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

Nat Med. 2011 Aug 28;17(9):1121-7. doi: 10.1038/nm.2421.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agouti-Related Protein / metabolism
  • Anilides / pharmacology
  • Animals
  • Cell Line
  • Eating / physiology
  • Electrophysiology
  • Energy Metabolism / physiology*
  • Green Fluorescent Proteins
  • Hypothalamus / cytology
  • Hypothalamus / metabolism*
  • Leptin / metabolism*
  • Mice
  • Mice, Obese
  • Neurons / metabolism*
  • Neuropeptide Y / metabolism
  • PPAR gamma / antagonists & inhibitors
  • PPAR gamma / metabolism*
  • Peroxisomes / physiology*
  • Polymerase Chain Reaction
  • Pro-Opiomelanocortin / metabolism
  • Reactive Oxygen Species / metabolism*


  • 2-chloro-5-nitrobenzanilide
  • Agouti-Related Protein
  • Anilides
  • Leptin
  • Neuropeptide Y
  • PPAR gamma
  • Reactive Oxygen Species
  • Green Fluorescent Proteins
  • Pro-Opiomelanocortin