ROLE OF CRTC-2, A NEW CREB CO-ACTIVATOR, IN THE NEURAL REGULATION OF GLUCOSE PRODUCTION

• Grant number: 15/20700-2
• Support Opportunities: Regular Research Grants
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Luiz Carlos Carvalho Navegantes
• Grantee: Luiz Carlos Carvalho Navegantes
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Isis Do Carmo Kettelhut

Abstract

The second messenger cAMP mediates the hyperglycemic effects of sympathetic catecholamines in response to stress. Recent studies indicate that the cyclic AMP-responsive element-binding protein (CREB) binds to a family of cAMP-regulated transcriptional co-activators (CRTCs), whose regulation and physiological role are still unknown. Thus, we hypothesized that the CRTC-2 is a critical signal in the neural regulation of hepatic glucose production. Indeed, our initial findings at Salk Institute (CA, USA) show that liver-specific CRTC-2/3 knockout mice develop hypoglycemia and do not survive to the thermal stress. To continue these studies, we intend to use different molecular approaches to assess gene expression and protein content of CRTC-2 and signaling pathways associated with this co-activator in the liver of sympathectomized mice submitted to stress (low temperature and immobilization). Animals will be injected with viral vectors that induce gene silencing of CREB and CRTC-2. The transcriptional activity of CREB in vivo will be evaluated by an imaging system in transgenic animals that expresses the reporter for CRE-luciferase. The direct effect of catecholamines on the phosphorylation of CREB/CRTC-2 and its translocation from the cytoplasm to the nucleus will be evaluated in primary hepatocytes and associated with CREB-target genes related to the regulation of glucose production. The gluconeogenic flux will be estimated by the rate of incorporation of [14-C] bicarbonate into circulating glucose and enzymatic activities of PEPCK and glucose-6-phosphatase. These results may contribute to the development of therapeutic strategies to combat the impairment of glucose homeostasis. (AU)