreticulin appears to function as a Ca(2+)-dependent molecular switch that regulates commitment to adipocyte differentiation by preventing the expression and transcriptional activation of critical proadipogenic transcription factors.
Szabo
Eva
E
Department of Laboratory Medicine and Pathobiology, Institute of Medical Sciences, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Qiu
Yuanyuan
Y
Baksh
Shairaz
S
Michalak
Marek
M
Opas
Michal
M
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D050156:Adipogenesis; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D037282:Calreticulin / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019070:Cell Lineage; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D042541:Intracellular Space / Q000378:metabolism; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport
D022763:CCAAT-Enhancer-Binding Protein-alpha; D002147:Calmodulin; D037282:Calreticulin; D017362:Cyclic AMP Response Element-Binding Protein; D047495:PPAR gamma; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D019703:Calcineurin; D002118:Calcium