Leptin-regulated endocannabinoids are involved in maintaining food intake

Leptin is the primary signal through which the hypothalamus senses nutritio nal state and modulates food intake and energy balance(1). Leptin reduces f ood intake by upregulating anorexigenic (appetite-reducing) neuropeptides, such as a-melanocyte-stimulating hormone(2,3), and downregulating orexigeni c (appetite-stimulating) factors, primarily neuropeptide Y-4. Genetic defec ts in anorexigenic signalling, such as mutations in the melanocortin-4 (ref . 5) or leptin receptors(6), cause obesity. However, alternative orexigenic pathways maintain food intake in mice deficient in neuropeptide Y-7. CB1 c annabinoid receptors(8) and the endocannabinoids anandamide and 2-arachidon oyl glycerol are present in the hypothalamus(9), and marijuana(10) and anan damide(11,12) stimulate food intake. Here we show that following temporary food restriction, CB1 receptor knockout mice eat less than their wild-type littermates, and the CB1 antagonist SR141716A reduces food intake in wild-t ype but not knockout mice. Furthermore, defective leptin signalling is asso ciated with elevated hypothalamic, but not cerebellar, levels of endocannab inoids in obese db/db and ob/ob mice and Zucker rats. Acute leptin treatmen t of normal rats and ob/ob mice reduces anandamide and 2-arachidonoyl glyce rol in the hypothalamus. These findings indicate that endocannabinoids in t he hypothalamus may tonically activate CB1 receptors to maintain food intak e and form part of the neural circuitry regulated by leptin.