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Central deficiency of IL-6Ra in mice impairs glucose-stimulated insulin secretion

OBJECTIVE: IL-6 is an important contributor to glucose and energy homeostasis through changes in whole-body glucose disposal, insulin sensitivity, food intake and energy expenditure. However, the relative contributions of peripheral versus central IL-6 signaling to these metabolic actions are presen...

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Autores principales: McNeilly, Alison D., Yianakas, Adonis, Gallagher, Jennifer G., Tarlton, Jamie, Ashford, Michael LJ., McCrimmon, Rory J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9065900/
https://www.ncbi.nlm.nih.gov/pubmed/35470093
http://dx.doi.org/10.1016/j.molmet.2022.101488
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author McNeilly, Alison D.
Yianakas, Adonis
Gallagher, Jennifer G.
Tarlton, Jamie
Ashford, Michael LJ.
McCrimmon, Rory J.
author_facet McNeilly, Alison D.
Yianakas, Adonis
Gallagher, Jennifer G.
Tarlton, Jamie
Ashford, Michael LJ.
McCrimmon, Rory J.
author_sort McNeilly, Alison D.
collection PubMed
description OBJECTIVE: IL-6 is an important contributor to glucose and energy homeostasis through changes in whole-body glucose disposal, insulin sensitivity, food intake and energy expenditure. However, the relative contributions of peripheral versus central IL-6 signaling to these metabolic actions are presently unclear. A conditional mouse model with reduced brain IL-6Ra expression was used to explore how blunted central IL-6 signaling alters metabolic status in lean and obese mice. METHODS: Transgenic mice with reduced levels of central IL-6 receptor alpha (IL-6Ra) (IL-6Ra KD mice) and Nestin Cre controls (Cre(+/-) mice) were fed standard chow or high-fat diet for 20 weeks. Obese and lean mouse cohorts underwent metabolic phenotyping with various measures of energy and glucose homeostasis determined. Glucose-stimulated insulin secretion was assessed in vivo and ex vivo in both mouse groups. RESULTS: IL-6Ra KD mice exhibited altered body fat mass, liver steatosis, plasma insulin, IL-6 and NEFA levels versus Cre(+/-) mice in a diet-dependent manner. IL-6Ra KD mice had increased food intake, higher RER, decreased energy expenditure with diminished cold tolerance compared to Cre(+/-) controls. Standard chow-fed IL-6Ra KD mice displayed reduced plasma insulin and glucose-stimulated insulin secretion with impaired glucose disposal and unchanged insulin sensitivity. Isolated pancreatic islets from standard chow-fed IL-6Ra KD mice showed comparable morphology and glucose-stimulated insulin secretion to Cre(+/-) controls. The diminished in vivo insulin secretion exhibited by IL-6Ra KD mice was recovered by blockade of autonomic ganglia. CONCLUSIONS: This study shows that central IL-6Ra signaling contributes to glucose and energy control mechanisms by regulating food intake, energy expenditure, fuel flexibility and insulin secretion. A plausible mechanism linking central IL-6Ra signaling and pancreatic insulin secretion is through the modulation of autonomic output activity. Thus, brain IL-6 signaling may contribute to the central adaptive mechanisms engaged in response to metabolic stress.
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spelling pubmed-90659002022-05-04 Central deficiency of IL-6Ra in mice impairs glucose-stimulated insulin secretion McNeilly, Alison D. Yianakas, Adonis Gallagher, Jennifer G. Tarlton, Jamie Ashford, Michael LJ. McCrimmon, Rory J. Mol Metab Original Article OBJECTIVE: IL-6 is an important contributor to glucose and energy homeostasis through changes in whole-body glucose disposal, insulin sensitivity, food intake and energy expenditure. However, the relative contributions of peripheral versus central IL-6 signaling to these metabolic actions are presently unclear. A conditional mouse model with reduced brain IL-6Ra expression was used to explore how blunted central IL-6 signaling alters metabolic status in lean and obese mice. METHODS: Transgenic mice with reduced levels of central IL-6 receptor alpha (IL-6Ra) (IL-6Ra KD mice) and Nestin Cre controls (Cre(+/-) mice) were fed standard chow or high-fat diet for 20 weeks. Obese and lean mouse cohorts underwent metabolic phenotyping with various measures of energy and glucose homeostasis determined. Glucose-stimulated insulin secretion was assessed in vivo and ex vivo in both mouse groups. RESULTS: IL-6Ra KD mice exhibited altered body fat mass, liver steatosis, plasma insulin, IL-6 and NEFA levels versus Cre(+/-) mice in a diet-dependent manner. IL-6Ra KD mice had increased food intake, higher RER, decreased energy expenditure with diminished cold tolerance compared to Cre(+/-) controls. Standard chow-fed IL-6Ra KD mice displayed reduced plasma insulin and glucose-stimulated insulin secretion with impaired glucose disposal and unchanged insulin sensitivity. Isolated pancreatic islets from standard chow-fed IL-6Ra KD mice showed comparable morphology and glucose-stimulated insulin secretion to Cre(+/-) controls. The diminished in vivo insulin secretion exhibited by IL-6Ra KD mice was recovered by blockade of autonomic ganglia. CONCLUSIONS: This study shows that central IL-6Ra signaling contributes to glucose and energy control mechanisms by regulating food intake, energy expenditure, fuel flexibility and insulin secretion. A plausible mechanism linking central IL-6Ra signaling and pancreatic insulin secretion is through the modulation of autonomic output activity. Thus, brain IL-6 signaling may contribute to the central adaptive mechanisms engaged in response to metabolic stress. Elsevier 2022-04-22 /pmc/articles/PMC9065900/ /pubmed/35470093 http://dx.doi.org/10.1016/j.molmet.2022.101488 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Original Article
McNeilly, Alison D.
Yianakas, Adonis
Gallagher, Jennifer G.
Tarlton, Jamie
Ashford, Michael LJ.
McCrimmon, Rory J.
Central deficiency of IL-6Ra in mice impairs glucose-stimulated insulin secretion
title Central deficiency of IL-6Ra in mice impairs glucose-stimulated insulin secretion
title_full Central deficiency of IL-6Ra in mice impairs glucose-stimulated insulin secretion
title_fullStr Central deficiency of IL-6Ra in mice impairs glucose-stimulated insulin secretion
title_full_unstemmed Central deficiency of IL-6Ra in mice impairs glucose-stimulated insulin secretion
title_short Central deficiency of IL-6Ra in mice impairs glucose-stimulated insulin secretion
title_sort central deficiency of il-6ra in mice impairs glucose-stimulated insulin secretion
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9065900/
https://www.ncbi.nlm.nih.gov/pubmed/35470093
http://dx.doi.org/10.1016/j.molmet.2022.101488
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