Leptin-regulated endocannabinoids are involved in maintaining food intake

Leptin is the primary signal through which the hypothalamus senses nutritional state and modulates food intake and energy balance1. Leptin reduces food intake by upregulating anorexigenic (appetite-reducing) neuropeptides, such as α-melanocyte-stimulating hormone2,3, and downregulating orexigenic (appetite-stimulating) factors, primarily neuropeptide Y4. Genetic defects in anorexigenic signalling, such as mutations in the melanocortin-4 (ref. 5) or leptin receptors6, cause obesity. However, alternative orexigenic pathways maintain food intake in mice deficient in neuropeptide Y7. CB1 cannabinoid receptors8 and the endocannabinoids anandamide and 2-arachidonoyl glycerol are present in the hypothalamus9, and marijuana10 and anandamide11,12 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-type but not knockout mice. Furthermore, defective leptin signalling is associated with elevated hypothalamic, but not cerebellar, levels of endocannabinoids in obese db/db and ob/ob mice and Zucker rats. Acute leptin treatment of normal rats and ob/ob mice reduces anandamide and 2-arachidonoyl glycerol in the hypothalamus. These findings indicate that endocannabinoids in the hypothalamus may tonically activate CB1 receptors to maintain food intake and form part of the neural circuitry regulated by leptin.