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Sexual dimorphism in the molecular mechanisms of insulin resistance during a critical developmental window in Wistar rats
BACKGROUND: Insulin resistance (IR) is a condition in which the response of organs to insulin is impaired. IR is an early marker of metabolic dysfunction. However, IR also appears in physiological contexts during critical developmental windows. The molecular mechanisms of physiological IR are largel...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9554987/ https://www.ncbi.nlm.nih.gov/pubmed/36224569 http://dx.doi.org/10.1186/s12964-022-00965-6 |
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author | Ortiz-Huidobro, Rosa Isela Larqué, Carlos Velasco, Myrian Chávez-Maldonado, Juan Pablo Sabido, Jean Sanchez-Zamora, Yuriko Itzel Hiriart, Marcia |
author_facet | Ortiz-Huidobro, Rosa Isela Larqué, Carlos Velasco, Myrian Chávez-Maldonado, Juan Pablo Sabido, Jean Sanchez-Zamora, Yuriko Itzel Hiriart, Marcia |
author_sort | Ortiz-Huidobro, Rosa Isela |
collection | PubMed |
description | BACKGROUND: Insulin resistance (IR) is a condition in which the response of organs to insulin is impaired. IR is an early marker of metabolic dysfunction. However, IR also appears in physiological contexts during critical developmental windows. The molecular mechanisms of physiological IR are largely unknown in both sexes. Sexual dimorphism in insulin sensitivity is observed since early stages of development. We propose that during periods of accelerated growth, such as around weaning, at postnatal day 20 (p20) in rats, the kinase S6K1 is overactivated and induces impairment of insulin signaling in its target organs. This work aimed to characterize IR at p20, determine its underlying mechanisms, and identify whether sexual dimorphism in physiological IR occurs during this stage. METHODS: We determined systemic insulin sensitivity through insulin tolerance tests, glucose tolerance tests, and blood glucose and insulin levels under fasting and fed conditions at p20 and adult male and female Wistar rats. Furthermore, we quantified levels of S6K1 phosphorylated at threonine 389 (T389) (active form) and its target IRS1 phosphorylated at serine 1101 (S1101) (inhibited form). In addition, we assessed insulin signal transduction by measuring levels of Akt phosphorylated at serine 473 (S473) (active form) in white adipose tissue and skeletal muscle through western blot. Finally, we determined the presence and function of GLUT4 in the plasma membrane by measuring the glucose uptake of adipocytes. Results were compared using two-way ANOVA (With age and sex as factors) and one-way ANOVA with post hoc Tukey’s tests or t-student test in each corresponding case. Statistical significance was considered for P values < 0.05. RESULTS: We found that both male and female p20 rats have elevated levels of glucose and insulin, low systemic insulin sensitivity, and glucose intolerance. We identified sex- and tissue-related differences in the activation of insulin signaling proteins in p20 rats compared to adult rats. CONCLUSIONS: Male and female p20 rats present physiological insulin resistance with differences in the protein activation of insulin signaling. This suggests that S6K1 overactivation and the resulting IRS1 inhibition by phosphorylation at S1101 may modulate to insulin sensitivity in a sex- and tissue-specific manner. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-022-00965-6. |
format | Online Article Text |
id | pubmed-9554987 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-95549872022-10-13 Sexual dimorphism in the molecular mechanisms of insulin resistance during a critical developmental window in Wistar rats Ortiz-Huidobro, Rosa Isela Larqué, Carlos Velasco, Myrian Chávez-Maldonado, Juan Pablo Sabido, Jean Sanchez-Zamora, Yuriko Itzel Hiriart, Marcia Cell Commun Signal Research BACKGROUND: Insulin resistance (IR) is a condition in which the response of organs to insulin is impaired. IR is an early marker of metabolic dysfunction. However, IR also appears in physiological contexts during critical developmental windows. The molecular mechanisms of physiological IR are largely unknown in both sexes. Sexual dimorphism in insulin sensitivity is observed since early stages of development. We propose that during periods of accelerated growth, such as around weaning, at postnatal day 20 (p20) in rats, the kinase S6K1 is overactivated and induces impairment of insulin signaling in its target organs. This work aimed to characterize IR at p20, determine its underlying mechanisms, and identify whether sexual dimorphism in physiological IR occurs during this stage. METHODS: We determined systemic insulin sensitivity through insulin tolerance tests, glucose tolerance tests, and blood glucose and insulin levels under fasting and fed conditions at p20 and adult male and female Wistar rats. Furthermore, we quantified levels of S6K1 phosphorylated at threonine 389 (T389) (active form) and its target IRS1 phosphorylated at serine 1101 (S1101) (inhibited form). In addition, we assessed insulin signal transduction by measuring levels of Akt phosphorylated at serine 473 (S473) (active form) in white adipose tissue and skeletal muscle through western blot. Finally, we determined the presence and function of GLUT4 in the plasma membrane by measuring the glucose uptake of adipocytes. Results were compared using two-way ANOVA (With age and sex as factors) and one-way ANOVA with post hoc Tukey’s tests or t-student test in each corresponding case. Statistical significance was considered for P values < 0.05. RESULTS: We found that both male and female p20 rats have elevated levels of glucose and insulin, low systemic insulin sensitivity, and glucose intolerance. We identified sex- and tissue-related differences in the activation of insulin signaling proteins in p20 rats compared to adult rats. CONCLUSIONS: Male and female p20 rats present physiological insulin resistance with differences in the protein activation of insulin signaling. This suggests that S6K1 overactivation and the resulting IRS1 inhibition by phosphorylation at S1101 may modulate to insulin sensitivity in a sex- and tissue-specific manner. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-022-00965-6. BioMed Central 2022-10-12 /pmc/articles/PMC9554987/ /pubmed/36224569 http://dx.doi.org/10.1186/s12964-022-00965-6 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Ortiz-Huidobro, Rosa Isela Larqué, Carlos Velasco, Myrian Chávez-Maldonado, Juan Pablo Sabido, Jean Sanchez-Zamora, Yuriko Itzel Hiriart, Marcia Sexual dimorphism in the molecular mechanisms of insulin resistance during a critical developmental window in Wistar rats |
title | Sexual dimorphism in the molecular mechanisms of insulin resistance during a critical developmental window in Wistar rats |
title_full | Sexual dimorphism in the molecular mechanisms of insulin resistance during a critical developmental window in Wistar rats |
title_fullStr | Sexual dimorphism in the molecular mechanisms of insulin resistance during a critical developmental window in Wistar rats |
title_full_unstemmed | Sexual dimorphism in the molecular mechanisms of insulin resistance during a critical developmental window in Wistar rats |
title_short | Sexual dimorphism in the molecular mechanisms of insulin resistance during a critical developmental window in Wistar rats |
title_sort | sexual dimorphism in the molecular mechanisms of insulin resistance during a critical developmental window in wistar rats |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9554987/ https://www.ncbi.nlm.nih.gov/pubmed/36224569 http://dx.doi.org/10.1186/s12964-022-00965-6 |
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