The endocannabinoid system is an important modulator of metabolism with CB1 receptors present in the hypothalamus, the central control of metabolism, and peripherally in hepatocytes, skeletal muscles, adipose tissues, and the endocrine cells of the pancreas. In the thalamus, the ECS is active tonically, driving appetite by antagonizing leptin function while also being necessary to facilitate ghrelin and orexin functions. In the periphery, ECS activation increases ghrelin production in the stomach lining while decreasing the production of CCK in the small intestine; both effects resulted in increased appetite and feeding. Consumption of omega-6 fatty acids in mice drives increased endocannabinoid production, which could then drive appetite and further consumption of more omega-6 fatty acids, a rare instance of the ECS participating in a feed-forward loop rather than feedback inhibition. Activation of CB1 receptors in adipocytes leads to increased fat production as well as decreased adiponectin. CB2 receptor appears to have an opposing effect in adipose tissues. Activation of CB1 receptor in liver cells leads to decreased insulin clearance by downregulating its degradation enzyme, which causes a hyper-insulin state and then insulin resistance. In the pancreas, CB1 activation decreased GLP-1 release, as well as islet cell proliferation. In skeletal muscle tissues, CB1 activation decreased fatty acid metabolism. Anorexia nervosa may represent an ECS deficiency syndrome as patients with this condition have lower ECS levels and a number of polymorphisms in the ECS system have been linked to it as well. Additional ligands capable of binding to endocannabinoid receptors such as hemopressin, OEA, and PEA also have metabolic effects.