Ubiquitin carboxyl-terminal hydrolase l3 promotes insulin signaling and adipogenesis.
Insulin is a potent adipogenic hormone that triggers the induction of a series of transcription factors and specific proteins governing the differentiation of preadipocytes into mature adipocytes. Here we report that ubiquitin carboxyl-terminal hydrolase (UCH)-L3, a deubiquitinating enzyme, promotes insulin signaling and adipogenesis. Uchl3(-/-) mice had less visceral white adipose tissue compared with wild-type mice. In vitro adipogenesis experiments revealed that mouse embryonic fibroblasts (MEFs) and preadipocytes from Uchl3(-/-) mice had impaired ability to differentiate into mature adipocytes than those from wild-type mice. This difference was diminished by removing insulin from the medium. RT-PCR analysis showed that insulin-regulated expression of srebp1c, fas, glut4, and adiponectin is impaired in Uchl3(-/-) cells. The phosphorylation of insulin/IGF-I receptor, Akt, glycogen synthase kinase-3beta, and FoxO1 was decreased in Uchl3(-/-) MEFs treated with insulin. Moreover, ectopic expression of wild-type UCH-L3 restored the phosphorylation of insulin/IGF-I receptor and adipocyte differentiation in Uchl3(-/-) MEFs. In contrast, hydrolase activity-deficient UCH-L3 did not enhance insulin signaling and the expression of glut4, fabp4, and adiponectin, resulting in impaired formation of large lipid droplets. These results suggest that UCH-L3 promotes adipogenesis by enhancing insulin signaling in a hydrolase activity-dependent manner.
Suzuki
Mari
M
Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
Setsuie
Rieko
R
Wada
Keiji
K
D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D050156:Adipogenesis / Q000235:genetics / Q000502:physiology*; D052242:Adiponectin / Q000235:genetics; D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D051275:Glucose Transporter Type 4 / Q000235:genetics; D015151:Immunoblotting; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D019014:fas Receptor / Q000235:genetics
D052242:Adiponectin; C491899:Fas protein, mouse; D051275:Glucose Transporter Type 4; C495693:Slc2a4 protein, mouse; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; C526917:UCHL3 protein, mouse; D019014:fas Receptor; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D043222:Ubiquitin Thiolesterase