Nuclear lamin A inhibits adipocyte differentiation: implications for Dunnigan-type familial partial lipodystrophy.
Mutations in the LMNA gene encoding A-type lamins cause several diseases, including Emery-Dreifuss muscular dystrophy and Dunnigan-type familial partial lipodystrophy (FPLD). We analyzed differentiation of 3T3-L1 preadipocytes to adipocytes in cells overexpressing wild-type lamin A as well as lamin A with amino acid substitutions at position 482 that cause FPLD. We also examined adipogenic conversion of mouse embryonic fibroblasts lacking A-type lamins. Overexpression of both wild-type and mutant lamin A inhibited lipid accumulation, triglyceride synthesis and expression of adipogenic markers. This was associated with inhibition of expression of peroxisome-proliferator-activated receptor gamma 2 (PPARgamma2) and Glut4. In contrast, embryonic fibroblasts lacking A-type lamins accumulated more intracellular lipid and exhibited elevated de novo triglyceride synthesis compared with wild-type fibroblasts. They also had increased basal phosphorylation of AKT1, a mediator of insulin signaling. We conclude that A-type lamins act as inhibitors of adipocyte differentiation, possibly by affecting PPARgamma2 and insulin signaling.
Boguslavsky
Revekka L
RL
Department of Medicine and Anatomy, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA.
Stewart
Colin L
CL
Worman
Howard J
HJ
D016475:3T3 Cells; D017667:Adipocytes / Q000378:metabolism*; D019943:Amino Acid Substitution; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D003923:Diabetes Mellitus, Lipoatrophic / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000378:metabolism; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism; D017354:Point Mutation; D015398:Signal Transduction / Q000235:genetics
D007328:Insulin; D034904:Lamin Type A; D047495:PPAR gamma