Glucose and energy metabolism are impaired in mice deficient for orexins

in Journal of Endocrinology
Authors:
Mélodie Devère University Rouen Normandie, Inserm, Normandie University, NorDiC UMR 1239, Rouen, France

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Saloua Takhlidjt University Rouen Normandie, Inserm, Normandie University, NorDiC UMR 1239, Rouen, France

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David Godefroy University Rouen Normandie, Inserm, Normandie University, NorDiC UMR 1239, Rouen, France

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Jean-Luc do Rego University Rouen Normandie, Normandie University, INSERM US 51, CNRS UAR 2026, HeRacLeS, Rouen, France

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Jean-Claude do Rego University Rouen Normandie, Normandie University, INSERM US 51, CNRS UAR 2026, HeRacLeS, Rouen, France

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Alexandre Bénani Center for Taste and Feeding Behaviour, CNRS (UMR6265), INRA (UMR1324), AgroSup Dijon, Université de Bourgogne-Franche Comté, Dijon, France

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Emmanuelle Nedelec Center for Taste and Feeding Behaviour, CNRS (UMR6265), INRA (UMR1324), AgroSup Dijon, Université de Bourgogne-Franche Comté, Dijon, France

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Nicolas Chartrel University Rouen Normandie, Inserm, Normandie University, NorDiC UMR 1239, Rouen, France

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https://orcid.org/0000-0002-3469-3736
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Marie Picot University Rouen Normandie, Inserm, Normandie University, NorDiC UMR 1239, Rouen, France

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Correspondence should be addressed to N Chartrel: nicolas.chartrel@univ-rouen.fr
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Graphical abstract

Abstract

The present study aims to investigate the impact of orexin deficiency on the regulation of energy and glucose metabolism using a mouse model depleted of the prepro-orexin gene. Our data reveal that, despite a decrease in food consumption (at least in males), orexin deficiency induces a significant increase in body weight that is associated with an alteration in the body composition, as male and female orexin-deficient mice display increased fat mass compared to wild-type littermates. Nevertheless, no significant differences of global energy expenditure and locomotor activity were observed in the mutant mice relative to the control. Glucose homeostasis is also impaired in the absence of orexins, since glucose tolerance and insulin secretion are diminished, and insulin sensitivity is slightly reduced. In addition, the livers of male orexin-KO mice are significantly larger and heavier with more adipose tissue than wild-type mice. Interestingly, orexin-deficient mice present an upregulation of liver enzymes involved in gluconeogenesis and a downregulation of GCK, an enzyme that promotes glycogen storage, which may participate to the altered glucose metabolism of orexin mutant mice. To conclude, the present study indicates that orexin deficiency induces profound alterations in the regulation of energy and glucose metabolism, which is more pronounced in males than in females. These findings support the idea that dysfunction of this orexin system may promote obesity and diabetes, and could represent an interesting therapeutic target in the context of ‘diabesity’.

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