On the Cannabinoid Regulation of Energy Homeostasis: Past, Present and Future

The term “cannabinoid” refers to the class of 60 or so compounds found in the plant Cannabis sativa, of which Δ9-tetrahydrocannabinol (THC) is the major bioactive constituent. In addition, endogenous cannabinoids such as anandamide and 2-arachidonyl glycerol are synthesized de novo from phospholipids via the enzymatic activities of phospholipases such as phospholipase (PL)C, PLD and diacylglycerol lipase. These compounds act to varying degrees at three subtypes of cannabinoid receptors: the CB1 and CB2 receptors, as well as GPR55. There is a wealth of evidence demonstrating that both endogenous and exogenous cannabinoids regulate energy homeostasis by increasing energy intake and decreasing energy expenditure. Based on our current understanding it is apparent that this occurs via complex interactions between the gut, liver, pancreas, brainstem, hypothalamus and limbic forebrain. Moreover, the regulatory effects of cannabinoids on energy balance are sexually differentiated and subject to the modulatory influences of steroid and peptide hormones. This chapter endeavors to explore the continuum of developments in the intensive, 40+-year study of how cannabinoids regulate food intake, gastrointestinal motility and secretion, fat and carbohydrate disposition, mitochondrial respiration and core body temperature. It is anticipated that this work will offer new insight and provide a newfound appreciation of the pleiotropic mechanisms through which cannabinoids control energy homeostasis.

Keywords: Cannabinoids, appetite, metabolism, hypothalamus, brain stem, GI tract, body temperature, POMC neurons, contraction, secretion, transmitter release