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Insulin/IGF-I Regulation of Necdin and Brown Adipocyte Differentiation Via CREB- and FoxO1- Associated Pathways
journal contribution
posted on 2013-11-01, 00:00 authored by Aaron M. Cypess, Hongbin Zhang, Tim J. Schulz, Tian Lian Huang, Daniel O. Espinoza, Karsten Kristiansen, Terry G. Unterman, Yu-Hua TsengBrown 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 pathwayto
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.
Funding
This work was supported by the Eli Lilly Foundation and National Institutes of Health Grants DK070722, DK077097, P30 DK46200, and P30 DK040561 (to Y.-H.T.), DK33201, DK046200, DK081604, DK087317, and RR025757 (to Endocrinology, October 2011, 152(10):3680–3689 endo.endojournals.org 3687 A.M.C.), andDK41430(to T.G.U.), the Eleanor and Miles Shore 50th Anniversary Fellowship Program from Harvard Medical School (Y.-H.T.), the Clinical Investigator Training Program, Beth Israel Deaconess Medical Center-Harvard/Massachusetts Institute of Technology Health Sciences and Technology, in collaboration with Pfizer, Inc. and Merck & Co. (A.M.C.), and the Department of Veterans Affairs Merit Review Program (T.G.U.).
History
Publisher Statement
This is a copy of an article published in Endocrinology © 2011 Endocrine Society.Publisher
Endocrine SocietyLanguage
- en_US
issn
1945-7170Issue date
2011-10-01Usage metrics
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