title: Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance.
abstract: Macroautophagy is a lysosomal degradative pathway that maintains cellular homeostasis by turning over cellular components. Here we demonstrate a role for autophagy in hypothalamic agouti-related peptide (AgRP) neurons in the regulation of food intake and energy balance. We show that starvation-induced hypothalamic autophagy mobilizes neuron-intrinsic lipids to generate endogenous free fatty acids, which in turn regulate AgRP levels. The functional consequences of inhibiting autophagy are the failure to upregulate AgRP in response to starvation, and constitutive increases in hypothalamic levels of pro-opiomelanocortin and its cleavage product α-melanocyte-stimulating hormone that typically contribute to a lean phenotype. We propose a conceptual framework for considering how autophagy-regulated lipid metabolism within hypothalamic neurons may modulate neuropeptide levels to have immediate effects on food intake, as well as long-term effects on energy homeostasis. Regulation of hypothalamic autophagy could become an effective intervention in conditions such as obesity and the metabolic syndrome.
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Susmita
authors.initials: S
authors.lastname: Kaushik
authors.forename: Jose Antonio
authors.initials: JA
authors.lastname: Rodriguez-Navarro
authors.forename: Esperanza
authors.initials: E
authors.lastname: Arias
authors.forename: Roberta
authors.initials: R
authors.lastname: Kiffin
authors.forename: Srabani
authors.initials: S
authors.lastname: Sahu
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Schwartz
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Cuervo
authors.forename: Rajat
authors.initials: R
authors.lastname: Singh
mesh_terms: D054369:Agouti-Related Protein / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071193:Autophagy-Related Protein 7; D002478:Cells, Cultured; D004435:Eating; D004734:Energy Metabolism; D005227:Fatty Acids / Q000096:biosynthesis; D007031:Hypothalamus / Q000378:metabolism* / Q000502:physiology; D008055:Lipids / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D013217:Starvation; D000521:alpha-MSH / Q000096:biosynthesis
chemical_list: D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; C502661:Atg7 protein, mouse; D005227:Fatty Acids; D008055:Lipids; D008869:Microtubule-Associated Proteins; D000521:alpha-MSH; D011333:Pro-Opiomelanocortin; D000071193:Autophagy-Related Protein 7