Impaired regulation of hepatic glucose production in mice lacking the forkhead transcription factor Foxo1 in liver.

By M. Matsumoto, A. Pocai, L. Rossetti, R. DePinho, D. Accili. Cell Metabolism, 2007

600 citations recorded by the source corpus.

The hallmark of type 2 diabetes is excessive hepatic glucose production. Several transcription factors and coactivators regulate this process in cultured cells. But gene ablation experiments have yielded few clues as to the physiologic mediators of this process in vivo. We show that inactivation of the gene encoding forkhead protein Foxo1 in mouse liver results in 40% reduction of glucose levels at birth and 30% reduction in adult mice after a 48 hr fast. Gene expression and glucose clamp studies demonstrate that Foxo1 ablation impairs fasting- and cAMP-induced glycogenolysis and gluconeogenesis. Pgc1alpha is unable to induce gluconeogenesis in Foxo1-deficient hepatocytes, while the cAMP response is significantly blunted. Conversely, Foxo1 deletion in liver curtails excessive glucose production caused by generalized ablation of insulin receptors and prevents neonatal diabetes and hepatosteatosis in insulin receptor knockout mice. The data provide a unifying mechanism for regulation of hepatic glucose production by cAMP and insulin.

Subfields: Aging, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/3e3a50f16dab5880c48d16fa522b15e998ae9637

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Aging

1. W. Gu
2. D. Accili
3. A. Brunet
4. S. Manolagas
5. Hilmar Bading
6. G. Hardingham

In Molecular Biology

1. W. Gu
2. A. Brunet
3. N. Kon
4. M. Birnbaum
5. A. V. D. Heuvel
6. David H. Gross
7. L. Rossetti
8. M. Matsumoto

Citations in the corpus

• SirT1 gain-of-function increases energy efficiency and prevents diabetes in mice (2008, positive): “Metabolic and Glucose Clamp Studies We performed all assays as described (Lin et al., 2007; Matsumoto et al., 2007).”
• Energy Metabolism in the Liver (2014, neutral): “3A) (71, 73, 166, 187, 214, 298).”
• The role of FoxO in the regulation of metabolism (2008, background): “Loss of FoxO1 in the liver reduces IGFBP1 expression in fasted mice (Matsumoto et al., 2007).”
• The evolution of Fox genes and their role in development and disease (2009, background): “Furthermore, when Foxo1 was conditionally ablated in mouse hepatocytes, stimulation of hepatic glucose production by both glycogenolysis and gluconeogenesis was impaire”
• FoxO transcription factors in the maintenance of cellular homeostasis during aging. (2008, background): “FoxO1 regulates glucose levels by acting on target genes such as glucose-6phosphatase (G6pc) (glycogenolytic), and phosphoenolpyruvate carboxykinase 1 (Pck1), and peroxisome proliferatoractivated receptor gamma coactivator 1a (Ppargc1a) (gluconeogenetic) (Table 1) [29,57 ,58].”