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Serum neuregulin 4 is negatively correlated with insulin sensitivity in humans and impairs mitochondrial respiration in HepG2 cells

Neuregulin 4 (NRG4) has been described to improve metabolic disturbances linked to obesity status in rodent models. The findings in humans are controversial. We aimed to investigate circulating NRG4 in association with insulin action in humans and the possible mechanisms involved. Insulin sensitivit...

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Autores principales: Martínez, Cristina, Latorre, Jèssica, Ortega, Francisco, Arnoriaga-Rodríguez, María, Lluch, Aina, Oliveras-Cañellas, Núria, Díaz-Sáez, Francisco, Aragonés, Julian, Camps, Marta, Gumà, Anna, Ricart, Wifredo, Fernández-Real, José Manuel, Moreno-Navarrete, José María
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9521671/
https://www.ncbi.nlm.nih.gov/pubmed/36187779
http://dx.doi.org/10.3389/fphys.2022.950791
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author Martínez, Cristina
Latorre, Jèssica
Ortega, Francisco
Arnoriaga-Rodríguez, María
Lluch, Aina
Oliveras-Cañellas, Núria
Díaz-Sáez, Francisco
Aragonés, Julian
Camps, Marta
Gumà, Anna
Ricart, Wifredo
Fernández-Real, José Manuel
Moreno-Navarrete, José María
author_facet Martínez, Cristina
Latorre, Jèssica
Ortega, Francisco
Arnoriaga-Rodríguez, María
Lluch, Aina
Oliveras-Cañellas, Núria
Díaz-Sáez, Francisco
Aragonés, Julian
Camps, Marta
Gumà, Anna
Ricart, Wifredo
Fernández-Real, José Manuel
Moreno-Navarrete, José María
author_sort Martínez, Cristina
collection PubMed
description Neuregulin 4 (NRG4) has been described to improve metabolic disturbances linked to obesity status in rodent models. The findings in humans are controversial. We aimed to investigate circulating NRG4 in association with insulin action in humans and the possible mechanisms involved. Insulin sensitivity (euglycemic hyperinsulinemic clamp) and serum NRG4 concentration (ELISA) were analysed in subjects with a wide range of adiposity (n = 89). In vitro experiments with human HepG2 cell line were also performed. Serum NRG4 was negatively correlated with insulin sensitivity (r = −0.25, p = 0.02) and positively with the inflammatory marker high-sensitivity C reative protein (hsCRP). In fact, multivariant linear regression analyses showed that insulin sensitivity contributed to BMI-, age-, sex-, and hsCRP-adjusted 7.2% of the variance in serum NRG4 (p = 0.01). No significant associations were found with adiposity measures (BMI, waist circumference or fat mass), plasma lipids (HDL-, LDL-cholesterol, or fasting triglycerides) or markers of liver injury. Cultured hepatocyte HepG2 treated with human recombinant NRG4 had an impact on hepatocyte metabolism, leading to decreased gluconeogenic- and mitochondrial biogenesis-related gene expression, and reduced mitochondrial respiration, without effects on expression of lipid metabolism-related genes. Similar but more pronounced effects were found after neuregulin 1 administration. In conclusion, sustained higher serum levels of neuregulin-4, observed in insulin resistant patients may have deleterious effects on metabolic and mitochondrial function in hepatocytes. However, findings from in vitro experiments should be confirmed in human primary hepatocytes.
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spelling pubmed-95216712022-09-30 Serum neuregulin 4 is negatively correlated with insulin sensitivity in humans and impairs mitochondrial respiration in HepG2 cells Martínez, Cristina Latorre, Jèssica Ortega, Francisco Arnoriaga-Rodríguez, María Lluch, Aina Oliveras-Cañellas, Núria Díaz-Sáez, Francisco Aragonés, Julian Camps, Marta Gumà, Anna Ricart, Wifredo Fernández-Real, José Manuel Moreno-Navarrete, José María Front Physiol Physiology Neuregulin 4 (NRG4) has been described to improve metabolic disturbances linked to obesity status in rodent models. The findings in humans are controversial. We aimed to investigate circulating NRG4 in association with insulin action in humans and the possible mechanisms involved. Insulin sensitivity (euglycemic hyperinsulinemic clamp) and serum NRG4 concentration (ELISA) were analysed in subjects with a wide range of adiposity (n = 89). In vitro experiments with human HepG2 cell line were also performed. Serum NRG4 was negatively correlated with insulin sensitivity (r = −0.25, p = 0.02) and positively with the inflammatory marker high-sensitivity C reative protein (hsCRP). In fact, multivariant linear regression analyses showed that insulin sensitivity contributed to BMI-, age-, sex-, and hsCRP-adjusted 7.2% of the variance in serum NRG4 (p = 0.01). No significant associations were found with adiposity measures (BMI, waist circumference or fat mass), plasma lipids (HDL-, LDL-cholesterol, or fasting triglycerides) or markers of liver injury. Cultured hepatocyte HepG2 treated with human recombinant NRG4 had an impact on hepatocyte metabolism, leading to decreased gluconeogenic- and mitochondrial biogenesis-related gene expression, and reduced mitochondrial respiration, without effects on expression of lipid metabolism-related genes. Similar but more pronounced effects were found after neuregulin 1 administration. In conclusion, sustained higher serum levels of neuregulin-4, observed in insulin resistant patients may have deleterious effects on metabolic and mitochondrial function in hepatocytes. However, findings from in vitro experiments should be confirmed in human primary hepatocytes. Frontiers Media S.A. 2022-09-15 /pmc/articles/PMC9521671/ /pubmed/36187779 http://dx.doi.org/10.3389/fphys.2022.950791 Text en Copyright © 2022 Martínez, Latorre, Ortega, Arnoriaga-Rodríguez, Lluch, Oliveras-Cañellas, Díaz-Sáez, Aragonés, Camps, Gumà, Ricart, Fernández-Real and Moreno-Navarrete. https://creativecommons.org/licenses/by/4.0/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.
spellingShingle Physiology
Martínez, Cristina
Latorre, Jèssica
Ortega, Francisco
Arnoriaga-Rodríguez, María
Lluch, Aina
Oliveras-Cañellas, Núria
Díaz-Sáez, Francisco
Aragonés, Julian
Camps, Marta
Gumà, Anna
Ricart, Wifredo
Fernández-Real, José Manuel
Moreno-Navarrete, José María
Serum neuregulin 4 is negatively correlated with insulin sensitivity in humans and impairs mitochondrial respiration in HepG2 cells
title Serum neuregulin 4 is negatively correlated with insulin sensitivity in humans and impairs mitochondrial respiration in HepG2 cells
title_full Serum neuregulin 4 is negatively correlated with insulin sensitivity in humans and impairs mitochondrial respiration in HepG2 cells
title_fullStr Serum neuregulin 4 is negatively correlated with insulin sensitivity in humans and impairs mitochondrial respiration in HepG2 cells
title_full_unstemmed Serum neuregulin 4 is negatively correlated with insulin sensitivity in humans and impairs mitochondrial respiration in HepG2 cells
title_short Serum neuregulin 4 is negatively correlated with insulin sensitivity in humans and impairs mitochondrial respiration in HepG2 cells
title_sort serum neuregulin 4 is negatively correlated with insulin sensitivity in humans and impairs mitochondrial respiration in hepg2 cells
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9521671/
https://www.ncbi.nlm.nih.gov/pubmed/36187779
http://dx.doi.org/10.3389/fphys.2022.950791
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