Introduction

Control of energy homeostasis involves a complex network of both peripheral and central signals which permanently inform central nervous system (CNS) about nutritional status thus allowing an adaptive response in regard to energy demand. At the level of the hypothalamus, the arcuate nucleus (ARC) plays a fundamental role in the integration of circulating signals of hunger and satiety that cannot cross the blood brain barrier such as leptin, insulin, ghrelin or the peptide YY (PYY3-36). The ARC contains at least two neuronal populations that are crucially involved in the regulation of energy balance: the neurons that make Neuropeptide Y (NPY) and Agouti-related Protein (AgRP) both powerful orexigenic peptide and the neurons that make the pro-opiomélanocortin (POMC), which secretes the alpha-melanocyte-stimulating-hormone (alpha-MSH) and the cocain and amphetamine related transcript (CART) which are powerful anorectic peptide. Both NPY/AgRP and POMC/CART neurons are considered as “1st order” neurons and in the integration of peripheral circulating factors of hunger and satiety.

The NPY/AgRP neurons and POMC neurons exert opposite action on each and project toward second order neurons located in other region of the hypothalamus where an integrated response takes place to regulate energy balance. The POMC/CART neurons decrease food intake and increase energy expenditure through the activation of melanocortin receptors (MC3R and MC4R) while NPY/AgRP neurons have opposite action by exerting a inhibitory tone onto directly o.nto POMC/CART neurons and by secreting AgRP which is a natural antagonist of alpha-MSH. This so called “melanocortin system” is essential for energy balance regulation. Other areas of CNS like brainstem or dopaminergic mesolimbic system come in addition to the hypothalamus regulation of food intake and represent potential target for the development of therapeutic strategy against feeding behavior disorders like anorexia, or at the opposite hyperphagia on the one hand but also the establishment of obesity and insulin resistance.

By using genetic approaches in combination with fully integrated approaches we explore two main axes the function of the brain in the regulation of feeding behavior and energy expenditure.

I. Obesity-related diseases : a defect in inter-organ communication ?

It has become evident that obesity-related metabolic complications are not solely caused by excessive nutrient intake, but also involve the inappropriate conversion, storage and utilization of nutrients. Obesity-related diseases such as diabetes and dyslipidemia result from metabolic alterations including the defective conversion, storage and utilization of nutrients, but the central mechanisms that regulate this process of nutrient partitioning remain elusive.
Hypothalamic AgRP-neurons control peripheral substrate utilization and nutrient partitioning.
We have developed a mouse model in which hypothalamic orexigenic neurons that make Neuropeptide Y and Agouti-related can be selectively ablated at neonatal stage to study the role of this neuronal population in different aspect of energy balance. As positive regulators of feeding behavior, agouti-related protein (AgRP) producing neurons are crucial to the hypothalamic integration of energy balance. Using an animal model in which AgRP-neurons can be selectively ablated we demonstrate a new role for AgRP-neurons in the control of nutrient partitioning. We found that ablation of AgRP neurons leads to a change in autonomic output onto liver, muscle, and pancreas that favor the utilization of lipids over carbohydrates. As a consequence, mice lacking AgRP-neurons become obese and hyperinsulinemic on regular chow but display reduced body weight gain and paradoxical improvement in glucose tolerance on high fat diet. These results establish a novel role for AgRP-neurons in the coordination of efferent organ activity and nutrient partitioning, providing a mechanistic link between obesity and obesity-related disorders.
Joly, A., et al (2012). Hypothalamic AgRP-neurons control peripheral substrate utilization and nutrient partitioning. The EMBO J Nov 14;31(22):4276-88.

Ongoing investigations are:

Hypothalamic AgRP-neurons control peripheral substrate utilization and nutrient partitioning
We have developed a mouse model in which Neuropeptide Y and Agouti-related protein expressing neurons can be selectively ablated at neonatal stage to study the role of this neuronal population in different aspect of energy balance. Using an animal model in which AgRP-neurons can be selectively ablated we demonstrate a new role for AgRP-neurons in the control of nutrient partitioning. We will further investigate the concept of central control of peripheral nutrient partitioning with a specific regards to the integration of circulating of hunger and satiety such as leptin, ghrelin or nervous input.

Liver-brain dialogue and the control of nutrient partitioning
The liver acts as a fundamental integrator of metabolic signals and therefore is capable of sensing disease-associated alterations that originate from peripheral tissues such as adipose tissue, gut, muscle, and brain. Additionally, alterations of genes and pathways in the liver are causal to the development of diverse metabolic diseases, which impact both on the function of the liver itself but also on the function of peripheral metabolic tissues. Moreover, beside brain-liver signals, liver-brain inputs is also critically involved in the overall regulation of energy balance. Indeed, liver-specific modulation of lipogenic program triggers a global change in energy expenditure that is relayed by the liver to the brain through vagal input. Moreover, a rapid switch of substrate utilization, transformation and storage is a unique ability of the liver and is reflected, in human like in rodent by the acute change in metabolic efficiency and substrate utilization.
Exploring Liver-brain dialogue in the general framework of metabolic adaptability and peripheral substrate utilization plasticity might provide a core mechanism linking obesity and obesity-related diseases.

The COFFEE team is part of a FP7 European collaborative research consortium “Health and the Understanding of Metabolism, Aging and Nutrition (HUMAN)
The primary tool of the consortium is a mouse model of with a Humanized hepatocyte. This model will be used to study the contribution of a genetic susceptibility of cell derived from patient bearing polymorphism for obesity/diabetes target identified through GWAS studies.

The overarching aim of our work in HUMAN project is to fully characterize the metabolic and behavioural phenotype of humanized mice. A methodological pipeline will be set up for standardized phenotyping with specific attention to how the genetic variation introduced in the iPSC/hepatocyte background affects susceptibility to metabolic disorders. This entails measurements of metabolic characteristics (e.g. feeding behaviour, metabolic efficiency and flexibility, glucose metabolism, effects on lipoprotein and lipid metabolism) on control diets and “Westernized’ diet and after different drug treatments such as antidiabetic or lipid lowering agents.

II. The motivational & hedonic drive to feed : a primary mechanism in feeding behavior alteration

It has been recently suggested that elevated circulating levels of long-chain fatty acids (LCFAs), which are often elevated in obese and diabetic individuals, could be an important causative link in the association of obesity with insulin resistance and type 2 diabetes. In particular, there is growing evidence that lipid metabolism within discrete brain regions can function as sensor of nutrient availability that can integrate multiple nutritional and hormonal signals and directly control feeding behavior, as well as peripheral glucose metabolism and energy expenditure.

Central lipid sensing: a possible mechanism for addictive like behavior associated with high fat high sugar diet?

We have established an original model a model that closely recapitulates post-prandial increase of Triglyceride (TG) through intra carotid perfusion in freely moving mice. By using this model we found that TG entering the brain might directly exert a control on the rewarding and motivational of feeding. Indeed brain specific perfusion of TG specifically decreases locomotors activity, energy expenditure and suppress the rewarding aspect of palatable high fat/high sugar diet suggesting that brain lipid sensing per se could directly activate the brain’s reward system. And similar to drugs of abuse, the motivational or rewarding aspects of food intake are largely dependent on the mesolimbic dopamine system. In that regards, the team has imported the conceptual and technical tools to study rewarding and motivational aspect of rodent behaviour. Our results support an original and provocative hypothesis that central detection of nutritional lipid could be a key mechanism in the development of addictive behavior facing calories-dense food.
Ongoing investigation involves an active collaborative work with the Dr T. Hansko, University of California, San-Diego and relies on the use of virus-mediated gene delivery to further decipher the mechanism by which nutritional lipid could act directly in the brain the way drug of abuse do.