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

Sabrina Diano, Zhong Wu Liu, Jin Kwon Jeong, Marcelo O. Dietrich, Hai Bin Ruan, Esther Kim, Shigetomo Suyama, Kaitlin Kelly, Erika Gyengesi, Jack L. Arbiser, Denise D. Belsham, David A. Sarruf, Michael W. Schwartz, Anton M. Bennett, Marya Shanabrough, Charles V. Mobbs, Xiaoyong Yang, Xiao Bing Gao, Tamas L. Horvath

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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.

Original languageEnglish (US)
Pages (from-to)1121-1128
Number of pages8
JournalNature Medicine
Volume17
Issue number9
DOIs
StatePublished - Sep 2011

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