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Présentation «flash» : projet de recherche (Oxylino) en cours inter-collaboratif du Dr Frédéric Capel; National audience

National audience

Excessive dietary lipid intake, coupled with lack of exercise, are the major causes of the development and progression of metabolic syndrome features e. g. obesity, hepatic steatosis, insulin resistance, type 2 diabetes and cardiovascular diseases. These metabolic diseases are associated with both structural and functional alterations of mitochondria. Cardiolipin (CL) is a unique phospholipid that is almost exclusively localized in the mitochondrial inner membrane. Cardiolipin is at the heart of mitochondrial metabolism playing a key role in several processes of mitochondrial bioenergetics as well as in mitochondrial membrane stability and dynamics, and in many of the mitochondrial-dependent steps of apoptosis. Indeed, alterations to CL content and acyl chain profile have been associated with mitochondrial dysfunction in multiple tissues in Barth syndrome and in many other physio-pathological conditions. After a brief overview of the biological roles of CL, we highlight the consequences of lipid overload-related nutritional manipulations as well as related metabolic disorders on both CL content and its fatty acid composition in the major metabolic tissues, the heart, muscle and liver. The goal of this review is to fill a void in the CL literature concerning the effects of CL abundance and form that arise following high lipid supplementation and the related metabolic disorders.

We have shown that maternal administration of a lipid (8%) and cholesterol (0.2%)-enriched diet (HH diet) in a rabbit model leads to intrauterine growth factor (IUGR) and increased offspring susceptibility to excess body fat, overweight and hypertension in adults.1 To examine the link between the fetal development and metabolic consequences in later life, placental development has been explored. Female rabbits were fed with a control (C) or HH diet from 10 weeks of age and throughout gestation. At 28 days of gestation, dams were anesthetized and a laparotomy was performed to collect placenta and plasma. Fetal weight in HH group was significantly reduced compared with C. Total cholesterol and triglycerides concentrations in HH fetuses were significantly increased by 1.2- and 2.3-fold, respectively, compared with C. The structural analysis of HH placentas revealed an abnormal accumulation of light vesicles, identified as lipid droplets in the trophoblast layer. Total content of cholesterol esters and triglycerides were also significantly increased in HH placentas. The expression of genes involved in placental growth, vascularization and nutrient transfer has been studied. HH placentas were characterized by a significant decrease in LDL- receptor, CD36, LXR-a, ABC-G1, SLC38A1 and SLC38A2 transcripts. The downregulation of LXR-a mRNA was correlated with a decrease in protein expression. These data demonstrate that maternal HH diet reduced cholesterol transport through the placenta as evidenced by placental gene expression and cholesterol ester accumulation. In contrast, fatty acid transport was not regulated, which could explain the excess of body fat in adults.

International audience

International audience

L’obésité, considérée comme pandémique, est associée à l’apparition de troubles cognitifs et émotionnels chez l’Homme comme chez l’animal. La prévalence de l’obésité augmente de manière drastique chez les enfants et les adolescents. Or l’adolescence est une période primordiale pour la maturation des structures cérébrales (notamment l’hippocampe et l’amygdale) qui vont sous-tendre les processus cognitifs pour le restant de la vie de l’individu. Cependant, aucune étude n’avait investigué la potentielle vulnérabilité de cette période développementale aux effets de l’obésité sur la mémoire, comparativement à l’âge adulte. Nous avons donc effectué cette comparaison chez le rongeur, en modélisant l’obésité par une exposition à un régime hyper-lipidique (HL) pendant une période incluant l’adolescence versus à l’âge adulte uniquement (i.e. excluant l’adolescence). Nous mettons en évidence que l’obésité induite à l’adolescence provoque des altérations mnésiques, qui ne sont pas retrouvés lorsque l’obésité est induite à l’âge adulte. La majorité des études sur les effets de l’obésité ayant mis en évidence une altération des mémoires dépendantes de l’hippocampe, nous nous sommes tout d’abord focalisés sur les fonctions hippocampiques. Nous avons ensuite exploré le système amygdalien, impliqué dans les mémoires émotionnelles et peu étudié dans le cadre de l’obésité. Ces deux systèmes fonctionnels ont été appréhendés au travers d’approches comportementales visant à évaluer les performances mnésiques, mais également d’approches d’imagerie cellulaire et d’électrophysiologie afin d’évaluer la plasticité cellulaire au sein de ces structures. Nous mettons en évidence que l’obésité induite à l’adolescence impacte la mémoire et la plasticité de ces systèmes de manière bidirectionnelle en dégradant les fonctions hippocampiques et en exacerbant les fonctions amygdaliennes. Concernant les mécanismes impliqués dans ces effets nous mettons en évidence l’existence d’une exacerbation de la réponse inflammatoire spécifiquement au niveau de l’hippocampe chez les animaux exposés au régime HL à l’adolescence, ce qui pourrait expliquer les déficits des fonctions hippocampiques. Enfin, nous montrons que la dérégulation de l’axe corticotrope chez ces animaux est responsable des effets comportementaux et cellulaires observés au niveau des fonctions amygdaliennes. L’ensemble de ces résultats montre l’urgence de développer les études sur l’obésité juvénile, dont les effets importants sur les fonctions cognitives et émotionnelles pourraient engendrer une altération importante de la qualité de vie et une prise en charge accrue de ces sujets tout au long de leur vie., The obesity pandemic is linked to cognitive and emotional disorders in humans. Obesity prevalence in adolescence is increasing at an alarming rate. Adolescence is a crucial period for maturation of brain structures, like hippocampus and amygdala, particularly important for neurocognitive shaping required for whole life duration. However, no study investigated a potential higher vulnerability of this specific developmental period to the effects of obesity on memory. For this purpose we compared, in rodent models, the effects of high-fat diet (HFD)-induced obesity during adolescence (from weaning to adulthood) or at adulthood. We were able to demonstrate that adolescence is more vulnerable than adulthood to the effects of obesity on memory. Most of the studies interested in the effects of obesity on memory found deficits in hippocampal dependent memories. We therefore first focused on hippocampal functioning. We also extended this investigation to another memory system depending on amygdala, since little was known about the effects of obesity on this structure. Using behavioral approaches to evaluate memory performances, but also cellular imaging and electrophysiology to assess cellular plasticity, we evidenced that juvenile obesity affects both memory and plasticity in a bidirectional way, impairing hippocampal function and enhancing amygdala function. Looking for mechanisms to explain these effects, we found a potentiated inflammatory response specifically in the hippocampus that could explain decreased hippocampal function. We also demonstrated that deregulation of hypothalamo-pituitary-adrenal axis is responsible for increased amygdala plasticity and memory. Altogether these results suggest that obesity during adolescence predisposes to later maladaptive cognitive and emotional functions. This is a major concern as it could induce a significant impairment in quality of life of these individuals and contribute considerably to their social and occupational dysfunction.

International audience