HDACs confer glucagon responsiveness to FoxO for gluconeogenesis in the liver

Abstract

In mammals deprived of food, induction of hepatic glucose production (HGP) is important to ensure energy homeostasis, including prevention of hypoglycemia in response to the energy demands [1], and is especially critical in sites that predominantly utilize glucose as an energy source, such as the brain, red blood cells, and renal medulla. Glucose homeostasis is maintained through tight regulation of glucose production (i.e., glycogenolysis and gluconeogenesis) in the liver during the state of fasting and uptake of glucose in peripheral tissues under the fed condition. The pancreatic hormones glucagon and insulin are central to this regulation. During fasting, glucagon enhances HGP to maintain euglycemia. Conversely, when nutrients are increased after a meal, insulin blunts HGP and increases glucose uptake in the skeletal muscle and adipose tissue to prevent hyperglycemia. However, these processes are dysregulated in type 2 diabetes, resulting in the development of hyperglycemia [2]. The aberrant increase of HGP during the postabsorptive state in diabetic patients is primarily due to suppression failure by insulin, resulting primarily from excessive gluconeogenesis rather than glycogenolysis [3]. Gluconeogenesis is mainly regulated at the transcriptional level of rate-limiting gluconeogenic enzymes, such as glucose-6-phosphatase (G6pc; G6Pase) and phosphoenolpyruvate carboxykinase (Pck1; PEPCK) through hormone-dependent modulation of transcriptional regulators, including the transcription factors for FoxO (forkhead box O), CREB (cAMP response element binding protein), HNF4ahepatocytes nuclear factor 4a and glucocorticoid receptor, and transcriptional coactivators, such as PGC-1a (peroxisome proliferator-activated receptor gamma coactivator-1 alpha), CRTC2 (CREB-regulated transcription coactivator 2), and the histone acetyltransferase CBP (CREB-binding protein) [4]. Glucagon stimulates the induction of gluconeogenic genes through the following signaling pathway: cAMP, a second messenger of the glucagon receptor, leads cAMPdependent protein kinase (PKA)-mediated activation of the CRTC2/CREB complex to induce PGC-1a, which in turn coactivates the FoxO and HNF4a transcription factors on the G6pc and Pck1 promoters (Fig. 1). Insulin blunts gluconeogenic gene induction by affecting the same pathway. This is mediated mainly through the serine/threonine kinase Akt, which inactivates FoxO and PGC-1a via direct phosphorylation, as well as CRTC2 via SIK (salt-inducible kinase) 1/2 [5] (Fig. 1). The FoxO family of transcription factors, mainly FoxO1 and FoxO3 in mammalian liver [6], plays pivotal roles in regulating gluconeogenesis, as shown by studies on in vivo loss of and gain of function study; FoxO1 loss of function in the liver reduces HGP by inhibiting gluconeogenesis and glycogenolysis, resulting in neonatal and fasting-induced hypoglycemia [6], whereas its gain of function impairs hormonal regulation of HGP, including gluconeogenesis [7]. FoxO is regulated by insulin; Akt-dependent phosphorylation promotes its nuclear exclusion and inactivates FoxO1, leading to the reduction of gluconeogenic genes [8]. FoxO is also controlled by cAMP, which promotes its dephosphorylation and nuclear retention in cultured hepatocytes [8]. In vivo, FoxO1 loss of function in the liver attenuates gluconeogenic gene induction and HGP during fasting [6]. Although these findings indicate that FoxO is indispensable for cAMP-dependent induction of gluconeogenic genes, the M. Matsumoto (&) Department of Molecular Metabolic Regulation, Diabetes Research Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan e-mail: mmatsumoto@ri.ncgm.go.jp