title: Loss of autophagy in pro-opiomelanocortin neurons perturbs axon growth and causes metabolic dysregulation.
abstract: The hypothalamic melanocortin system, which includes neurons that produce pro-opiomelanocortin (POMC)-derived peptides, is a major negative regulator of energy balance. POMC neurons begin to acquire their unique properties during neonatal life. The formation of functional neural systems requires massive cytoplasmic remodeling that may involve autophagy, an important intracellular mechanism for the degradation of damaged proteins and organelles. Here we investigated the functional and structural effects of the deletion of an essential autophagy gene, Atg7, in POMC neurons. Lack of Atg7 in POMC neurons caused higher postweaning body weight, increased adiposity, and glucose intolerance. These metabolic impairments were associated with an age-dependent accumulation of ubiquitin/p62-positive aggregates in the hypothalamus and a disruption in the maturation of POMC-containing axonal projections. Together, these data provide direct genetic evidence that Atg7 in POMC neurons is required for normal metabolic regulation and neural development, and they implicate hypothalamic autophagy deficiency in the pathogenesis of obesity.
authors.affiliation: The Saban Research Institute, Neuroscience Program, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA 90027, USA.
authors.forename: Bérengère
authors.initials: B
authors.lastname: Coupé
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ishii
authors.forename: Marcelo O
authors.initials: MO
authors.lastname: Dietrich
authors.forename: Masaaki
authors.initials: M
authors.lastname: Komatsu
authors.forename: Tamas L
authors.initials: TL
authors.lastname: Horvath
authors.forename: Sebastien G
authors.initials: SG
authors.lastname: Bouret
mesh_terms: D050154:Adiposity / Q000235:genetics; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology* / Q000378:metabolism; D001343:Autophagy / Q000502:physiology*; D000071193:Autophagy-Related Protein 7; D001369:Axons / Q000502:physiology*; D001835:Body Weight / Q000235:genetics; D018149:Glucose Intolerance / Q000235:genetics; D015151:Immunoblotting; D053858:Metabolic Networks and Pathways / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008854:Microscopy, Electron; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics*; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
chemical_list: C502661:Atg7 protein, mouse; C490981:Gtf2h1 protein, mouse; D008869:Microtubule-Associated Proteins; D014157:Transcription Factors; D025801:Ubiquitin; D051758:Transcription Factor TFIIH; D011333:Pro-Opiomelanocortin; D000071193:Autophagy-Related Protein 7