Integration of endocannabinoid and leptin signaling in an appetite-related neural circuit.
Recently developed therapeutics for obesity, targeted against cannabinoid receptors, result in decreased appetite and sustained weight loss. Prior studies have demonstrated CB1 receptors (CB1Rs) and leptin modulation of cannabinoid synthesis in hypothalamic neurons. Here, we show that depolarization of perifornical lateral hypothalamus (LH) neurons elicits a CB1R-mediated suppression of inhibition in local circuits thought to be involved in appetite and "natural reward." The depolarization-induced decrease in inhibitory tone to LH neurons is blocked by leptin. Leptin inhibits voltage-gated calcium channels in LH neurons via the activation of janus kinase 2 (JAK2) and of mitogen-activated protein kinase (MAPK). Leptin-deficient mice are characterized by both an increase in steady-state voltage-gated calcium currents in LH neurons and a CB1R-mediated depolarization-induced suppression of inhibition that is 6-fold longer than that in littermate controls. Our data provide direct electrophysiological support for the involvement of endocannabinoids and leptin as modulators of hypothalamic circuits underlying motivational aspects of feeding behavior.
Jo
Young-Hwan
YH
Department of Pathology and Cell Biology, Center for Neurobiology and Behavior, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA. yjo@aecom.yu.edu
Chen
Ying-Jiun J
YJ
Chua
Streamson C
SC
Talmage
David A
DA
Role
Lorna W
LW
D000818:Animals; D001069:Appetite Regulation / Q000187:drug effects / Q000502:physiology*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism* / Q000494:pharmacology; D063388:Endocannabinoids; D007026:Hypothalamic Area, Lateral / Q000187:drug effects / Q000378:metabolism*; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology; D053614:Janus Kinase 2; D020738:Leptin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009042:Motivation; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D054411:Receptors, Leptin; D012201:Reward; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
D015220:Calcium Channels; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D020738:Leptin; D011518:Proto-Oncogene Proteins; D043884:Receptor, Cannabinoid, CB1; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2