title: Hypothalamic AgRP-neurons control peripheral substrate utilization and nutrient partitioning.
abstract: 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. As positive regulators of feeding behaviour, agouti-related protein (AgRP) producing neurons are indispensible for the hypothalamic integration of energy balance. Here, we demonstrate a role for AgRP-neurons in the control of nutrient partitioning. We report that ablation of AgRP-neurons leads to a change in autonomic output onto liver, muscle and pancreas affecting the relative balance between lipids and carbohydrates metabolism. 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 provide a direct demonstration of a role for AgRP-neurons in the coordination of efferent organ activity and nutrient partitioning, providing a mechanistic link between obesity and obesity-related disorders.
authors.affiliation: Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, Paris, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Joly-Amado
authors.forename: Raphaël G P
authors.initials: RG
authors.lastname: Denis
authors.forename: Julien
authors.initials: J
authors.lastname: Castel
authors.forename: Amélie
authors.initials: A
authors.lastname: Lacombe
authors.forename: Céline
authors.initials: C
authors.lastname: Cansell
authors.forename: Claude
authors.initials: C
authors.lastname: Rouch
authors.forename: Nadim
authors.initials: N
authors.lastname: Kassis
authors.forename: Julien
authors.initials: J
authors.lastname: Dairou
authors.forename: Patrice D
authors.initials: PD
authors.lastname: Cani
authors.forename: Renée
authors.initials: R
authors.lastname: Ventura-Clapier
authors.forename: Alexandre
authors.initials: A
authors.lastname: Prola
authors.forename: Melissa
authors.initials: M
authors.lastname: Flamment
authors.forename: Fabienne
authors.initials: F
authors.lastname: Foufelle
authors.forename: Christophe
authors.initials: C
authors.lastname: Magnan
authors.forename: Serge
authors.initials: S
authors.lastname: Luquet
mesh_terms: D054369:Agouti-Related Protein / Q000378:metabolism*; D000818:Animals; D050260:Carbohydrate Metabolism / Q000502:physiology; D004435:Eating / Q000502:physiology; D007031:Hypothalamus / Q000378:metabolism*; D050356:Lipid Metabolism / Q000502:physiology; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism; D015430:Weight Gain / Q000502:physiology
chemical_list: D054369:Agouti-Related Protein; C515199:Agrp protein, mouse