Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/149507
Title: Endothelial Mitofusin 2 deficiency improves systemic metabolic health and delays age-associated decline
Author: Chivite, Íñigo
Director/Tutor: Claret i Carles, Marc
Graupera i Garcia-Milà, Mariona
Keywords: Metabolisme
Endoteli
Vasos sanguinis
Obesitat
Envelliment
Metabolism
Endothelium
Blood vessels
Obesity
Aging
Issue Date: 24-Jan-2020
Publisher: Universitat de Barcelona
Abstract: [eng] Blood vessels distribute nutrients and oxygen to every single cell in the body. Endothelial cells define the vessel wall, and thus they are ideally located to crucially modulate nutrient availability and act as metabolic gatekeepers of the organism. In recent years, mitochondrial dynamics has emerged as a bioenergetic adaptation process to cellular metabolic demands. Mitofusins are GTPase-like proteins implicated in external mitochondrial membrane fusion. Our hypothesis is that mitochondrial fusion in endothelial cells is implicated in energy balance and metabolic control. In order to address this hypothesis, we generated mice lacking either Mitofusin 1 (Mfn1) or Mitofusin 2 (Mfn2) into adulthood by breeding a tamoxifen-inducible endothelial Cre line (PdgfbiCreERT2) with Mfn1 or Mfn2 floxed animals (hereafter called Mfn1ΔEC and Mfn2ΔEC respectively). Mfn2iΔEC mice showed a progressive reduction (25%) in body weight when compared to control counterparts. Intestinal nutrient absorption, food intake and locomotor activity were unaltered in knockout mice. However, enhanced energy expenditure and a shift towards lipid oxidation was observed, while the thermogenesis capacity was not different between groups. Consistent with this phenotype, Mfn2iΔEC mice exhibited lower fat mass and improved glucose tolerance and insulin sensitivity in the face of unaltered insulin release. Collectively, these results indicate that loss of Mfn2 in endothelial cells causes a lean phenotype as the consequence of enhanced lipid metabolism. However, endothelial Mfn1 deletion did not alter systemic metabolism. Upon high-fat diet administration, Mfn2iΔEC mice showed complete resistance to its obesogenic effects. In concordance with lower body weight due to reduced adiposity, mutant mice exhibited improved glucose homeostasis. Moreover, induction of endothelial Mfn2 ablation in established obesity reduced body weight to standard diet control levels and improved metabolic alterations. Interestingly, Mfn1iΔEC mice do not show any metabolic alteration when fed high-fat diet. Aged Mfn2iΔEC mice preserved young-like health-span parameters. Indeed, mutant mice exhibited improved age-associated physiological parameters such as kidney function or anaemia. Diverse motor and cognitive parameters were also preserved in old Mfn2i∆EC mice. Collectively, our results indicate that Mfn2 in endothelial cells is implicated in systemic energy homeostasis control as well as in ageing progression in mice.
URI: http://hdl.handle.net/2445/149507
Appears in Collections:Tesis Doctorals - Facultat - Medicina i Ciències de la Salut

Files in This Item:
File Description SizeFormat 
ICA_PhD_THESIS.pdf12.45 MBAdobe PDFView/Open


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.