Endocannabinoid System and Metabolism: The Influences of Sex

Abstract

The endocannabinoid system (ECS) is a lipid signaling system involved in numerous physiological processes, such as endocrine homeostasis, appetite control, energy balance, and metabolism. The ECS comprises endocannabinoids, their cognate receptors, and the enzymatic machinery that tightly regulates their levels within tissues. This system has been identified in various organs, including the brain and liver, in multiple mammalian and non-mammalian species. However, information regarding the sex-specific regulation of the ECS remains limited, even though increasing evidence suggests that interactions between sex steroid hormones and the ECS may ultimately modulate hepatic metabolism and energy homeostasis. Within this framework, we will review the sexual dimorphism of the ECS in various animal models, providing evidence of the crosstalk between endocannabinoids and sex hormones via different metabolic pathways. Additionally, we will underscore the importance of understanding how endocrine-disrupting chemicals and exogenous cannabinoids influence ECS-dependent metabolic pathways in a sex-specific manner.

Keywords: CB1; appetite; endocannabinoid system; lipid signaling; liver; metabolic disorders; sex hormones; sexual dimorphism.

Figure 1

A schematic illustration summarizing the endocannabinoid signaling occurring at VMN SF-1/ARC POMC synapses in females and males. In females, estrogen binding to ERs increases the activity of PI3K and the production of PIP3, which upregulates Akt and stimulates nNOS. Endocannabinoid levels in the synaptic cleft are then reduced by nNOS through the inhibition of their synthesis, the improvement of their catabolism, and the promotion of their reuptake. Moreover, the NO produced may act in a retrograde fashion to uncouple CB1 from its ligands in the glutamatergic nerve terminal. On the other hand, testosterone in males activates a putative membrane AR and raises the levels of intracellular calcium. A calcium increase activates CaMKK and the AMPK complex, improving the production of 2-AG by DAGL-α. The 2-AG release can retrogradely activate presynaptic CB1 in the VNM SF-1 neurons and inhibit calcium entry, ultimately decreasing glutamatergic input. VMN: ventromedial nucleus; SF-1: steroidogenic factor-1; ARC: arcuate nucleus; POMC: proopiomelanocortin; PI3K: phosphatidylinositol-3-kinase; PI3P: phosphatidylinositol-3-phosphate; nNOS: nitric oxide synthase; NO: nitric oxide; CaMKK: calmodulin-dependent protein kinase; AMPK: AMP-activated protein kinase; Akt: protein kinase B; ESRɑ: estrogen receptor ɑ; E2: estradiol; AR: androgen receptor; 2-AG: 2-arachidonoylglycerol; PLC: phospholipase C; DAGL: diacylglycerol lipases; CB1: cannabinoid receptor.

Figure 2

A summary of the sex-specific effects of a high-fat diet and calorie-restricted diet on gene expression and protein levels related to the ECS and metabolism in F1 mice. Dams were treated before pregnancy, during pregnancy and/or lactation. Cases when a treatment induced a significantly increased response are marked with a red “↑”; a significantly decreased response is marked with a blue “↓”; and no change is marked with a “=”. Cases with contradictory results found between studies are marked as “↑/=”, “↓/=”, or “↑/↓/=”. Readouts extracted from the bibliography are written in capital letters for protein levels, and in italics for gene expression [101,146,147,148,149]. Abbreviations: CB1/Cnr1: cannabinoid receptor 1; CB2: cannabinoid receptor 2; MGLL/Mgll: monoacylglycerol lipase; FAAH/Faah: fatty acid amide hydrolase 1; Nape-pld: N-acyl-phosphatidylethanolamine-hydrolysing phospholipase D; Srebf1c: sterol regulatory element binding factor-1c; Acaca: acetyl-coA carboxylase alpha; Acox1: acyl-CoA oxidase 1; Apob: apolipoprotein B; Hmgcr: 3-hydroxy-3-methylglutaryl-coenzyme A reductase; Ppar: peroxisome proliferator-activated receptor; Cpt1: carnitine palmitoyltransferase 1; Scd1: stearoyl-CoA desaturase; Cox4i1: cytochrome c oxidase subunit 4 isoform 1; ACC: acetyl coenzyme A carboxylase; CEBPα: CCAAT/enhancer binding protein α.