Partner 9, Université Paris-Diderot Paris 7, Unit of Functional and Adaptive Biology (BFA) CNRS EAC 4413
University Paris Diderot is a leading multidisciplinary university in France to offer a wide range of degrees in the Humanities, Medicine and the Sciences. With its 26,000 students, its 92 research laboratories, Paris Diderot is a major actor in European higher education and research Area.
Partner 9 team leader:
The COBE team, directed by Serge Luquet uses modern molecular genetic tools and mouse models in integrated approaches in order to dissect out the role of discrete neural circuit elements in the control of different aspect of energy balance. The COBE team is exquisitely positioned to tackles some specific aim of the proposal through the extensive use of both conceptual & technical ability to explore integrated metabolism and physiology at a preclinical level. The team focuses the physiological processes that occur during the development of the pathologies inherited form liver-specific defect in association to the brain-liver and liver-brain axis.
Dr. Luquet will direct the phenotypic analysis and metabolic validation of humanised mouse models in WP4 and investigate how transplanted hepatocyte will direct the progression of the disease through 1) a local hepatic specific alteration of liver biology and 2) through the coordinated nervous inputs from the liver to the brain. A genetic susceptibility/mutation transferred through liver-specific iPSC graft could propagate to peripheral tissue through nervous pathways, liver-borne vagal input to the brain will in turn be relayed by the brain to peripheral organs to affect energy expenditure, feeding behaviour or glucose metabolism. The role of the liver-brain axis will be addressed by performing either full vagotomy (FB) or selective blockade of hepatic vagal afferent (SB) afferent. iPSC-transplanted mice will undergo a complete behavioural & metabolic phenotyping (metabolic efficiency, insulin sensitivity) prior to and after FB or SB surgery. High throughput standardised acquisition and computational modelling will allow for the establishment of predictive factor linking he human mutation and the mouse phenotype in a iPSC-mediated humanised context. In addition, neuronal structure involved in the integration of circulating signals of hunger and satiety such as the hypothalamus structures might undergo adaptive change secondary to liver-borne inputs to the brain and result for instance in central leptin resistance –a common features associated with the metabolic syndrome.
Over the last few years the Luque’s team has worked on central control of energy balance. The recent concept highlighted by our works lies in the observation that nutrient partitioning: i.e the process that encompasses nutrient storage, utilization and transformation is a fundamentally linked to the development of obesity-related diseases. This mechanism in directly dependent on brain’s ability to direct inter-organ communication and can be instrumental in the difference between diabetic and non-diabetic obesity. Dr. Luquet is in charge of the Physiologic of Functional & Physiological Exploration Platform (FPE) which will be a cornerstone of the metabolic and behavioural phenotyping of transplanted animals.
1. Joly-Amado, A., et al., (2012). Hypothalamic AgRP-neurons control peripheral substrate utilization and nutrient partitioning. EMBO J 31, 4276-4288.
2. Luquet, S, et al. (2012) The central nervous system at the core of the regulation of energy homeostasis. Front Biosci (Schol Ed) 1:448-465.
3. Cansell, C, et al. (2012). Arcuate AgRP neurons and the regulation of energy balance. Front in Endoc. Dec 27;3:169.
4. Luquet, S et al.. (2005).NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates.. Science 310, 683-685.
5. Kammoun, H.L., et al. (2009). GRP78 expression inhibits insulin and ER stress-induced SREBP-1c activation and reduces hepatic steatosis in mice. J Clin Invest 119:1201-1215.