Integration of endocannabinoid and leptin signaling in an appetite-related neural circuit

Young Hwan Jo; Ying Jiun J. Chen; Streamson C. Chua; David A. Talmage; Lorna W. Role

doi:10.1016/j.neuron.2005.10.021

Integration of endocannabinoid and leptin signaling in an appetite-related neural circuit

Young Hwan Jo, Ying Jiun J. Chen, Streamson C. Chua, David A. Talmage, Lorna W. Role

Medicine

Research output: Contribution to journal › Article › peer-review

193 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	1055-1066
Number of pages	12
Journal	Neuron
Volume	48
Issue number	6
DOIs	https://doi.org/10.1016/j.neuron.2005.10.021
State	Published - Dec 22 2005

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neuron.2005.10.021

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title = "Integration of endocannabinoid and leptin signaling in an appetite-related neural circuit",

abstract = "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.",

author = "Jo, {Young Hwan} and Chen, {Ying Jiun J.} and Chua, {Streamson C.} and Talmage, {David A.} and Role, {Lorna W.}",

note = "Funding Information: We would like to thank Dr. R{\'e}my Schlichter for the valuable discussions. We also thank Drs. Steven Siegelbaum and Li Jiang for helpful comments on prior versions of this manuscript and Denise Wiedl for technical assistance. This work was supported by NS22061 and a NARSAD Grable Distinguished Investigator award to L.W.R.; by CA79737 to D.A.T.; by DK57621 to S.C.C.; and by an award from the New York Obesity Research Center to Y.-H.J.",

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AU - Role, Lorna W.

N1 - Funding Information: We would like to thank Dr. Rémy Schlichter for the valuable discussions. We also thank Drs. Steven Siegelbaum and Li Jiang for helpful comments on prior versions of this manuscript and Denise Wiedl for technical assistance. This work was supported by NS22061 and a NARSAD Grable Distinguished Investigator award to L.W.R.; by CA79737 to D.A.T.; by DK57621 to S.C.C.; and by an award from the New York Obesity Research Center to Y.-H.J.

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N2 - 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.

AB - 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.

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Integration of endocannabinoid and leptin signaling in an appetite-related neural circuit

Abstract

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