Antagonistic interplay between hypocretin and leptin in the lateral hypothalamus regulates stress responses

Nat Commun. 2015 Feb 19:6:6266. doi: 10.1038/ncomms7266.


The hypothalamic-pituitary-adrenal (HPA) axis functions to coordinate behavioural and physiological responses to stress in a manner that depends on the behavioural state of the organism. However, the mechanisms through which arousal and metabolic states influence the HPA axis are poorly understood. Here using optogenetic approaches in mice, we show that neurons that produce hypocretin (Hcrt)/orexin in the lateral hypothalamic area (LHA) regulate corticosterone release and a variety of behaviours and physiological hallmarks of the stress response. Interestingly, we found that Hcrt neuronal activity and Hcrt-mediated stress responses were inhibited by the satiety hormone leptin, which acts, in part, through a network of leptin-sensitive neurons in the LHA. These data demonstrate how peripheral metabolic signals interact with hypothalamic neurons to coordinate stress and arousal and suggest one mechanism through which hyperarousal or altered metabolic states may be linked with abnormal stress responses.

Publication types

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

MeSH terms

  • Animals
  • Down-Regulation / radiation effects
  • Food Deprivation
  • GABAergic Neurons / metabolism
  • GABAergic Neurons / radiation effects
  • Hypothalamic Area, Lateral / metabolism*
  • Hypothalamic Area, Lateral / radiation effects
  • Hypothalamo-Hypophyseal System / metabolism
  • Hypothalamo-Hypophyseal System / radiation effects
  • Leptin / antagonists & inhibitors*
  • Leptin / metabolism
  • Light
  • Male
  • Metabolic Networks and Pathways / radiation effects
  • Mice, Inbred C57BL
  • Orexins / metabolism*
  • Pituitary-Adrenal System / metabolism
  • Pituitary-Adrenal System / radiation effects
  • Signal Transduction / radiation effects
  • Stress, Physiological* / radiation effects


  • Leptin
  • Orexins