Venue : Centre Broca
Thesis defended in english
Evangelia Kyriakidou
IMN
Team : Neuroimmunology of metabolic health and disease (NOMAD)
Thesis directed by Agnès Nadjar
Title
A Female-Specific Microglial Redox Program Gates Susceptibility to Obesity
Abstract
Over the course of evolution, energy metabolism developed as an adaptive system able to store calories during food availability to sustain energy needs in periods of scarcity. However, the present-day overabundance of hypercaloric foods hijacks this ancestral mechanism: excessive lipid intake imposes a chronic allostatic pressure that disrupts metabolic homeostasis and underlies the obesity pandemic. Microglia, the brain’s resident immune cells, are sensitive sensors of environmental changes, and particularly of nutritional variations. In response, they adapt their metabolism and, consequently, their functions to maintain brain homeostasis. Excess lipids drive microglia toward a pro-inflammatory state in male mice, which in turn disrupts the hypothalamic circuits that regulate whole-body energy balance. Notably, these cells display sexual dimorphism, as does the regulation of metabolic homeostasis. We therefore hypothesized that microglia differentially regulate metabolic homeostasis in males and females in response to an obesogenic diet. Our data show that in females, but not males, microglia engage a protective metabolic reprogramming, characterized by increased antioxidant capacity and mitochondrial remodeling, conferring resistance to early weight gain. Over time, activation of mTORC1 signaling in microglia impairs this metabolic adaptation and abolishes this transient resilience, culminating in weight gain. These findings show that microglial mTORC1 determines, in a sex-specific manner, the shift toward resilience or vulnerability to obesity, and position microglial metabolism as a potential therapeutic target for sex-informed weight control.
Keys words
Keywords: Microglia, high-fat diet, immunometabolism, sex dimorphism, mTORC1, mitochondria, anti-oxidant program
Jury
M. Stefano PLUCHINO, Department of Clinical Neurosciences, University of Cambridge, rapporteur
Mme Rosa Chiara PAOLICELLI, Département des sciences biomédicales, Université de Lausanne, rapporteur
M. Arnaud MOURIER, Institut de biochimie et génétique cellulaires (IBGC), UMR 5095, Président
Mme Claire MARTIN, Biologie fonctionnelle et adaptative (BFA), UMR 8251, examinatrice
Mme Agnès NADJAR, Institut des Maladies Neurodégénératives – CNRS UMR 5293, Université de Bordeaux, directrice de thèse