PI3K integrates the action of insulin and leptin on hypothalamic neurons

J Clin Invest. 2005 Apr;115(4):951-8. doi: 10.1172/JCI24301. Epub 2005 Mar 10.


Central control of energy balance depends on the ability of proopiomelanocortin (POMC) or agouti-related protein (Agrp) hypothalamic neurons to sense and respond to changes in peripheral energy stores. Leptin and insulin have been implicated as circulating indicators of adiposity, but it is not clear how changes in their levels are perceived or integrated by individual neuronal subtypes. We developed mice in which a fluorescent reporter for PI3K activity is targeted to either Agrp or POMC neurons and used 2-photon microscopy to measure dynamic regulation of PI3K by insulin and leptin in brain slices. We show that leptin and insulin act in parallel to stimulate PI3K in POMC neurons but in opposite ways on Agrp neurons. These results suggest a new view of hypothalamic circuitry, in which the effects of leptin and insulin are integrated by anorexigenic but not by orexigenic neurons.

Publication types

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

MeSH terms

  • Agouti-Related Protein
  • Animals
  • Energy Metabolism*
  • Enzyme Activation
  • Gene Expression Regulation, Enzymologic
  • Genes, Reporter
  • Homeostasis
  • Hypothalamus / cytology*
  • Insulin / metabolism*
  • Intercellular Signaling Peptides and Proteins
  • Leptin / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Microscopy, Confocal
  • Neurons / cytology
  • Neurons / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Pro-Opiomelanocortin / metabolism
  • Proteins / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Synaptic Transmission / physiology


  • Agouti-Related Protein
  • Agrp protein, mouse
  • Insulin
  • Intercellular Signaling Peptides and Proteins
  • Leptin
  • Proteins
  • Recombinant Fusion Proteins
  • Pro-Opiomelanocortin
  • Phosphatidylinositol 3-Kinases