Foxing Around with Lipid Metabolism

Abstract

Under fasting conditions, the liver burns fats and produces glucose through gluconeogenesis. Insulin, released after a meal, activates signaling pathways that inhibit fatty-acid oxidation and gluconeogenesis. In type 2 diabetes, and prediabetic insulin resistance, the response to insulin is blunted so that gluconeogenesis is maintained after a meal although inhibition of fatty acid oxidation still takes place (see Montminy and Koo). Insulin signaling leads to the phosphorylation and nuclear exclusion of the gluconeogenesis-promoting transcription factor Foxo1. Now Wolfrum et al. have investigated the role of Foxa2, a second transcription factor whose activity is inhibited through insulin signaling. Immunoblot and immunohistochemical analysis indicated that the phosphorylation and nuclear localization of Foxa2 were more sensitive than that of Foxo1 to feeding or insulin. Moreover, in hyperinsulinemic mouse models of insulin resistance, Foxa2 was in the cytoplasm in both fed and starved mice. Experiments in which insulin-receptor substrate-1 or -2 (IRS-1 or -2) was silenced with short interfering RNA in HepG2 cells indicated that insulin signaling through either IRS-1 or IRS-2 led to phosphorylation and nuclear exclusion of Foxa-2, whereas Foxo1 was a target of signaling only through IRS-2. Diabetic or insulin-resistant mice expressing a phosphorylation-resistant constitutively active Foxa2 mutant in their livers had decreased plasma glucose and insulin concentrations, decreased liver triglyceride content, weight loss, and increased insulin sensitivity. Consistent changes in the expression of enzymes involved in lipid metabolism and glycolysis were also observed. Thus, the sensitivity of Foxa2 to insulin signaling even in insulin-resistant conditions may enable the continued inhibition of fatty acid oxidation and thus the accumulation of liver triglycerides. C. Wolfrum, E. Asilmaz, E. Luca, J. M. Friedman, M. Stoffel, Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes. Nature 432 , 1027-1031 (2004). [PubMed] M. Montminy, S.-H. Koo, Outfoxing insulin resistance? Nature 432 , 958-959 (2004). [PubMed]