Claudia Manca, Besma Boubertakh, Nadine Leblanc, Thomas Deschênes, Sebastien Lacroix, Cyril Martin, Alain Houde, Alain Veilleux, Nicolas Flamand, Giulio G. Muccioli, Frédéric Raymond, Patrice D. Cani, Vincenzo Di Marzo, Cristoforo Silvestri

Significance: Endocannabinoids act retrogradely at presynaptic sites to activate cannabinoid receptor type 1 (CB ₁ ) receptors, thereby inhibiting neurotransmitter release and fine-tuning synaptic transmission. In murine models of obesity with leptin deficiency, we report that orexin-A neurons undergo a shift from predominant control by CB ₁ -expressing excitatory to CB ₁ -expressing inhibitory inputs. In addition, endocannabinoid biosynthesis is increased in these neurons. CB ₁ activation by endocannabinoids reduces the inhibition of orexinergic neurons in obese mice, thereby enhancing orexin-A release in target brain areas and contributing to hyperphagia and increased body weight, as well as to alterations of hormone levels typical of obesity.

Lifestyle is a well-known environmental factor that plays a major role in facilitating the development of metabolic syndrome or eventually exacerbating its consequences. Various lifestyle factors, especially changes in dietary habits, extreme temperatures, unusual light–dark cycles, substance abuse, and other stressful factors, are also established modifiers of the endocannabinoid system and its extended version, the endocannabinoidome. The endocannabinoidome is a complex lipid signaling system composed of a plethora (>100) of fatty acid-derived mediators and their receptors and anabolic and catabolic enzymes (>50 proteins) which are deeply involved in the control of energy metabolism and its pathological deviations. A strong link between the endocannabinoidome and another major player in metabolism and dysmetabolism, the gut microbiome, is also emerging. Here, we review several examples of how lifestyle modifications (westernized diets, lack or presence of certain nutritional factors, physical exercise, and the use of cannabis) can modulate the propensity to develop metabolic syndrome by modifying the crosstalk between the endocannabinoidome and the gut microbiome and, hence, how lifestyle interventions can provide new therapies against cardiometabolic risk by ensuring correct functioning of both these systems.