Role of CRTC2 in Metabolic Homeostasis: Key Regulator of Whole-Body Energy Metabolism?

Abstract

Cyclic adenosine monophosphate (cAMP) signaling is critical for regulating metabolic homeostasis in mammals. In particular, transcriptional regulation by cAMP response element-binding protein (CREB) and its coactivator, CREB-regulated transcription coactivator (CRTC), is essential for controlling the expression of critical enzymes in the metabolic process, leading to more chronic changes in metabolic flux. Among the CRTC isoforms, CRTC2 is predominantly expressed in peripheral tissues and has been shown to be associated with various metabolic pathways in tissue-specific manners. While initial reports showed the physiological role of CRTC2 in regulating gluconeogenesis in the liver, recent studies have further delineated the role of this transcriptional coactivator in the regulation of glucose and lipid metabolism in various tissues, including the liver, pancreatic islets, endocrine tissues of the small intestines, and adipose tissues. In this review, we discuss recent studies that have utilized knockout mouse models to delineate the role of CRTC2 in the regulation of metabolic homeostasis.

Keywords: CRTC2 protein, human; Crtc2 protein, mouse; Cyclic AMP; Energy metabolism; Transcription, genetic.

Fig. 1. The structure and regulatory mechanisms of CREB-regulated transcription coactivator 2 (CRTC2). CRTC2 comprises a CREB-binding domain (CBD), a regulatory domain (RD), and a transactivation domain (TAD), each of which is targeted by various regulatory enzymes described in the text. CREB, cyclic adenosine monophosphate (cAMP) response element-binding protein; PRMT6, protein arginine methyltransferase 6; AMPK, adenosine monophosphate-activated protein kinase; SIK, salt-inducible kinase; PP2B, protein phosphatase 2B; PP4, protein phosphatase 4; OGT, O-linked β-N-acetylglucosamine transferase; CBP, CREB-binding protein; Sirt1, sirtuin 1; HDAC, histone deacetylase; COP1, constitutive photomorphogenic 1; N, amino-terminus; R, arginine; S, serine; K, lysine; C, carboxy-terminus.

Fig. 2. Role of CREB-regulated transcription coactivator 2 (CRTC2) in the regulation of metabolic pathways in various tissues. In the liver, CRTC2 is critical for the regulation of gluconeogenesis by coactivating cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) and CREBH. CRTC2 is also involved in the regulation of lipid metabolism via miR-34a-mediated repression of fatty acid β oxidation and the inhibition of sterol regulatory element-binding protein 1 (SREBP-1)-dependent lipogenic gene transcription. CRTC2 is also crucial for the control of systemic glucose homeostasis, by regulating pancreatic β-cell function and the production of glucagon-like peptide 1 (GLP-1) from intestinal L cells. The role of CRTC2 in white adipocytes requires further study, but the depletion of CRTC2 leads to improved glucose uptake as well as an increase in adiponectin secretion by the white adipocytes in vitro. PKA, protein kinase A; PP4, protein phosphatase 4; PP2B, protein phosphatase 2B; CBP, CREB binding protein; PEPCK, phosphoenolpyruvate carboxykinase; ERRγ, estrogen-related receptor γ; GR, glucocorticoid receptor; FoxO1, forkhead box protein O1; HNF, hepatic nuclear factor; Sirt1, sirtuin 1; PPARα, peroxisome proliferator-activated receptor α; FGF21, fibroblast growth factor 21; mTOR, mammalian target of rapamycin; ATP, adenosine triphosphate; IRS2, insulin receptor substrate 2; SIK2, salt-inducible kinase 2; KO, knockout; ATF3, activating transcription factor 3; Glut4, glucose transporter 4; TGR5, Takeda-G-protein-receptor-5; AC, adenylyl cyclase; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1α; Gcg, glucagon; oxphos, oxidative phosphorylation.