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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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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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. |
format | Online Article Text |
id | pubmed-9521671 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
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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