Acetylate During Fasting

Science Signaling  15 Nov 2011:
Vol. 4, Issue 199, pp. ec316
DOI: 10.1126/scisignal.4199ec316

The FoxO family of transcription factors mediates changes in gene expression to metabolic status. The activity of FoxO1 is decreased by acetylation at at least 7 lysine residues, and acetylation of FoxO1 is decreased in fasted animals and increased in animals that are refed after fasting. Banks et al. generated knockin mice with recombinant Foxo1 alleles encoding mutants in which glutamine was substituted for lysine residues to mimic a constitutively acetylated FoxO1 (Foxo1KQ/KQ mice) or in which arginine was substituted for lysine residues to mimic a constitutively deacetylated FoxO1 (Foxo1KR/KR mice). Foxo1KQ/KQ embryos showed impaired vasculogenesis and died in utero. Foxo1KR/KR mice were viable and, compared with wild-type mice, showed impaired glucose metabolism, as indicated by increased glucose and insulin concentrations after fasting and refeeding and increased hepatic glucose production. In contrast, lipid metabolism was improved in Foxo1KR/KR mice, as indicated by decreased concentrations of plasma free fatty acids, triglyceride, and total cholesterol. Foxo1KR/KR mice showed increased expression of genes encoding enzymes involved in hepatic gluconeogenesis and a pattern of changes in the expression of genes encoding proteins involved in lipid metabolism that suggested increased lipid oxidation. When fed a high-fat diet, Foxo1KR/KR mice gained more weight and fat mass compared with littermate controls and, when crossed with db/db mice (a model of obesity), weighed more than did controls. However, both sets of mice did not show decreased insulin resistance or a predisposition to developing diabetes. Analysis of respiratory exchanges, locomotor activity, and energy expenditure suggested that Foxo1KR/KR mice relied more heavily on lipids than on glucose as an energy source. Because other posttranslational modifications also inactivate FoxO1, the authors propose that acetylation may be a “fail-safe” mechanism to inactivate FoxO1 during prolonged fasting conditions that promotes lipid usage as an energy source.

A. S. Banks, J. Y. Kim-Muller, T. L. Mastracci, N. M. Kofler, L. Qiang, R. A. Haeusler, M. J. Jurczak, D. Laznik, G. Heinrich, V. T. Samuel, G. I. Shulman, V. E. Papaioannou, D. Accili, Dissociation of the glucose and lipid regulatory functions of FoxO1 by targeted knockin of acetylation-defective alleles in mice. Cell Metab. 14, 587–597 (2011). [PubMed]