Metabolic homeostasis: HDACs take center stage

Abstract

Hormonal regulation of glucose and lipid metabolism is pivotal for metabolic homeostasis and energy balance. Two studies in this issue of Cell (Mihaylova et al., 2011 and Wang et al., 2011) introduce a new conserved signaling mechanism controlling catabolic gene expression: class IIa histone deacetylases (HDACs) regulate Foxo activity in Drosophila and mice.

Figure 1. Model for How Type IIa HDACs Regulate Foxo in Drosophila and Mice

Left: In vertebrates, insulin and glucagon control glucose homeostasis by differentially regulating a well-characterized pathway that involves the cAMP-dependent Protein Kinase A (PKA), AMP-activated protein kinase (AMPK), SIK1/2 (salt-inducible kinase 1/2), and the Akt kinase. This signaling cascade ultimately leads to the regulation of the Forkhead box o (Foxo) transcription factors, which control transcription of gluconeogenic genes. Mihaylova et al. (2011) find that class IIa histone deacetylases (HDACs) also control gluconeogenic gene expression in mouse hepatocytes by regulating the acetylation state of Foxo. Right: In invertebrates, glucose homeostasis is also regulated by insulin- and glucagon-like hormones, such as the Drosophila insulin-like peptides (dILPs) and the adipokinetic hormone (AKH). Wang et al. (2011) find that, in Drosophila, class IIa HDACs also regulate Foxo acetylation and ultimately gluconeogenic gene expression in the fly’s fat body. The fat body is the fly equivalent of the mammalian adipose tissue, but it also has functions similar to those of the liver.