The endocannabinoid system in appetite regulation and treatment of obesity

Abstract

The endocannabinoid system (ECS) is a complex cell-signaling system that is responsible for maintaining homeostasis by modulating various regulatory reactions in response to internal and environmental changes. The influence of ECS on appetite regulation has been a subject of much recent research, however, the full extent of its impact remains unknown. Current evidence links human obesity to ECS activation, increased endocannabinoid levels in both central and peripheral tissues, along with cannabinoid receptor type 1 (CBR1) up-regulation. These findings imply the potential pharmacological use of the ECS in the treatment of obesity. Here, we present various pathophysiological processes in obesity involving the ECS, highlighting different pharmacological options for modulating endocannabinoid activity to treat obesity. However, the potential of those pharmacological possibilities remains under investigation and requires further research.

FIGURE 1

Simplified overview of ECS signaling. A neurotransmitter is released from a vesicle in the presynaptic neuron into the synaptic cleft due to Ca2+ influx, where it binds to its specific receptor on the membrane of the postsynaptic neuron. This binding activates the enzymes NAPE‐PLD and DAGL, which synthesize AEA and 2‐AG, respectively, in the postsynaptic neuron. Both AEA and 2‐AG are hydrophobic, allowing them to diffuse from the postsynaptic membrane. AEA and 2‐AG then travel back across the synaptic cleft and bind to the CBR1 receptor on the presynaptic neuron. The CBR1 receptor is linked to the Gi protein, which inhibits the voltage‐gated Ca2+ channel, causing membrane hyperpolarization by stimulating K+ channels and reducing depolarization. This process decreases Ca2+ influx, thereby decreasing neurotransmitter exocytosis. Subsequently, 2‐AG undergoes passive diffusion into the presynaptic membrane, where it is degraded by MAGL, while AEA undergoes passive diffusion into the postsynaptic membrane, where it is degraded by FAAH. 2‐AG ‐ 2‐arachidonoylglycerol; AEA ‐ N‐arachidonoylethanolamine; CBR1 – cannabinoid receptor type 1; DAGL ‐ diacylglycerol lipase; FAAH ‐ fatty acid amide hydrolase; MAGL ‐ monoacylglycerol lipase; NAPE‐PLD – N‐acyl phosphatidylethanolamine‐specific phospholipase D.

FIGURE 2

The Role of CB1 receptor stimulation in appetite regulation and obesity. CB1 receptor stimulation promotes orexigenic pathways leading to the increase in the synthesis of molecules such as ghrelin, NPY, and β‐endorphin, which are associated with increased appetite and potential weight gain. Conversely, CB1 receptor activation decreases anorexigenic signals by reducing leptin sensitivity and adiponectin synthesis, diminishing the body's ability to suppress appetite and regulate energy balance. AMPK ‐ AMP‐activated protein kinase; mTOR ‐ mammalian target of rapamycin; NPY ‐ neuropeptide Y; STAT3 ‐ signal transducer and activator of transcription 3; UCP2 ‐ mitochondrial uncoupling protein 2.