Immunometabolism exerts a bimodal action at the interface of extracellular immune response and intracellular metabolism (Chi. Cell Mol Immunol (19)). Hence, immunometabolic pathways represent an worthy target as a dual checkpoint for the inflammatory cycle. NLRX1 & PLXDC2 have been identified in immunometabolic pathways in multiple cell types in inflammatory bowel disease (IBD, Leber, et al. J Immunol 203(12); Tubau-Juni, et al. J Immunol 206(Supp)). This analysis compares these two key immunometabolic pathways. For both programs, in vitro murine T cell & macrophage differentiation & in vivo mouse dextran sodium sulfate (DSS) colitis models, gene expression, metabolic profiles & cytokine expression were assessed. NX-13, a novel NLRX1 agonist, resulted in regulation of cellular metabolism: activation of mitochondrial genes such as mt-nd3 & odgh and down-regulation of glucose uptake by murine T cells. NLRX1 stabilization by NX-13 increased antioxidant enzyme expression & reduced ROS in T cells. NX-13 specifically reduced effector T cells. These bimodal effects converge to dampened acute DSS colitis (Fig1A). PLXDC2 activation by LABP-69 directly reduced glycolysis, reflected by decreased extracellular acidification in bone marrow-derived macrophages (BMDM) stimulated with lipopolysaccharide as well as reduced superoxide levels in BMDM. PLXDC2 activation downregulated inflammatory cytokines TNFα & IFNγ in T cells. The PLXDC2 agonist PX-04 decreased inflammation in acute DSS colitis in mice (Fig1B). Agents targeting immunometabolism demonstrate innovative potential therapeutic MOAs applicable in IBD. NLRX1 & PLXDC2 represent distinct pathways that modulate the metabolic state simultaneously with inflammation and hence can be targeted to stop chronic inflammation.

Excessive accumulation of visceral fat in obesity often leads to insulin resistance, inflammation, type 2 diabetes and cardiovascular diseases. However, some obese individuals with obesity show healthy expansion of white adipose tissue (WAT), without cardiometabolic complications, and such obese condition is named metabolically healthy obesity (MHO). Global deletion of the monoacylglycerol (MAG) hydrolase, α/β-hydrolase domain-containing 6 (ABHD6) has revealed the therapeutic potential of ABHD6 inhibitors against obesity, yet the immunometabolic role of adipocyte ABHD6 in WAT expansion and energy balance in obesity is not known. We now show that while inducible adipocyte-specific ABHD6-KO (AA-KO) mice become obese upon high-fat diet (HFD) feeding, they do not display insulin resistance, fatty liver, and inflammation. AA-KO HFD-fed mice, show healthy expansion of visceral fat with smaller adipocytes, curtailed inflammation, and elevated lipolysis and fatty acid oxidation. AA-KO adipocytes-conditioned medium but not that from control mice promotes preadipocyte differentiation and anti-inflammatory polarization of WAT macrophages. We provide evidence that the favorable properties of the AA-KO adipocytes secretome may be due in part to the increased adiponectin and decreased IL-6 levels, and to the enhanced MAG levels which activates PPARs. The ABHD6 interactome consists in part of proteins involved in insulin signaling and inflammatory pathways. ABHD6 suppression in preadipocytes inhibits their proliferation and promotes adipocyte differentiation, synergistically with insulin. In insulin resistant female subjects, ABHD6 expression is elevated in the visceral fat and positively correlates with obesity and altered metabolic indices. Overall, the results indicate that adipose ABHD6 suppression prevents the metabolic and inflammation complications of obesity, but not obesity per se, possibly via MAG/PPAR activation and enhanced insulin signaling, and that AA-KO mice show promise as a model for the study of MHO.

Obesity is currently considered as a multifactorial chronic disease and is accompanied by health complications including type-2 diabetes (T2D). Growing evidence has shown that low-grade inflammation associated with obesity and subsequent loss of gut barrier function contributes to insulin resistance. The endocannabinoids (eCBs), 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA, anandamide), and their main targets, the cannabinoid CB1 and CB2 receptors, are all expressed in the intestine. CB1 is present in metabolic tissues and regulates their function, while CB2 is predominant in immune cells where it modulates inflammation. Deciphering gut eCB signaling, therefore, encompasses both energy metabolism and chronic low-grade inflammation associated with obesity. We aimed to characterize the inflammatory status of the gut in response to long-term adaptation to obesity and T2D as well as to define how the human eCB system acts at the interface between energy metabolism and immunity. We obtained human ileal samples from bariatric surgery in subject with and without T2D. We showed that intestinal and circulating levels of eCBs and eCB-like compounds are higher in subjects with T2D. Moreover, expression analysis of 200 genes involved in inflammatory processes revealed that the expression of TLR4 and of genes coding for pro-inflammatory cytokines (i.e. IL1, IL6 and IL15) was lower in subjects with T2D. This apparent reduced local inflammatory status in the gut is opposed to the presence of a low-grade systemic inflammatory status, which has been previously reported in subjects with T2D, and this might be due in part to the fact that the T2D subjects were under treatment. Our study highlights gut specific inflammation mechanisms possibly linked to the eCB system. Understanding this process could lead to the identification of new targets for the treatment of obesity and related metabolic disorders.