The DOI matches its Crossref record; 60 of the 60 references it cites were found in a registry or an index.
Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1
Open accessAbstract
Considerable data support the idea that forkhead box O1 (Foxo1) drives the liver transcriptional program during fasting and is then inhibited by thymoma viral proto-oncogene 1 (Akt) after feeding. Here we show that mice with hepatic deletion of Akt1 and Akt2 were glucose intolerant, insulin resistant and defective in their transcriptional response to feeding in the liver. These defects were normalized with concomitant liver-specific deletion of Foxo1. Notably, in the absence of both Akt and Foxo1, mice adapted appropriately to both the fasted and fed state, and insulin suppressed hepatic glucose production normally. A gene expression analysis revealed that deletion of Akt in liver led to the constitutive activation of Foxo1-dependent gene expression, but again, concomitant ablation of Foxo1 restored postprandial regulation, preventing the inhibition of the metabolic response to nutrient intake caused by deletion of Akt. These results are inconsistent with the canonical model of hepatic metabolism in which Akt is an obligate intermediate for proper insulin signaling. Rather, they show that a major role of hepatic Akt is to restrain the activity of Foxo1 and that in the absence of Foxo1, Akt is largely dispensable for insulin- and nutrient-mediated hepatic metabolic regulation in vivo.
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Cites
Akt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor
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Insulin signalling and the regulation of glucose and lipid metabolism
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Self-citationTSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling
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Critical nodes in signalling pathways: insights into insulin action
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Self-citationActivation of a metabolic gene regulatory network downstream of mTOR complex 1
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Self-citationInsulin-regulated hepatic gluconeogenesis through FOXO1–PGC-1α interaction
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SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth
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Research works printed but not linked: 1
- Inoki, K., Li, Y., Zhu, T., Wu, J. & Guan, K.L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol. 4, 648–657 (2002). · DOI · Paper page
Cited by
AKT/PKB Signaling: Navigating the Network
Manning, B. D., & Toker, A. (2017) · Cell · doi:10.1016/j.cell.2017.04.001 · Cited by 3,772
Mechanisms of Insulin Action and Insulin Resistance
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The PI3K/AKT Pathway in Obesity and Type 2 Diabetes
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“Additionally, those mice still maintained the normal postprandial state, even in the absence of canonical liver insulin signalling [85, 87].”
BackgroundResultThe pathogenesis of insulin resistance: integrating signaling pathways and substrate flux
Samuel, V. T., & Shulman, G. I. (2016) · Journal of Clinical Investigation · doi:10.1172/jci77812 · Cited by 1,484
The integrative biology of type 2 diabetes
Roden, M., & Shulman, G. I. (2019) · Nature · doi:10.1038/s41586-019-1797-8 · Cited by 1,167
Metadata
- Authors
- Lu, M., Wan, M., Leavens, K. F., Chu, Q., Monks, B. R., Fernandez, S., Ahima, R. S., Ueki, K., Kahn, C. R., & Birnbaum, M. J.
- Venue
- Nature Medicine
- Published
- 2012-02-19
- Volume
- 18
- Issue
- 3
- Pages
- 388-395
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2056085420
- Cited by
- 395
- References
- 60
- FWCI
- 12.43
- Type
- journal article
- Language
- en
- Open access
- green
- Licence
- www.springer.com/tdm (tdm)
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- Lu, M., Wan, M., Leavens, K. F., Chu, Q., Monks, B. R., Fernandez, S., Ahima, R. S., Ueki, K., Kahn, C. R., & Birnbaum, M. J. (2012). Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1. Nature Medicine. https://doi.org/10.1038/nm.2686
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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