Palmitic Acid Reduces the Autophagic Flux and Insulin Sensitivity Through the Activation of the Free Fatty Acid Receptor 1 (FFAR1) in the Hypothalamic Neuronal Cell Line N43/5

Chronic consumption of high fat diets (HFDs), rich in saturated fatty acids (SatFAs) like palmitic acid (PA), is associated with the development of obesity and obesity-related metabolic diseases such as type II diabetes mellitus (T2DM). Previous studies indicate that PA accumulates in the hypothalamus following consumption of HFDs; in addition, HFDs consumption inhibits autophagy and reduces insulin sensitivity. Whether malfunction of autophagy specifically in hypothalamic neurons decreases insulin sensitivity remains unknown. PA does activate the Free Fatty Acid Receptor 1 (FFAR1), also known as G protein-coupled receptor 40 (GPR40); however, whether FFAR1 mediates the effects of PA on hypothalamic autophagy and insulin sensitivity has not been shown. Here, we demonstrate that exposure to PA inhibits the autophagic flux and reduces insulin sensitivity in a cellular model of hypothalamic neurons (N43/5 cells). Furthermore, we show that inhibition of autophagy and the autophagic flux reduces insulin sensitivity in hypothalamic neuronal cells. Interestingly, the inhibition of the autophagic flux, and the reduction in insulin sensitivity are prevented by pharmacological inhibition of FFAR1. Our findings show that dysregulation of autophagy reduces insulin sensitivity in hypothalamic neuronal cells. In addition, our data suggest FFAR1 mediates the ability of PA to inhibit autophagic flux and reduce insulin sensitivity in hypothalamic neuronal cells. These results reveal a novel cellular mechanism linking PA-rich diets to decreased insulin sensitivity in the hypothalamus and suggest that hypothalamic autophagy might represent a target for future T2DM therapies

Epidemiología molecular y análisis filogenético de la infección por el virus del papiloma humano en mujeres con lesiones cervicales y cáncer en la región litoral del Ecuador

The aim of the present study was to gather information regarding the molecular epidemiology of Human papillomavirus (HPV) and related risk factors in a group of women with low- and high-grade cervical lesions and cancer from the coastal region of Ecuador. In addition, we studied the evolution of HPV variants from the most prevalent types and provided a temporal framework for their emergence, which may help to trace the source of dissemination within the region. We analyzed 166 samples, including 57 CIN1, 95 CIN2/3 and 14 cancer cases. HPV detection and typing was done by PCR-sequencing (MY09/MY11). HPV variants and estimation of the time to most recent common ancestor (tMRCA) was assessed through phylogeny and coalescence analysis. HPV DNA was found in 54.4% of CIN1, 74.7% of CIN2/3 and 78.6% of cancer samples. HPV16 (38.9%) and HPV58 (19.5%) were the most prevalent types. Risk factors for the development of cervical lesions/cancer were the following: three or more pregnancies (OR = 4.3), HPV infection (OR = 3.7 for high-risk types; OR = 3.5 for HPV16), among others. With regard to HPV evolution, HPV16 isolates belonged to lineages A (69%) and D (31%) whereas HPV58 isolates belonged only to lineage A. The period of emergence of HPV16 was in association with human populations (tMRCA = 91. 052 years for HPV16A and 27. 000 years for HPV16D), whereas HPV58A preceded Homo sapiens evolution (322. 257 years). This study provides novel data on HPV epidemiology and evolution in Ecuador, which will be fundamental in the vaccine era.Fil: Bedoya Pilozo, Cesar H.. Escuela Superior Politécnica del Litoral; Ecuador. Instituto Nacional de Investigaciones en Salud Pública; EcuadorFil: Medina Magües, Lex G.. Escuela Superior Politécnica del Litoral; EcuadorFil: Espinosa García, Maylen. Instituto Nacional de Investigaciones en Salud Pública; EcuadorFil: Sánchez, Martha. Instituto Nacional de Investigaciones en Salud Pública; EcuadorFil: Parrales Valdiviezo, Johanna V.. Instituto Nacional de Investigaciones en Salud Pública; EcuadorFil: Molina, Denisse. Instituto Nacional de Investigaciones en Salud Pública; EcuadorFil: Ibarra, María A.. Instituto Nacional de Investigaciones en Salud Pública; EcuadorFil: Quimis Ponce, María. Instituto Nacional de Investigaciones en Salud Pública; EcuadorFil: España, Karool. Instituto Nacional de Investigaciones en Salud Pública; EcuadorFil: Párraga Macias, Karla E.. Instituto Nacional de Investigaciones en Salud Pública; EcuadorFil: Cajas Flores, Nancy V.. Instituto Nacional de Investigaciones en Salud Pública; EcuadorFil: Solon, Orlando A.. Instituto Nacional de Investigaciones en Salud Pública; Ecuador. Universidad Agraria del Ecuador; EcuadorFil: Robalino Penaherrera, Jorge A.. Instituto Nacional de Investigaciones en Salud Pública; EcuadorFil: Chedraui, Peter. Hospital Gineco-Obstétrico Enrique C. Sotomayor; EcuadorFil: Escobar, Saul. Universidad Católica de Guayaquil; EcuadorFil: Loja Chango, Rita D.. Universidad Católica de Guayaquil; EcuadorFil: Ramirez Morán, Cecibel. Universidad Católica de Guayaquil; EcuadorFil: Espinoza Caicedo, Jasson. Universidad Católica de Guayaquil; EcuadorFil: Sánchez Giler, Sunny. Universidad Especialidades Espíritu Santo. Facultad de Ciencias Médicas; EcuadorFil: Limia, Celia M.. Instituto de Medicina Tropical Pedro Kouri; CubaFil: Alemán, Yoan. Instituto de Medicina Tropical Pedro Kouri; CubaFil: Soto, Yudira. Instituto de Medicina Tropical Pedro Kouri; CubaFil: Kouri, Vivian. Instituto de Medicina Tropical Pedro Kouri; CubaFil: Culasso, Andrés Carlos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Virología; ArgentinaFil: Badano, Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste; Argentina. Secretaría de Educación Superior, Ciencia, Tecnología e Innovación; Ecuador. Universidad Nacional de Misiones. Facultad de Ciencias Exactas, Químicas y Naturales. Laboratorio de Biología Molecular Aplicada; Argentin

Fetal asphyctic preconditioning in rats results in a preserved placental inflammatory phenotype at birth

Introduction: Perinatal asphyxia (PA) is a major cause of neonatal mortality and morbidity. Research has shown that in rats fetal asphyxia (FA) can provoke neuroprotection against a subsequent more severe perinatal asphyctic insult. This is called fetal asphyctic preconditioning (PC). Our objective was to investigate alterations in the placental inflammatory phenotype associated with PC. Methods: FA was induced in the rat at embryonic day 17 by reversibly clamping the uterine circulation and PA was induced at birth by submersion of the uterine horns in a saline bath for 19 min. The effect of PC was studied by inducing FA at E17, followed by PA at E21. Placental TNF-alpha, IL-1 beta, IL-6 and IL-10 mRNA and protein levels were measured by qPCR and ELISA. Results: IL-1 beta mRNA increased in the labouring FA group, but IL-10 protein decreased after both FA and PA. In the PC group, IL-113 mRNA and protein levels were similar to controls. IL-6 protein increased 6 h after FA, however decreased 24 h after FA. IL-6 mRNA was higher in the labouring PA group. IL-10 protein decreased 24 h after FA. At birth, IL-10 mRNA increased in the PA group; however, IL-10 protein decreased in both the PA and the FA group. In the PC group, IL-10 mRNA and protein were similar to control levels. Discussion: Depleted protein concentrations of IL-10 and IL-113 after one single asphyctic insult were reversed after fetal asphyctic PC. In addition, PC placentas showed less up-regulation of IL-6 mRNA compared to the PA ones. This modulated placental inflammatory phenotype might contribute to the improved neonatal outcome showed after fetal asphyctic PC

Polymorphism of the THOC5 of the transcription/export multiprotein complex and its correlation with the lipid and metabolic profile in middle-aged women

The transcription/export complex (TREX) is formed by a core called THO. These are necessary for the transcription and packaging of messenger RNA and its subsequent nuclear exportation. Studies have correlated THO-specific polymorphisms with abnormalities of HDL-C metabolism. To correlate lipid and metabolic parameters with the genetic variants of the rs8135828 polymorphism of the THOC5 gene in middle-aged women. DNA was extracted from the whole blood of 183 women aged 40-65 and tested for the rs8135828 polymorphism of the THOC5 gene using real-time PCR. HDL-C, LDL-C, triglyceride, and total cholesterol levels, as well as other metabolic parameters, were correlated with the polymorphism genotypes: GG, AG, and AA. Mean age of women was 50.6 +/- 6.3 years, 54.6% were postmenopausal and 16.4% had the metabolic syndrome. GG was the most frequently determined genotype (62.3%). There were no differences in lipid levels according to genotypes; although there was a trend for lower HDL-C levels for the AA and AG + AA genotypes. Those with the AG and AG + AA genotypes displayed significantly higher glucose levels (p = .02 and p = .002, respectively); with a trend toward a higher metabolic syndrome prevalence and increased abdominal perimeters in both variants (AG and AG + AA). The AG genotype was related to higher glucose levels but not with abnormal lipid parameters. There is a need for more research in this regard

Palmitic acid reduces the autophagic flux and insulin sensitivity through the activation of the free fatty acid receptor 1 (FFAR1) in the hypothalamic neuronal cell line N43/5

Copyright © 2019 Hernández-Cáceres, Toledo-Valenzuela, Díaz-Castro, Ávalos, Burgos, Narro, Peña-Oyarzun, Espinoza-Caicedo, Cifuentes-Araneda, Navarro-Aguad, Riquelme, Troncoso, Criollo and Morselli. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Chronic consumption of high fat diets (HFDs), rich in saturated fatty acids (SatFAs) like palmitic acid (PA), is associated with the development of obesity and obesity-related metabolic diseases such as type II diabetes mellitus (T2DM). Previous studies indicate that PA accumulates in the hypothalamus following consumption of HFDs; in addition, HFDs consumption inhibits autophagy and reduces insulin sensitivity. Whether malfunction of autophagy specifically in hypothalamic neurons decreases insulin sensitivity remains unknown. PA does activate the Free Fatty Acid Receptor 1 (FFAR1), also known as G protein-coupled receptor 40 (GPR40); however, whether FFAR1 mediates the effects of PA on hypothalamic autophagy and insulin sensitivity has not been shown. Here, we demonstrate that exposure to PA inhibits the autophagic flux and reduces insulin sensitivity in a cellular model of hypothalamic neurons (N43/5 cells). Furthermore, we show that inhibition of autophagy and the autophagic flux reduces insulin sensitivity in hypothalamic neuronal cells. Interestingly, the inhibition of the autophagic flux, and the reduction in insulin sensitivity are prevented by pharmacological inhibition of FFAR1. Our findings show that dysregulation of autophagy reduces insulin sensitivity in hypothalamic neuronal cells. In addition, our data suggest FFAR1 mediates the ability of PA to inhibit autophagic flux and reduce insulin sensitivity in hypothalamic neuronal cells. These results reveal a novel cellular mechanism linking PA-rich diets to decreased insulin sensitivity in the hypothalamus and suggest that hypothalamic autophagy might represent a target for future T2DM therapies