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

Autor:	McNeilly AD; Division of Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK. Electronic address: a.d.mcneilly@dundee.ac.uk., Yianakas A; Division of Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK., Gallagher JG; Division of Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK., Tarlton J; Division of Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK., Ashford ML; Division of Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK., McCrimmon RJ; Division of Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK.
Jazyk:	angličtina
Zdroj:	Molecular metabolism [Mol Metab] 2022 Jul; Vol. 61, pp. 101488. Date of Electronic Publication: 2022 Apr 22.
DOI:	10.1016/j.molmet.2022.101488
Abstrakt:	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. (Copyright © 2022 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
Databáze:	MEDLINE
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