FoxOs function synergistically to promote glucose production

Abstract

Hepatic glucose production (HGP) plays a vital role in maintaining the supply of glucose to the body, and transcription factor FoxO1 is known to confer hormone responsiveness onto HGP. Mice with a liver-specific FoxO1 deletion (L-FoxO1) show reduced HGP and reduced expression of glucose production genes. To determine the contribution of additional transcription factors to HGP, we created double and triple liver-specific knock-outs lacking FoxO1, FoxO3, and FoxO4 or the related protein FoxA2. We show that, when compared with single knock-out of FoxO1, triple ablation of FoxO genes causes more pronounced fasting hypoglycemia, increased glucose tolerance, and enhanced insulin sensitivity, with decreased plasma insulin levels. In contrast, combined ablation of FoxO1 and FoxA2 phenocopied the single knock-out of FoxO1. These data indicate that FoxOs work in concert to regulate multiple aspects of hepatic glucose metabolism.

FIGURE 1.

FoxO expression in single and compound knock-out mice. Mice were fasted for 5 h prior to sacrifice, and livers were analyzed by qPCR (n = 6–7). Values shown are relative to same strain littermate controls. **, p < 0.01, ***, p < 0.001.

FIGURE 2.

Glucose metabolism. A, glucose at postnatal day 2 (n = 4–16). B, serum insulin during ad libitum feeding or after a 5-h fast (n = 6–21). C, glucose tolerance tests (n = 9–18/group). The mean values of all control mice are shown here. D, area under the curve, relative to same strain littermate controls. *, p < 0.05, **, p < 0.01, ***, p < 0.001.

FIGURE 3.

Gene expression. mRNA was extracted from livers of mice fasted for 5 h. qPCR analyses were performed with n = 6–7/group, and values shown are relative to same strain controls. **, p < 0.01 versus same strain controls.