Mgll Knockout Mouse Resistance to Diet-Induced Dysmetabolism Is Associated with Altered Gut Microbiota

Abstract

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.

Role of the Endocannabinoid System in the Adipose Tissue with Focus on Energy Metabolism

“…When they compared the expression of genes associated with eCB system including receptors and metabolic enzymes in small intestine, they found an alteration of gene expression in germ-free mice which were reversed by fecal microbiota transplant [ 128 ]. The deletion of Mgll in mice leads to an obesity-resistant phenotype that could be partially explained by changes in the microbiota [ 129 ]. Furthermore, the administration of Akkermansia muciniphila in DIO mice is associated with a higher levels of eCBs in the small intestine and helps improving the metabolic parameters associated with obesity [ 130 ].…”

The Endocannabinoid System: A Bridge between Alzheimer’s Disease and Gut Microbiota

“…In addition, the mutant mice exhibited lower levels of NAEs and a shift in gut microbiota composition as decreased levels of Lactobacillus and Allobaculum genera were observed [ 155 ]. Mice lacking the Mgll gene were protected against high-fat diet (HFD)-induced obesity, insulin resistance and hepatic steatosis [ 156 ] and exhibited significantly higher levels of Hydrogenoanaerobacterium , Roseburia , and Ruminococcus [ 157 ]. Reduction of colonic CB 1 mRNA expression accompanied by increased expression of FAAH and reduction of AEA levels were reported in a genetic model of obesity, the ob / ob mice, treated with prebiotics for 5 weeks.…”

“…Therefore, it is likely to suggest that the interplay between eCBs and leptin is one of the not well-investigated mechanisms through which the gut-brain axis is regulated under pathological conditions, especially in the context of AD. As mentioned in the previous sections, elevated tissue levels of 2-AG in Mgll −/− mice are associated with resistance to the metabolic alterations induced by a HFD as they accumulated less fat and became less glucose intolerant and insulin resistant than WT mice following HFD [ 156 ] and changes in Mgll −/− mice microbiome have been reported to contribute to their obesity resistant phenotype [ 156 , 157 ]. In addition, pharmacological elevation of 2-AG levels with MAGL inhibitor prevented neuroinflammation and decreased neurodegeneration in different AD-like animal models [ 188 , 189 ].…”

Oral Capsaicinoid Administration Alters the Plasma Endocannabinoidome and Fecal Microbiota of Reproductive-Aged Women Living with Overweight and Obesity

“…Some of these molecules, such as long-chain unsaturated mono-acyl-glycerols (MAGs) and, particularly, N -acyl-ethanolamines (NAEs), are well-established endogenous activators of TRPV1 channels [ 34 , 35 ]. Interestingly, the eCBome is increasingly understood to communicate with the gut microbiome in the context of metabolic disorders [ 36 , 37 , 38 ]. Similarly, capsaicin modulates the gut microbiota population, which represents a critical factor for the anti-obesity effects that are exerted by this natural compound, contributing to improving glucose homeostasis through increasing short-chain fatty acids, regulating gastrointestinal hormones and inhibiting pro-inflammatory cytokines [ 39 , 40 ].…”