Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pone.0006189
Title: Insulin stimulates adipogenesis through the Akt-TSC2-mTORC1 pathway
Authors: Zhang H.H.
Huang J. 
D黺el K.
Boback B.
Wu S.
Squillance R.M.
Wu C.-L.
Manning B.D.
Keywords: insulin
mammalian target of rapamycin
messenger RNA
peroxisome proliferator activated receptor gamma
protein kinase B
triacylglycerol
tuberin
insulin
messenger RNA
mTORC1 protein, mouse
peroxisome proliferator activated receptor gamma
transcription factor
tuberin
tumor suppressor protein
adipocyte
adipogenesis
adipose tissue
angiomyolipoma
animal cell
article
cell differentiation
cell strain 3T3
controlled study
embryo
enzyme activation
enzyme activity
enzyme phosphorylation
fibroblast culture
hormonal regulation
hormone action
human
human cell
human tissue
insulin resistance
kidney tumor
mouse
nonhuman
protein expression
protein protein interaction
protein targeting
signal transduction
smooth muscle
tuberous sclerosis
adipocyte
animal
cell division
cytology
drug effect
gene silencing
genetics
immunohistochemistry
phosphorylation
physiology
Western blotting
Mammalia
3T3-L1 Cells
Adipocytes
Animals
Blotting, Western
Cell Division
Gene Knockdown Techniques
Humans
Immunohistochemistry
Insulin
Mice
Phosphorylation
PPAR gamma
Proto-Oncogene Proteins c-akt
RNA, Messenger
Signal Transduction
Transcription Factors
Tumor Suppressor Proteins
Issue Date: 2009
Citation: Zhang H.H., Huang J., D黺el K., Boback B., Wu S., Squillance R.M., Wu C.-L., Manning B.D. (2009). Insulin stimulates adipogenesis through the Akt-TSC2-mTORC1 pathway. PLoS ONE 4 (7) : e6189. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0006189
Rights: Attribution 4.0 International
Abstract: Background: The signaling pathways imposing hormonal control over adipocyte differentiation are poorly understood. While insulin and Akt signaling have been found previously to be essential for adipogenesis, the relative importance of their many downstream branches have not been defined. One direct substrate that is inhibited by Akt-mediated phosphorylation is the tuberous sclerosis complex 2 (TSC2) protein, which associates with TSC1 and acts as a critical negative regulator of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1). Loss of function of the TSC1-TSC2 complex results in constitutive mTORC1 signaling and, through mTORC1-dependent feedback mechanisms and loss of mTORC2 activity, leads to a concomitant block of Akt signaling to its other downstream targets. Methodology/Principal Findings: We find that, despite severe insulin resistance and the absence of Akt signaling, TSC2-deficient mouse embryo fibroblasts and 3T3-L1 pre-adipocytes display enhanced adipocyte differentiation that is dependent on the elevated mTORC1 activity in these cells. Activation of mTORC1 causes a robust increase in the mRNA and protein expression of peroxisome proliferator-activated receptor gamma (PPAR?), which is the master transcriptional regulator of adipocyte differentiation. In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis. Finally, renal angiomyolipomas from patients with tuberous sclerosis complex contain both adipose and smooth muscle-like components with activated mTORC1 signaling and elevated PPARc expression. Conclusions/Significance: This study demonstrates that activation of mTORC1 signaling is a critical step in adipocyte differentiation and identifies TSC2 as a primary target of Akt driving this process. Therefore, the TSC1-TSC2 complex regulates the differentiation of mesenchymal cell lineages, at least in part, through its control of mTORC1 activity and PPAR? expression. � 2009 Zhang et al.
Source Title: PLoS ONE
URI: https://scholarbank.nus.edu.sg/handle/10635/161836
ISSN: 19326203
DOI: 10.1371/journal.pone.0006189
Rights: Attribution 4.0 International
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