ABSTRACT
BACKGROUND AND AIM: Although it is well established that hormones like glucagon stimulates gluconeogenesis via the PKA-mediated phosphorylation of CREB and dephosphorylation of the cAMP-regulated CREB coactivators CRTC2, the role of neural signals in the regulation of gluconeogenesis remains uncertain. METHODS AND RESULTS: Here, we characterize the noradrenergic bundle architecture in mouse liver; we show that the sympathoexcitation induced by acute cold exposure promotes hyperglycemia and upregulation of gluconeogenesis via triggering of the CREB/CRTC2 pathway. Following its induction by dephosphorylation, CRTC2 translocates to the nucleus and drives the transcription of key gluconeogenic genes. Rodents submitted to different models of sympathectomy or knockout of CRTC2 do not activate gluconeogenesis in response to cold. Norepinephrine directly acts in hepatocytes mainly through a Ca2+-dependent pathway that stimulates CREB/CRTC2, leading to activation of the gluconeogenic program. CONCLUSION: Our data demonstrate the importance of the CREB/CRTC2 pathway in mediating effects of hepatic sympathetic inputs on glucose homeostasis, providing new insights into the role of norepinephrine in health and disease.
ABSTRACT
INTRODUCTION: Objective: this study aimed to evaluate the association between polymorphisms of INSIG, PCSK9 and FTO genes with anthropometric, biochemical characteristics and presence of metabolic syndrome in patients with severe obesity. Material and methods: the present study enrolled 150 patients with grade II or III obesity, who were submitted to nutritional assessment, blood pressure measurement and peripheral blood collection. INSIG2 (rs75666605), PCSK9 (rs505151), and FTO (rs9939609) polymorphisms were genotyped using TaqMan Pre-Designed SNP Genotyping Assays probes in real time polymerase chain reaction (PCR). The experimental data are processed in SPSS Statistics 22.0 (p < 0.05). Results: in this study, 72.2% of obese subjects had metabolic syndrome (MS). There was a higher prevalence of AA (86.9%), CG (51.1%) and AT (46.2%) genotypes for the PCSK9, INSIG2 and FTO polymorphisms, respectively. There was no association of these polymorphisms with the prevalence of MS (p > 0.05). On the other hand, individuals with at least one variant allele (G) for the INSIG2 gene had higher triglycerides levels, systolic and diastolic blood pressure (p < 0.05). Conclusions: the polymorphism rs7566605 of the INSIG2 gene is associated with higher triglycerides levels and blood pressure values, which are also considered as risk factors for the development of MS.
INTRODUCCIÓN: Objetivo: este estudio tuvo como objetivo evaluar la asociación entre polimorfismos de los genes INSIG, PCSK9 y FTO con las características antropométricas, bioquímicas y la presencia de síndrome metabólico (SM) en pacientes con obesidad grave. Material y métodos: el presente estudio incluyó 150 pacientes con obesidad de grado II o III, que fueron sometidos a evaluación nutricional, medición de la presión arterial y extracción de sangre periférica. Los polimorfismos INSIG2 (rs75666605), PCSK9 (rs505151) y FTO (rs9939609) fueron genotipados utilizando sondas TaqMan Pre-Designed SNP Genotyping Assays en la reacción en cadena de la polimerasa en tiempo real (PCR). Los datos experimentales se procesan en SPSS Statistics 22.0 (p < 0,05). Resultados: en este estudio, el 72,2% de los sujetos obesos tenían síndrome metabólico (EM). Hubo una mayor prevalencia de genotipos AA (86,9%), CG (51,1%) y AT (46,2%) para los polimorfismos PCSK9, INSIG2 y FTO, respectivamente. No hubo asociación de estos polimorfismos con la prevalencia de SM (p > 0,05). Por otro lado, los individuos con al menos una variante de alelo (G) para el gen INSIG2 tenían niveles más altos de triglicéridos, presión arterial sistólica y diastólica (p < 0,05). Conclusiones: el polimorfismo rs7566605 del gen INSIG2 se asocia con niveles más altos de triglicéridos y valores de presión arterial, que también se consideran factores de riesgo para el desarrollo del síndrome metabólico.
