Impaired Regulation of Hepatic Glucose Production in Mice Lacking the Forkhead Transcription Factor Foxo1 in Liver

Abstract

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.

Sequence variation between the mouse and human glucose-6-phosphatase catalytic subunit gene promoters results in differential activation by peroxisome proliferator activated receptor gamma coactivator-1α

“…This is consistent with the synergistic interaction between FOXO1 and PGC-1α seen in both H4IIE cells [41] and immortalised mouse hepatocytes [40]. However, while the effect of PGC-1α on G6pc expression was markedly reduced in primary hepatocytes lacking FOXO1, a~20-fold induction remained [45]. In contrast, the ability of PGC-1α to stimulate G6pc expression in hepatocytes derived from mice lacking HNF-4α is completely lost [20].…”

“…In contrast, the ability of PGC-1α to stimulate G6pc expression in hepatocytes derived from mice lacking HNF-4α is completely lost [20]. The results of Matsumoto and colleagues [45] are therefore consistent with our model, in which PGC-1α stimulates G6PC-luciferase fusion gene expression through HNF-4α, with the binding of FOXO1 to the G6PC promoter being neither required nor sufficient for this induction, although it does act synergistically to enhance the response [41]. Published reports suggest that this model is also consistent with the mechanism of action of PGC-1α on PEPCK expression.…”

“…The synergistic action of FOXO1 and PGC-1α on G6PC-luciferase fusion gene transcription could then feasibly be mediated through combined binding to CREB binding protein/p300. More recently, Matsumoto and colleagues [45] demonstrated in primary hepatocytes lacking FOXO1 that the induction of G6PC expression by PGC-1α was markedly reduced. This is consistent with the synergistic interaction between FOXO1 and PGC-1α seen in both H4IIE cells [41] and immortalised mouse hepatocytes [40].…”

The hepatic FOXQ1 transcription factor regulates glucose metabolism in mice

“…The expression of key gluconeogenic genes, Pck1 and G6pc, which encode phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), respectively, is controlled at the transcriptional level by hormones, including insulin, glucagon and glucocorticoids [3,4]. In contrast, insulin inhibits hepatic gluconeogenesis by negatively regulating transcriptional factors, including FOXO1 and PGC-1α [2,[5][6][7][8][9][10].…”

“…In contrast, the decreased blood insulin levels during fasting promote FOXO1 nuclear localisation, where it collaborates with peroxisome proliferator-activated receptor, γ, co-activator 1 α (PGC-1α) to increase the expression of the key gluconeogenic genes, Pck1 and G6pc, via direct binding to insulin response elements (IREs) in their promoters [2,11,14,15]. Hepatic FOXO1 deficiency in mice impairs fasting-induced gluconeogenesis, subsequently leading to lowered blood glucose level [8].…”