Central lipid metabolism: a fundamental regulator of energy balance – Fat4Brain

The regulation of energy balance by the central nervous system (CNS) is a key actor of energy homeostasis in mammals. Deregulations of the fine mechanisms of nutrient sensing in brain could lead to several metabolic diseases such as obesity and type 2 diabetes. The Fat4Brain project will investigate in preclinical models the role of triglyceride (TG) rich-lipoproteins hydrolysis in strategic brain areas involved in both the homeostatic and non-homeostatic regulation of energy balance. Indeed, the hypothalamus, the main integrative center of energy-related peripheral information, and key regions of the mesocorticolimbic system (MCL) encoding reward associated with food present high expression of several proteins involved in lipid handling, in particular the lipoprotein lipase (LPL), a key enzyme involved in the hydrolysis of TG.
We will focus on the cellular mechanisms involved in LPL action in brain. Indeed we have preliminary knowledge acquired by the consortium that a decreased LPL activity in different brain areas is associated with alteration of energy homeostasis. We postulate that decreased LPL activity will reduce the availability of exogenous fatty acids in brain structures concomitantly to an increase in endogenous fatty acid synthesis from glucose, i.e. lipogenesis. This could have several consequences including increased synthesis of ceramides from de novo synthetized palmitoyl-CoA. Indeed, we have previously shown in a mouse model of hippocampal LPL deficiency that ceramide content was concomitantly increased and that, importantly, inhibition of ceramide synthesis reversed the deregulation of energy homeostasis in this model.
We will metabolically phenotype mice with a ventromedial hypothalamic specific LPL deletion (obese without hyperphagia) or conversely with LPL overexpression and determine the role of two key lipogenic transcription factors, SREBP-1c (sterol regulatory element-binding protein 1c) and ChREBP (carbohydrate responsive element-binding protein) in relaying central lipid effects, using pharmacological and genetic tools. The implication of the endocannabinoid system with also be assessed. Patch-clamp electrophysiology will allow the study of neuron responses to exogenous or endogenous lipid availability. The same approaches will be used in the MCL system with a special focus of reward associated with food, in order to get a broad -but precise- perspective of lipoprotein hydrolysis in the brain control of energy balance.
By increasing our knowledge of the mechanisms involved in the management of energy homeostasis in the central nervous system, we hope to provide novel ways of tackling obesity.