Orexin-expressing neurons (OX-n) are found in the lateral hypothalamic area (LHA) and project throughout the brain, thereby modulating food intake. In normal mice, the afferents onto OX-n are mostly excitatory and retrogradely modulated by release of endocannabinoids acting through CB1 receptor. This innervation is enhanced by low levels of the hormone leptin (as it happens during food deprivation). Little is known about OX-n innervation -and its modulation- during obesity, a condition affecting millions of people worldwide.

We show that OX-n synthesize the endocannabinoid 2-arachidonoyl glycerol. In the transgenic mouse strain ob/ob made obese by leptin deficiency, we describe a much higher CB1-expressing inhibitory innervation of OX-n compared to wt. Consequently, mIPSC frequency in weaned ob/ob mice is 2 - 3 times higher than in wt. No difference is observed in pre-weaning mice. The administration of a CB1 receptor agonist (WIN) reduces sIPSC frequency more in ob/ob then in wt, an effect reversed by the receptor antagonist AM251. When artificially depolarized, ob/ob (but not wt) OX-n retrogradely reduce sIPSC frequency, an effect prevented by AM251 and suggestive of endocannabinoid release. As a consequence of this strong dis-inhibition, ob/ob mice express higher levels of orexin in the brain areas innervated by OX-n compared to wt. All these effects are reversed within 24hours by in vivo leptin administration.