Monoglyceride lipase (MGLL) regulates metabolism by catabolizing monoacylglycerols (MAGs), including the endocannabinoid 2-arachidonoyl glycerol (2-AG) and some of its bioactive congeners, to the corresponding free fatty acids. Mgll knockout mice (Mgll^−/−) exhibit elevated tissue levels of MAGs in association with resistance to the metabolic and cardiovascular perturbations induced by a high fat diet (HFD). The gut microbiome and its metabolic function are disrupted in obesity in a manner modulated by 2-arachidonoyl glycerol (2-AG’s) main receptors, the cannabinoid CB1 receptors. We therefore hypothesized that Mgll^−/− mice have an altered microbiome, that responds differently to diet-induced obesity from that of wild-type (WT) mice. We subjected mice to HFD and assessed changes in the microbiomes after 8 and 22 weeks. As expected, Mgll^−/− mice showed decreased adiposity, improved insulin sensitivity, and altered circulating incretin/adipokine levels in response to HFD. Mgll^−/− mice on a chow diet exhibited significantly higher levels of Hydrogenoanaerobacterium, Roseburia, and Ruminococcus than WT mice. The relative abundance of the Lactobacillaceae and Coriobacteriaceae and of the Lactobacillus, Enterorhabdus, Clostridium_XlVa, and Falsiporphyromonas genera was significantly altered by HFD in WT but not Mgll^−/− mice. Differently abundant families were also associated with changes in circulating adipokine and incretin levels in HFD-fed mice. Some gut microbiota family alterations could be reproduced by supplementing 2-AG or MAGs in culturomics experiments carried out with WT mouse fecal samples. We suggest that the altered microbiome of Mgll^−/− mice contributes to their obesity resistant phenotype, and results in part from increased levels of 2-AG and MAGs.

We investigated the influence of different dietary formulation of n-3 polyunsaturated fatty acids (PUFA) on rat tissue fatty acid (FA) incorporation and consequent modulation of their bioactive metabolite N-acylethanolamines (NAE). For 10 weeks, rats were fed diets with 12% of fat from milk + 4% soybean oil and 4% of oils with different n-3 PUFA species: soybean oil as control, linseed oil rich in α-linolenic (ALA), Buglossoides arvensis oil rich in ALA and stearidonic acid (SDA), fish oil rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), Nannochloropsis microalga oil rich in EPA or Schizochytrium microalga oil rich in DHA. FA and NAE profiles were determined in plasma, liver, brain and adipose tissues. Different dietary n-3 PUFA distinctively influenced tissue FA profiles and consequently NAE tissue concentrations. Interestingly, in visceral adipose tissue the levels of N-arachidonoylethanolamide (AEA) and N-docosahexaenoylethanolamide (DHEA), NAE derived from arachidonic acid (AA) and DHA, respectively, significantly correlated with NAE in plasma, and circulating DHEA levels were also correlated with those in liver and brain. Circulating NAE derived from stearic acid, stearoylethanolamide (SEA), palmitic acid and palmitoylethanolamide (PEA) correlated with their liver concentrations. Our data indicate that dietary n-3 PUFA are not all the same in terms of altering tissue FA and NAE concentrations. In addition, correlation analyses suggest that NAE levels in plasma may reflect their concentration in specific tissues. Given the receptor-mediated tissue specific metabolic role of each NAE, a personalized formulation of dietary n-3 PUFA might potentially produce tailored metabolic effects in different pathophysiological conditions.

To evaluate whether a peculiar plasma profile of fatty acids and endocannabinoidome (eCBome)-related mediators may be associated to longevity, we assessed them in octogenarians (Old;n=42) living in the east-central mountain area of Sardinia, a High-Longevity Zone (HLZ), compared to sexagenarian (Young;n=21) subjects from the same area, and to Olds (n=22) from the Northern Sardinia indicated as Lower-Longevity Zone (LLZ). We found significant increases in conjugated linoleic acid (CLA) and heptadecanoic acid (17:0) levels in Old-HLZ with respect to younger subjects and Old-LLZ subjects. Young-HLZ subjects exhibited higher circulating levels of pentadecanoic acid (15:0) and retinol. Palmitoleic acid (POA) was elevated in both Young and Old subjects from the HLZ. eCBome profile showed a significantly increased plasma level of the two endocannabinoids,N-arachidonoyl-ethanolamine (AEA) and 2-arachidonoyl-glycerol (2-AG) in Old-HLZ subjects compared to Young-HLZ and Old-LLZ respectively. In addition, we found increasedN-oleoyl-ethanolamine (OEA), 2-linoleoyl-glycerol (2-LG) and 2-oleoyl-glycerol (2-OG) levels in Old-HLZ group with respect to Young-HLZ (as for OEA an d 2-LG) and both the Old-LLZ and Young-HLZ for 2-OG. The endogenous metabolite of docosahexaenoic acid (DHA),N-docosahexaenoyl-ethanolamine (DHEA) was significantly increased in Old-HLZ subjects. In conclusion, our results suggest that in the HLZ area, Young and Old subjects exhibited a favourable, albeit distinctive, fatty acids and eCBome profile that may be indicative of a metabolic pattern potentially protective from adverse chronic conditions. These factors could point to a suitable physiological metabolic pattern that may counteract the adverse stimuli leading to age-related disorders such as neurodegenerative and metabolic diseases.

Vitamin D deficiency is associated with poor mental health and dysmetabolism. Several metabolic abnormalities are associated with psychotic diseases, which can be compounded by atypical antipsychotics that induce weight gain and insulin resistance. These side-effects may be affected by vitamin D levels. The gut microbiota and endocannabinoidome (eCBome) are significant regulators of both metabolism and mental health, but their role in the development of atypical antipsychotic drug metabolic side-effects and their interaction with vitamin D status is unknown. We studied the effects of different combinations of vitamin D levels and atypical antipsychotic drug (olanzapine) exposure on whole-body metabolism and the eCBome-gut microbiota axis in female C57BL/6J mice under a high fat/high sucrose (HFHS) diet in an attempt to identify a link between the latter and the different metabolic outputs induced by the treatments. Olanzapine exerted a protective effect against diet-induced obesity and insulin resistance, largely independent of dietary vitamin D status. These changes were concomitant with olanzapine-mediated decreases in Trpv1 expression and increases in the levels of its agonists, including various N-acylethanolamines and 2-monoacylglycerols, which are consistent with the observed improvement in adiposity and metabolic status. Furthermore, while global gut bacteria community architecture was not altered by olanzapine, we identified changes in the relative abundances of various commensal bacterial families. Taken together, changes of eCBome and gut microbiota families under our experimental conditions might contribute to olanzapine and vitamin D-mediated inhibition of weight gain in mice on a HFHS diet.