Female sex hormones are necessary for the metabolic effects mediated by loss of Interleukin 18 signaling

Objective: Interleukin (IL)-18 plays a crucial role in maintaining metabolic homeostasis and levels of this cytokine are influenced by gender, age, and sex hormones. The role of gender on IL-18 signaling, however, is unclear. We hypothesized that the presence of female sex hormone could preserve the...

Full description

Bibliographic Details
Main Authors: Birgitte Lindegaard, Julie Abildgaard, Sarah E. Heywood, Bente K. Pedersen, Mark A. Febbraio
Format: Article
Language:English
Published: Elsevier 2018-06-01
Series:Molecular Metabolism
Online Access:http://www.sciencedirect.com/science/article/pii/S2212877817308475
id doaj-323a7660a2b84386850aa5d634aafa19
record_format Article
spelling doaj-323a7660a2b84386850aa5d634aafa192020-11-24T22:56:20ZengElsevierMolecular Metabolism2212-87782018-06-01128997Female sex hormones are necessary for the metabolic effects mediated by loss of Interleukin 18 signalingBirgitte Lindegaard0Julie Abildgaard1Sarah E. Heywood2Bente K. Pedersen3Mark A. Febbraio4Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Denmark; Department of Pulmonary and Infectious Diseases, Nordsjællands Hospital, Hillerød, Denmark; Corresponding author. Rigshospitalet, Center for Inflammation and Metabolism (CIM), The Centre for Physical Activity Research (CFAS), Blegdamsvej 9, DK-2100 Copenhagen, Denmark.Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, DenmarkCentre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Denmark; Cellular and Molecular Metabolism Laboratory, Division of Diabetes & Metabolism, Garvan Institute for Medical Research, Sydney, AustraliaCentre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, DenmarkCellular and Molecular Metabolism Laboratory, Division of Diabetes & Metabolism, Garvan Institute for Medical Research, Sydney, Australia; Corresponding author. Division of Diabetes & Metabolism, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW 2010, Australia.Objective: Interleukin (IL)-18 plays a crucial role in maintaining metabolic homeostasis and levels of this cytokine are influenced by gender, age, and sex hormones. The role of gender on IL-18 signaling, however, is unclear. We hypothesized that the presence of female sex hormone could preserve the metabolic phenotype of the IL-18R−/− animals. Methods: We studied female mice with a global deletion of the α isoform of the IL-18 receptor (IL-18R−/−) and littermates control. Three studies were done: 1) animals fed a high fat diet (HFD) for 16 weeks; 2) animals fed chow diet for 72 weeks and 3) animals (3 weeks-old) randomized to either bilateral ovariectomy (OVX) or control surgery (SHAM) and followed for 16 weeks. Results: Female IL-18R−/− mice gained less weight and maintained glucose homeostasis on a chow diet compared with HFD, but no differences between genotypes were observed. The maintenance of body weight and glucose homeostasis in IL-18R−/− mice was lost with aging. By 72 weeks of age, IL-18R−/− mice became heavier compared with WT mice due to an increase in both visceral and subcutaneous adiposity and displayed glucose intolerance. OVX did not affect body weight in IL-18R−/− mice but exacerbated glucose intolerance and impaired liver insulin signaling when compared with SHAM mice. Conclusions: Female mice harboring a global deletion of the IL-18R, only present the same phenotype as reported in male IL-18R−/− mice if they are aged or have undergone OVX, in which circulating estrogen is likely to be blunted. The role of estrogen signaling in the protection against altered metabolic homeostasis in IL-18R−/− mice appears to be mediated by liver insulin signaling. We therefore suggest that the metabolic effects mediated by loss of IL-18 signaling are only present in a female sex hormone free environment. Keywords: IL-18, Obesity, Insulin resistance, Genderhttp://www.sciencedirect.com/science/article/pii/S2212877817308475
collection DOAJ
language English
format Article
sources DOAJ
author Birgitte Lindegaard
Julie Abildgaard
Sarah E. Heywood
Bente K. Pedersen
Mark A. Febbraio
spellingShingle Birgitte Lindegaard
Julie Abildgaard
Sarah E. Heywood
Bente K. Pedersen
Mark A. Febbraio
Female sex hormones are necessary for the metabolic effects mediated by loss of Interleukin 18 signaling
Molecular Metabolism
author_facet Birgitte Lindegaard
Julie Abildgaard
Sarah E. Heywood
Bente K. Pedersen
Mark A. Febbraio
author_sort Birgitte Lindegaard
title Female sex hormones are necessary for the metabolic effects mediated by loss of Interleukin 18 signaling
title_short Female sex hormones are necessary for the metabolic effects mediated by loss of Interleukin 18 signaling
title_full Female sex hormones are necessary for the metabolic effects mediated by loss of Interleukin 18 signaling
title_fullStr Female sex hormones are necessary for the metabolic effects mediated by loss of Interleukin 18 signaling
title_full_unstemmed Female sex hormones are necessary for the metabolic effects mediated by loss of Interleukin 18 signaling
title_sort female sex hormones are necessary for the metabolic effects mediated by loss of interleukin 18 signaling
publisher Elsevier
series Molecular Metabolism
issn 2212-8778
publishDate 2018-06-01
description Objective: Interleukin (IL)-18 plays a crucial role in maintaining metabolic homeostasis and levels of this cytokine are influenced by gender, age, and sex hormones. The role of gender on IL-18 signaling, however, is unclear. We hypothesized that the presence of female sex hormone could preserve the metabolic phenotype of the IL-18R−/− animals. Methods: We studied female mice with a global deletion of the α isoform of the IL-18 receptor (IL-18R−/−) and littermates control. Three studies were done: 1) animals fed a high fat diet (HFD) for 16 weeks; 2) animals fed chow diet for 72 weeks and 3) animals (3 weeks-old) randomized to either bilateral ovariectomy (OVX) or control surgery (SHAM) and followed for 16 weeks. Results: Female IL-18R−/− mice gained less weight and maintained glucose homeostasis on a chow diet compared with HFD, but no differences between genotypes were observed. The maintenance of body weight and glucose homeostasis in IL-18R−/− mice was lost with aging. By 72 weeks of age, IL-18R−/− mice became heavier compared with WT mice due to an increase in both visceral and subcutaneous adiposity and displayed glucose intolerance. OVX did not affect body weight in IL-18R−/− mice but exacerbated glucose intolerance and impaired liver insulin signaling when compared with SHAM mice. Conclusions: Female mice harboring a global deletion of the IL-18R, only present the same phenotype as reported in male IL-18R−/− mice if they are aged or have undergone OVX, in which circulating estrogen is likely to be blunted. The role of estrogen signaling in the protection against altered metabolic homeostasis in IL-18R−/− mice appears to be mediated by liver insulin signaling. We therefore suggest that the metabolic effects mediated by loss of IL-18 signaling are only present in a female sex hormone free environment. Keywords: IL-18, Obesity, Insulin resistance, Gender
url http://www.sciencedirect.com/science/article/pii/S2212877817308475
work_keys_str_mv AT birgittelindegaard femalesexhormonesarenecessaryforthemetaboliceffectsmediatedbylossofinterleukin18signaling
AT julieabildgaard femalesexhormonesarenecessaryforthemetaboliceffectsmediatedbylossofinterleukin18signaling
AT saraheheywood femalesexhormonesarenecessaryforthemetaboliceffectsmediatedbylossofinterleukin18signaling
AT bentekpedersen femalesexhormonesarenecessaryforthemetaboliceffectsmediatedbylossofinterleukin18signaling
AT markafebbraio femalesexhormonesarenecessaryforthemetaboliceffectsmediatedbylossofinterleukin18signaling
_version_ 1725653829823758336