Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1
Open Access
- 19 February 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Medicine
- Vol. 18 (3), 388-395
- https://doi.org/10.1038/nm.2686
Abstract
The insulin signaling pathway regulating glucose homeostasis that has been well accepted is insulin-to-insulin receptor-to-IRS proteins-to-PI3K-to-Akt-to-Foxo1—a pathway that does not respond properly in states of insulin resistance, including type 2 diabetes. In a new study from Morris Birnbaum and colleagues, an alternative insulin signaling pathway has been uncovered, as mice with liver-specific deletion of Akt and Foxo1 still respond normally to nutritional cues and properly regulate glucose metabolism. Although the exact nature of this alternative pathway needs to be identified, the results should open many new avenues of exploration in the field of type 2 diabetes. 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.Keywords
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