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Mol Metab. 2017 Apr 22;6(6):594-601. doi: 10.1016/j.molmet.2017.04.005. eCollection 2017 Jun.

Endocannabinoid-dependent disinhibition of orexinergic neurons: Electrophysiological evidence in leptin-knockout obese mice.

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Department of Neuroscience Biomedicine and Movement, Section of Physiology and Psychology, University of Verona, 37134 Verona, Italy.
National Institute of Neuroscience, 37134 Verona, Italy.
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, 80078 Pozzuoli, Italy.



In the ob/ob mouse model of obesity, chronic absence of leptin causes a significant increase of orexin (OX) production by hypothalamic neurons and excessive food intake. The altered OX level is linked to a dramatic increase of the inhibitory innervation of OX producing neurons (OX neurons) and the over expression of the endocannabinoid 2-arachidonoylglycerol (2-AG) by OX neurons of ob/ob mice. Little is known about the function of the excitatory synapses of OX neurons in ob/ob mice, and their modulation by 2-AG. In the present study, we fill this gap and provide the first evidence of the overall level of activation of OX neurons in the ob/ob mice.


We performed in vitro whole-cell patch-clamp recordings on OX neurons located in the perifornical area of the lateral hypothalamus in acute brain slices of wt and ob/ob mice. We identified OX neurons on the basis of their electrophysiological membrane properties, with 96% of concordance with immunohistochemisty.


We found that OX neurons of ob/ob mice are innervated by less efficient and fewer excitatory synapses than wt mice. Consequently, ob/ob OX neurons show more negative resting membrane potential and lower action potential firing frequency than wt. The bath application of the cannabinoid type-1 receptor agonist WIN55,212-2, depresses both the excitatory and the inhibitory synapses in ob/ob animals, but only the excitatory synapses in wt animals. Finally, the physiologic release of 2-AG induces a prevalent depression of inhibition (disinhibition) of OX neurons in ob/ob animals but not in wt.


In ob/ob mice, chronic absence of leptin induces a 2-AG mediated functional disinhibition of OX neurons. This helps explain the increase of OX production and, consequently, the excessive food intake of ob/ob mice.


Endocannabinoids; Leptin; Obesity; Orexin

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