Peroxisome proliferation-associated control of reactive oxygen species sets melanocortin tone and feeding in diet-induced obesity

• Type of Material: Article
• Authors: Sabrina Diano, Yale University; Zhong-Wu Liu, Yale University; Jin Kwoan Jeong, Yale University; Marcelo O. Dietrich, Yale University; Hai-Bin Ruan, Yale University; Esther Kim, Mount Sinai School of Medicine; Shigetomo Suyama, Yale University; Kaitlin Kelly, Yale University; Erika Gyengesi, Yale University; Jack Arbiser, Emory University; Denise D. Belsham, University of Toronto; David A. Sarruf, University of Washington; Michael W. Schwartz, University of Washington; Anton M. Bennett, Yale University; Marya Shanabrough, Yale University; Charles V. Mobbs, Universidade Federal do Rio Grande do Sul; Xiaoyong Yang, Yale University; Xiao-Bing Gao, Yale University; Tamas L. Horvath, Yale University
• Language: English
• Date: 2011-09-01
• Publisher: Nature Research (part of Springer Nature)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2011 Nature America, Inc. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1038/nm.2421
• Title of Journal or Parent Work: Nature Medicine
• ISSN: 1078-8956
• Volume: 17
• Issue: 9
• Start Page: 1121
• End Page: U130
• Grant/Funding Information: This work was also supported by NIH grants DK089098 (X.Y.), DK072033 (C.V.M.) DK090320 (M.W.S), AR47901and P30 AR42687 (J.L.A).; This work was supported by US National Institutes of Health (NIH) grants DK084065 (S.D), DK080000 and OD006850 (T.L.H.), and by American Diabetes Association grant 7-08-MN-25 (T.L.H.).
• Keywords: PPAR-GAMMA; CENTRAL-NERVOUS-SYSTEM; ENDOPLASMIC-RETICULUM; OXIDATIVE STRESS; HYPOTHALAMUS; ENERGY-BALANCE; Biochemistry & Molecular Biology; ACTIVATED-RECEPTOR-GAMMA; Cell Biology; Life Sciences & Biomedicine; INFLAMMATION; NPY/AGRP NEURONS; Research & Experimental Medicine; Medicine, Research & Experimental; CENTRAL LEPTIN INFUSION; Science & Technology
• Research Categories: Chemistry, Biochemistry; Biology, Neuroscience; Health Sciences, Nutrition

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 Î 3 (PPAR-Î 3) mRNA levels within the hypothalamus. The proliferation of peroxisomes in POMC neurons induced by the PPAR-Î 3 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.