Functional Fine-Tuning of Metabolic Pathways by the Endocannabinoid System-Implications for Health and Disease

Abstract

The endocannabinoid system (ECS) employs a huge network of molecules (receptors, ligands, and enzymatic machinery molecules) whose interactions with other cellular networks have still not been fully elucidated. Endogenous cannabinoids are molecules with the primary function of control of multiple metabolic pathways. Maintenance of tissue and cellular homeostasis by functional fine-tuning of essential metabolic pathways is one of the key characteristics of the ECS. It is implicated in a variety of physiological and pathological states and an attractive pharmacological target yet to reach its full potential. This review will focus on the involvement of ECS in glucose and lipid metabolism, food intake regulation, immune homeostasis, respiratory health, inflammation, cancer and other physiological and pathological states will be substantiated using freely available data from open-access databases, experimental data and literature review. Future directions should envision capturing its diversity and exploiting pharmacological options beyond the classical ECS suspects (exogenous cannabinoids and cannabinoid receptor monomers) as signaling through cannabinoid receptor heteromers offers new possibilities for different biochemical outcomes in the cell.

Keywords: cancer; cannabinoid receptor; endocannabinoid system; homeostasis; metabolism regulation.

Figure 1

A schematic pictorial model of (a) CB1R and (b) CB2R expression in human organs and tissues according to the Tissue Atlas of the Human Protein Atlas database [10]. mRNA expression overview shows RNA as the consensus dataset based on a combination of three sources—RNA-sequencing data from internally generated Human Protein Atlas (HPA), RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project and Cap Analysis of Gene Expression (CAGE) data from the Functional ANnoTation Of the Mammalian genome 5 (FANTOM5) project. When available protein data for which a knowledge-based annotation gave inconclusive results, no protein expression data were displayed. Nx—Normalized eXpression (resulting transcript expression values calculated for each gene in every sample).

Figure 2

The expression of (a) CB1R and (b) CB2R in human tissues according to the Human Protein Atlas database [10]. mRNA expression overview shows RNA as the consensus dataset based on a combination of three sources—RNA-sequencing data from internally generated Human Protein Atlas (HPA), RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project and Cap Analysis of Gene Expression (CAGE) data from the Functional ANnoTation Of the Mammalian genome 5 (FANTOM5) project. When available protein data for which a knowledge-based annotation gave inconclusive results, no protein expression data were displayed. Nx—Normalized eXpression (resulting transcript expression values calculated for each gene in every sample).

Figure 3

A schematic representation of the role of the endocannabinoid signaling in selected physiological and pathological states.