title: Peroxisome proliferation-associated control of reactive oxygen species sets melanocortin tone and feeding in diet-induced obesity.
abstract: Previous studies have proposed roles for hypothalamic reactive oxygen species (ROS) in the modulation of circuit activity of the melanocortin system. Here we show that suppression of ROS diminishes pro-opiomelanocortin (POMC) cell activation and promotes the activity of neuropeptide Y (NPY)- and agouti-related peptide (AgRP)-co-producing (NPY/AgRP) neurons and feeding, whereas ROS-activates POMC neurons and reduces feeding. The levels of ROS in POMC neurons were positively correlated with those of leptin in lean and ob/ob mice, a relationship that was diminished in diet-induced obese (DIO) mice. High-fat feeding resulted in proliferation of peroxisomes and elevated peroxisome proliferator-activated receptor γ (PPAR-γ) mRNA levels within the hypothalamus. The proliferation of peroxisomes in POMC neurons induced by the PPAR-γ agonist rosiglitazone decreased ROS levels and increased food intake in lean mice on high-fat diet. Conversely, the suppression of peroxisome proliferation by the PPAR antagonist GW9662 increased ROS concentrations and c-fos expression in POMC neurons. Also, it reversed high-fat feeding-triggered elevated NPY/AgRP and low POMC neuronal firing, and resulted in decreased feeding of DIO mice. Finally, central administration of ROS alone increased c-fos and phosphorylated signal transducer and activator of transcription 3 (pStat3) expression in POMC neurons and reduced feeding of DIO mice. These observations unmask a previously unknown hypothalamic cellular process associated with peroxisomes and ROS in the central regulation of energy metabolism in states of leptin resistance.
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, Connecticut, USA. sabrina.diano@yale.edu
authors.forename: Sabrina
authors.initials: S
authors.lastname: Diano
authors.forename: Zhong-Wu
authors.initials: ZW
authors.lastname: Liu
authors.forename: Jin Kwon
authors.initials: JK
authors.lastname: Jeong
authors.forename: Marcelo O
authors.initials: MO
authors.lastname: Dietrich
authors.forename: Hai-Bin
authors.initials: HB
authors.lastname: Ruan
authors.forename: Esther
authors.initials: E
authors.lastname: Kim
authors.forename: Shigetomo
authors.initials: S
authors.lastname: Suyama
authors.forename: Kaitlin
authors.initials: K
authors.lastname: Kelly
authors.forename: Erika
authors.initials: E
authors.lastname: Gyengesi
authors.forename: Jack L
authors.initials: JL
authors.lastname: Arbiser
authors.forename: Denise D
authors.initials: DD
authors.lastname: Belsham
authors.forename: David A
authors.initials: DA
authors.lastname: Sarruf
authors.forename: Michael W
authors.initials: MW
authors.lastname: Schwartz
authors.forename: Anton M
authors.initials: AM
authors.lastname: Bennett
authors.forename: Marya
authors.initials: M
authors.lastname: Shanabrough
authors.forename: Charles V
authors.initials: CV
authors.lastname: Mobbs
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Yang
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Gao
authors.forename: Tamas L
authors.initials: TL
authors.lastname: Horvath
mesh_terms: D054369:Agouti-Related Protein / Q000378:metabolism; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D004435:Eating / Q000502:physiology; D004594:Electrophysiology; D004734:Energy Metabolism / Q000502:physiology*; D049452:Green Fluorescent Proteins; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism*; D051379:Mice; D008820:Mice, Obese; D009474:Neurons / Q000378:metabolism*; D009478:Neuropeptide Y / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020675:Peroxisomes / Q000502:physiology*; D016133:Polymerase Chain Reaction; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D054369:Agouti-Related Protein; D000813:Anilides; D020738:Leptin; D009478:Neuropeptide Y; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D049452:Green Fluorescent Proteins; D011333:Pro-Opiomelanocortin