The prevalence of obesity and its comorbidities has reached pandemic proportions and its economic and social burden highlights the need to develop therapeutic strategies beyond traditional lifestyle interventions. It is now well established that the obese brain is stressed, and the hypothesis that endoplasmic reticulum (ER) stress in hypothalamic cells is causally linked to obesity and associated comorbidities has been well supported. We have identified a novel thioredoxin-like protein called SELENOT that regulates redox homeostasis. The genetic invalidation of SELENOT in mice is lethal in utero and the reduction of its expression in POMC neurons or beta-pancreatic cells, major sites of metabolic integration, causes an alteration of hormonal secretions. Conversely, administration of a peptide mimetic of SELENOT, named PSELT, attenuates obesity and hyperglycemia in a pilot study performed in mice. Our goal is to demonstrate that SELENOT is an important regulator of ER stress and POMC production associated with energy homeostasis, and that the SELENOT peptide we developed may represent a valuable therapeutic tool against obesity and type 2 diabetes. In particular, we would like to answer the following questions: 1. What are the molecular mechanisms underlying the regulation of ER stress by SELENOT? 2. What is the role of SELENOT in POMC neuron function? 3. What are the metabolic effects of the PSELT peptide and its mechanism of action. The data obtained will be essential in order to use the PSELT as a therapy against obesity and its comorbidities, which represent a priority issue for the French health system.

A quarter of the adult population in industrialized countries experiences mental health issues during their lifetime. In France, despite the existence of specialized legislation, mental/neuro-psychiatric disorders are estimated to contribute to 32% of the global disease burden. Yet overall, and in France in particular, mental illness receives insufficient attention despite its substantial contribution to the nonfatal disease burden, chronic nature, and estimated 20-year reduction in life expectancy. To a large extent, in fact, premature mortality in individuals with mental illness is due to non-communicable physical disorders that have not been properly diagnosed or treated. In turn, in the Covid-19 pandemic context, the mental illness burden seems to be growing at an alarming rate and will likely continue to do so in the coming years. Another deleterious aspect of the current situation is that it exacerbates existing risk behaviors (i.e., increased smoking, alcohol use, snacking, sedentariness). MEMORIES is a 4-year multi-disciplinary project with 5 inter-related work packages; its main working hypothesis addresses the role of mental health status as a potentially modifiable determinant of nutrition-related chronic disorders such as obesity and type 2 diabetes among adults. MEMORIES has 3 specific aims: (1) estimate and rank the relative risk of nutrition-related chronic disorders associated with different mental disorders; (2) develop and validate an epidemiological, prospectively applicable mental multi-morbidity index; (3) investigate the prospective association of mental multi-morbidity with nutrition-related chronic disorders (obesity, type 2 diabetes and their comorbidity) in general (the French NutriNet-Santé e-cohort) and vulnerable (e.g., smokers, heavy alcohol users, individuals with poor dietary quality and/or high levels of sedentariness) population samples, and estimate the proportion of avoidable morbidity and mortality related to these disorders. The overarching goal of MEMORIES is to contribute to the reduction of morbidity and premature mortality rates in individuals with mental illnesses, based on new scientific tools and knowledge derived from a rigorous multidisciplinary approach encompassing epidemiology, nutrition, psychology, endocrinology, biostatistics, preventive medicine, and public health. The results can thus guide clinical practice, primary and secondary prevention, epidemiological and intervention research, and public health policy.

The formulation of healthy food acceptable by the consumer is penalized because flavor perception, which is built in our brain through integratory processes and which mainly drives food acceptability, is so far still unpredictable. In AROMA project I will investigate one strategy of sugar/salt reduction using aroma (OITE) -with a focus on a specific population (obese vs normal-weight), to unravel the key brain mechanisms of mental representation of food (flavor perception). This system will be investigated with a set of complementary brain imaging technics and a multidisciplinary approach: from food model formulation to brain imaging, including sensory evaluation. AROMA will provide valuable insights and new results: (1) on the key mechanisms of flavor perception through the prism of obesity and (2) on the validation of OITE as a strategy to reduce salt and sugar in food for a variety of consumers and (3) on proofed method in Neurosciences to study OITE.

Retinopathy of prematurity (ROP) is the leading cause of blindness in children. This disease is characterized by inflammatory processes and abnormalities in vascular development of the retina. Preliminary results from our laboratories and published data show that specific lipids, such as plasmalogens and endocannabinoids, can regulate inflammatory processes as well as the development of blood vessels in different tissues. The EndoROP project brings together specialists in lipid metabolisms, inflammation and angiogenesis in the retina. It will characterize in details the place of plasmalogens and endocannabinoids in the regulation of retinal vascular development in ROP by: 1) understanding the plasmalogen-dependent molecular mechanisms by which endocannabinoids regulate retinal vascular development in physiologic conditions (Work-Package 1) ; 2) deciphering the cellular and molecular mechanisms involving plasmalogens and endocannabinoids in the pathologic conditions of ROP (Work-Package 2), and 3) identifying new therapeutic targets and develop new therapeutic approaches to prevent or to limit the retinal vascular abnormalities observed in ROP (Work-Package 3). Altogether, our project will document the molecular mechanisms by which plasmalogens regulate the endocannabinoid system in the retina and offer new therapeutic strategies to prevent ROP in premature infants.

Age-related macular degeneration (AMD) is responsible for 50 % of the cases of blindness in industrialized countries. It results from a pathological ageing of the retina, linked to a dysfunction of the retinal pigment epithelium (RPE), responsible for the recycling of the photoreceptors outer segments and for the nutritional exchanges with the blood circulation, through the vascular choroid (CH). Current treatments are limited to the neovascular form of the disease, and cannot always avoid severe visual loss. Thus, preventive strategies aiming at the reduction of the incidence of AMD are still of major public health importance, as they may reduce the costs associated to the treatment of neovascular AMD, but also to the loss in autonomy and quality of life associated with AMD-related visual impairment. N-3 polyunsaturated fatty acids (PUFA) and cholesterol metabolisms are highly suspected to play a role in AMD pathophysiology. Indeed, epidemiological studies have very consistently shown a 40% reduction in risk for AMD in subjects with high dietary intake of n-3 PUFA, and in particular long-chain n-3 PUFA docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). In order to better understand the role of n-3 PUFA in retinal ageing, there is a need to identify reliable circulating biomarkers of n-3 PUFA retinal status. In an innovative approach using comprehensive lipidomics in a preliminary post-mortem study, we recently developed and identified several good candidates to be circulating biomarkers of n-3 PUFA retinal status. Whether these circulating biomarkers of lipid status may be associated with AMD remains to be determined. Besides, impairment of cholesterol metabolism in AMD was suggested by histological, experimental and genetic studies. HDL and LDL lipoproteins are carriers of n-3 PUFA to the retina. CETP (cholesterol ester transfer protein) and LCAT (lecithin-cholesterol acyltransferase) are key proteins in the remodeling of cholesteryl esters (CE) in lipoproteins. Among others, a gene polymorphism in CETP was associated with the risk of AMD. The results of our previous post-mortem study also suggested that the ratio of the DHA concentration in plasma CE to the DHA concentration in plasma phosphatidylcholines (PC) may represent a biomarker of the concentration of DHA in the RPE/CH. This ratio can be considered as an indirect indicator of the LCAT enzyme activity, which is responsible for the plasma CE synthesis in HDL. All these data comfort the implication of cholesterol metabolism in the transfer of n-3 PUFA to the retina. The objective of the proposal is to overcome two challenges: - A scientific one, to better understand the role of n-3 PUFA, cholesterol metabolism, and their interaction in AMD. - A technological one, to identify and validate new biomarkers of lipid status with high discriminative value for AMD. The multidisciplinary project will combine a case-control study of AMD, allowing the identification of biomarkers associated with AMD and two post-mortem studies allowing the study of the associations of these biomarkers with ocular n-3 PUFA status (retina, RPE/CH), firstly in elderly donors without AMD and secondly in eyes from donors affected by AMD. It represents a first step towards the design of a large scale interventional study, aiming at the reduction of the incidence of AMD with supplementation in n-3 PUFA. By studying a major aspect of retinal ageing, which has considerable repercussions on the wellbeing and autonomy of elderly subjects, the present project perfectly fits in the “health and wellbeing” challenge (3.4), and particularly of subtheme 12 “Normal and pathological ageing, autonomy and quality of life”.