Insulin/IGF-I regulation of necdin and brown adipocyte differentiation via CREB- and FoxO1-associated pathways
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Insulin/IGF-I regulation of necdin and brown adipocyte differentiation via CREB- and FoxO1-associated pathways. / Cypess, Aaron M; Zhang, Hongbin; Schulz, Tim J; Huang, Tian Lian; Espinoza, Daniel O; Kristiansen, Karsten; Unterman, Terry G; Tseng, Yu-Hua.
In: Endocrinology, Vol. 152, No. 10, 2011, p. 3680-9.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Insulin/IGF-I regulation of necdin and brown adipocyte differentiation via CREB- and FoxO1-associated pathways
AU - Cypess, Aaron M
AU - Zhang, Hongbin
AU - Schulz, Tim J
AU - Huang, Tian Lian
AU - Espinoza, Daniel O
AU - Kristiansen, Karsten
AU - Unterman, Terry G
AU - Tseng, Yu-Hua
PY - 2011
Y1 - 2011
N2 - Brown adipose tissue plays an important role in obesity, insulin resistance, and diabetes. We have previously shown that the transition from brown preadipocytes to mature adipocytes is mediated in part by insulin receptor substrate (IRS)-1 and the cell cycle regulator protein necdin. In this study, we used pharmacological inhibitors and adenoviral dominant negative constructs to demonstrate that this transition involves IRS-1 activation of Ras and ERK1/2, resulting in phosphorylation of cAMP response element-binding protein (CREB) and suppression of necdin expression. This signaling did not include an elevation of intracellular calcium. A constitutively active form of CREB expressed in IRS-1 knockout cells decreased necdin promoter activity, necdin mRNA, and necdin protein levels, leading to a partial restoration of differentiation. By contrast, forkhead box protein (Fox)O1, which is regulated by the phosphoinositide 3 kinase-Akt pathway, increased necdin promoter activity. Based on reporter gene assays using truncations of the necdin promoter and chromatin immunoprecipitation studies, we demonstrated that CREB and FoxO1 are recruited to the necdin promoter, likely interacting with specific consensus sequences in the proximal region. Based on these results, we propose that insulin/IGF-I act through IRS-1 phosphorylation to stimulate differentiation of brown preadipocytes via two complementary pathways: 1) the Ras-ERK1/2 pathway to activate CREB and 2) the phosphoinositide 3 kinase-Akt pathway to deactivate FoxO1. These two pathways combine to decrease necdin levels and permit the clonal expansion and coordinated gene expression necessary to complete brown adipocyte differentiation.
AB - Brown adipose tissue plays an important role in obesity, insulin resistance, and diabetes. We have previously shown that the transition from brown preadipocytes to mature adipocytes is mediated in part by insulin receptor substrate (IRS)-1 and the cell cycle regulator protein necdin. In this study, we used pharmacological inhibitors and adenoviral dominant negative constructs to demonstrate that this transition involves IRS-1 activation of Ras and ERK1/2, resulting in phosphorylation of cAMP response element-binding protein (CREB) and suppression of necdin expression. This signaling did not include an elevation of intracellular calcium. A constitutively active form of CREB expressed in IRS-1 knockout cells decreased necdin promoter activity, necdin mRNA, and necdin protein levels, leading to a partial restoration of differentiation. By contrast, forkhead box protein (Fox)O1, which is regulated by the phosphoinositide 3 kinase-Akt pathway, increased necdin promoter activity. Based on reporter gene assays using truncations of the necdin promoter and chromatin immunoprecipitation studies, we demonstrated that CREB and FoxO1 are recruited to the necdin promoter, likely interacting with specific consensus sequences in the proximal region. Based on these results, we propose that insulin/IGF-I act through IRS-1 phosphorylation to stimulate differentiation of brown preadipocytes via two complementary pathways: 1) the Ras-ERK1/2 pathway to activate CREB and 2) the phosphoinositide 3 kinase-Akt pathway to deactivate FoxO1. These two pathways combine to decrease necdin levels and permit the clonal expansion and coordinated gene expression necessary to complete brown adipocyte differentiation.
KW - Adipocytes, Brown
KW - Adipogenesis
KW - Animals
KW - Cell Differentiation
KW - Cells, Cultured
KW - Cyclic AMP Response Element-Binding Protein
KW - Extracellular Signal-Regulated MAP Kinases
KW - Forkhead Transcription Factors
KW - Insulin
KW - Insulin Receptor Substrate Proteins
KW - Insulin-Like Growth Factor I
KW - Mice
KW - Nerve Tissue Proteins
KW - Nuclear Proteins
KW - Phosphorylation
KW - Promoter Regions, Genetic
KW - Signal Transduction
U2 - 10.1210/en.2011-1229
DO - 10.1210/en.2011-1229
M3 - Journal article
C2 - 21862615
VL - 152
SP - 3680
EP - 3689
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
SN - 0013-7227
IS - 10
ER -
ID: 35397079