Understanding this circuitry has important practical implications because blocking the cannabinoid receptor, CB1, offers a promising approach to treating obesity. One such compound, rimonabant (trade name Acomplia
In an article in the December 22, 2005, issue of Neuron, Young-Hwan Jo and colleagues report how the circuitry of CB1 is integrated with signaling by the appetite-suppressing hormone leptin. The CB1 receptor is normally triggered by natural regulatory molecules, called endocannabinoids.
In their studies, the researchers concentrated on the lateral hypothalamus (LH) of the brain, known to be a center of control of food intake. Their studies involved detailed electrophysiological measurements of the effects of specific neurons that they had identified in previous studies as being important in endocannabinoid signaling.
Their studies revealed that activation of CB1 receptors, as by endocannabinoid molecules, induced these neurons to be rendered more excitable by a mechanism called "depolarization-induced suppression of inhibition" (DSI).
What's more, they found that leptin inhibits DSI. However, they found that leptin did not interfere with the CB1 receptors themselves. Rather, leptin "short-circuits" the endocannabinoid effects by inhibiting pore-like channels in the neurons that regulate the flow of calcium into the neurons. Such calcium is necessary for the synthesis of endocannabinoids.
In further studies of mice genetically altered to be leptin deficient, the researchers found the DSI to be more prolonged than in normal mice. Thus, they said, the findings "implicate this mechanism for leptin receptor/endocannabinoid signaling in contributing to the maintenance of weight balance...." The researchers also included that "upregulation of endocannabinoid signaling in the LH may explain, at least in part, the increased body weight consistent with a prior report of elevated endocannabinoids" in such leptin-deficient mice.
The researchers concluded that their findings "are consistent with the hypothesis that the integration of endocannabinoid and leptin signaling regulates the excitability of neurons on appetite-related circuits."
They also wrote that "the cellular mechanisms of recently developed antiobesity drugs, such as rimonabant, may include decreased endocannabinoid signaling and hence decreased excitability of LH circuits related to appetite, even in the context of leptin insufficiency or resistance."
The researchers included Young-Hwan Jo, Ying-Jiun J. Chen, Streamson C. Chua, Jr., David A. Talmage and Lorna W. Role of Columbia University in New York, New York. 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.
Jo et al.: "Integration Of Endocannabinoid and Leptin Signaling in an Appetite-Related Neural Circuit." Publishing in Neuron, Vol. 48, 1055-1066, December 22, 2005, DOI 10.1016/j.neuron.2005.10.021 www.neuron.org.