Inhibition of death-receptor mediated apoptosis in human adipocytes by the insulin-like growth factor I (IGF-I)/IGF-I receptor autocrine circuit.
Adipose tissue mass is reflected by the volume and the number of adipocytes and is subject to homeostatic regulation involving cell death mechanisms. In this study we have investigated the mechanisms of apoptosis in human preadipocytes and adipocytes that may play a role in the regulation of adipose tissue mass. We found that death receptors (CD95, TNF-related apoptosis-inducing ligand receptors 1 and 2, and TNF receptor 1) are expressed in human fat cells and that apoptosis can be induced by specific ligands. Sensitivity to apoptosis could be stimulated by an inhibitor of biosynthesis. In addition, inhibition of auto-/paracrine action of IGF-I dramatically sensitizes human adipocytes for death ligand-induced apoptosis. Phosphoinositide 3-kinase and, to a weaker extent, p38 MAPK are involved in IGF-I-mediated survival. IGF-I protects human fat cells from apoptosis by maintaining the expression of antiapoptotic proteins, Bcl-x(L) and Fas-associated death domain-like IL-1-converting enzyme inhibitory protein. In conclusion, we identified mechanisms of apoptosis induction in human fat cells. We furthermore demonstrate that human fat cells protect themselves from apoptosis by IGF-I in an auto-/paracrine manner.
Fischer-Posovszky
Pamela
P
Department of Pediatrics and Adolescent Medicine, University of Ulm, Germany.
Tornqvist
Hans
H
Debatin
Klaus-Michael
KM
Wabitsch
Martin
M
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D000328:Adult; D015703:Antigens, CD / Q000502:physiology; D017209:Apoptosis / Q000502:physiology*; D019898:Autocrine Communication / Q000502:physiology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism / Q000502:physiology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D015398:Signal Transduction; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D051020:bcl-X Protein; D019014:fas Receptor / Q000502:physiology
D015703:Antigens, CD; C494811:BCL2L1 protein, human; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D016895:Culture Media, Serum-Free; D047908:Intracellular Signaling Peptides and Proteins; D011500:Protein Synthesis Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; D051020:bcl-X Protein; D019014:fas Receptor; D007334:Insulin-Like Growth Factor I; D003513:Cycloheximide; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D020928:Mitogen-Activated Protein Kinases