In their recent article, Choi et al. ⁽ Reference Choi, Kim and Kwon ^{1 )} reported that prolonged ingestion of a high-fat diet (HFD) decreased energy expenditure and expression of genes controlling mitochondrial function as well as skeletal system development in the visceral adipose tissue in mice, and influenced the expression of a series of genes involved in immune and inflammatory responses. Interestingly, they have also demonstrated that HFD down-regulated specific genes involved in lipolysis and fatty acid (FA) metabolism, including those involved in FA activation and oxidation (Acsm3, Acacb, Acot4, Acadsb, Hadh and Faah). Here, we would like to add another layer to the study of Choi et al. ⁽ Reference Choi, Kim and Kwon ^{1 )} by focusing on the relationship between HFD and the endocannabinoid system (ECS) v. obesity.

Earlier studies have shown that HFD-induced obesity and insulin resistance were associated with an increased activity of the ECS and promotion of the hepatic expression of lipogenic genes, including stearoyl-CoA desaturase-1⁽ Reference Liu, Cinar and Xiong ^{2 )}. Moreover, HFD-induced increase in the hepatic levels of the endocannabinoid anandamide (AEA) has been attributed to the reduced activity of the AEA-degrading enzyme, fatty acid amide hydrolase (FAAH)⁽ Reference Liu, Cinar and Xiong ^{2 )}. Another study has shown that dietary FA composition modulated peripheral endocannabinoid levels in a differential and tissue-specific manner⁽ Reference Engeli, Lehmann and Kaminski ^{3 )}. Consequently, Engeli et al. ⁽ Reference Engeli, Lehmann and Kaminski ^{3 )} hypothesised that the peripheral ECS remains a promising target for dietary and pharmacological interventions in disease states related to obesity.

HFD-induced changes in the peripheral ECS could have important implications for the pathogenesis of metabolic diseases via ‘classical’ and ‘non-classical’ cannabinoid (CB) receptors. The former have already been shown to modulate pancreatic, adipose tissue, skeletal muscle and liver metabolism⁽ Reference Silvestri and Di Marzo ^{4 )}. For example, in their recent study, Di Marzo et al. ⁽ Reference Di Marzo, Capasso and Matias ^{5 )} reported that the ECS undergoes adaptive changes upon feeding HFD, as revealed by altered AEA and CB1 mRNA levels and by different potencies of the FAAH inhibitor AA-5-HT in delaying gastric emptying under this dietary regimen.

Since the pharmacology of ‘classical’ CB receptors is relatively well studied, it seems interesting to focus on the relationship between HFD and ‘non-classical’ CB receptors. These ‘non-classical’ CB receptors, such as GPR30, GPR55, TRPV1 or TRPV4, have been shown to participate in the endocannabinoid and non-CB lipophilic compound-dependent signalling. Now, it may be of interest to the readership to know whether ‘non-classical’ receptors have also been studied in relation to HFD and obesity.