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Pathogenetic Interplay Between IL-6 and Tryptophan Metabolism in an Experimental Model of Obesity.

ABSTRACT: Obesity is a metabolic disease characterized by a state of chronic, low-grade inflammation and dominated by pro-inflammatory cytokines such as IL-6. Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme that catalyzes the first step in the kynurenine pathway by transforming l-tryptophan (Trp) into l-kynurenine (Kyn), a metabolite endowed with anti-inflammatory and immunoregulatory effects. In dendritic cells, IL-6 induces IDO1 proteasomal degradation and shuts down IDO1-mediated immunosuppressive effects. In tumor cells, IL-6 upregulates IDO1 expression and favors tumor immune escape mechanisms. To investigate the role of IDO1 and its possible relationship with IL-6 in obesity, we induced the disease by feeding mice with a high fat diet (HFD). Mice on a standard diet were used as control. Experimental obesity was associated with high IDO1 expression and Kyn levels in the stromal vascular fraction of visceral white adipose tissue (SVF WAT). IDO1-deficient mice on HFD gained less weight and were less insulin resistant as compared to wild type counterparts. Administration of tocilizumab (TCZ), an IL-6 receptor (IL-6R) antagonist, to mice on HFD significantly reduced weight gain, controlled adipose tissue hypertrophy, increased insulin sensitivity, and induced a better glucose tolerance. TCZ also induced a dramatic inhibition of IDO1 expression and Kyn production in the SVF WAT. Thus our data indicated that the IL-6/IDO1 axis may play a pathogenetic role in a chronic, low-grade inflammation condition, and, perhaps most importantly, IL-6R blockade may be considered a valid option for obesity treatment.

SUBMITTER: Mondanelli G

PROVIDER: S-EPMC8361489 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:A major component of aging is chronic, low-grade inflammation, attributable in part by impaired gut barrier function. We previously reported that deletion of ghrelin, a peptidergic hormone released mainly from the gut, exacerbates experimental muscle atrophy in aged mice. In addition, ghrelin has been shown to ameliorate colitis in experimental models of inflammatory bowel disease (IBD), although the role of endogenous ghrelin in host-microbe interactions is less clear. Here, we showed that 22-month-old global ghrelin knockout (Ghrl-/-) mice exhibited significantly increased depressive-like behaviors, while anxiety levels and working memory were similar to littermate wild-type (WT) mice. Furthermore, old Ghrl-/- mice showed significantly increased intestinal permeability to fluorescein isothiocyanate (FITC)-dextran, significantly higher colonic interleukin (IL-1β) levels, and trends for higher colonic IL-6 and tumor necrosis factor-α (TNF-α) compared to WT mice. Interestingly, young Ghrl-/- and WT mice showed comparable depressive-like behavior and gut permeability, suggesting age-dependent exacerbation in gut barrier dysfunction in Ghrl-/- mice. While fecal short-chain fatty acids levels were comparable between old Ghrl-/- and WT mice, serum metabolome revealed alterations in metabolic cascades including tryptophan metabolism. Specifically, tryptophan and its microbial derivatives indole-3-acetic acid and indole-3-lactic acid were significantly reduced in old Ghrl-/-mice. Furthermore, in an experimental model of dextran sulfate sodium (DSS)-induced colitis, Ghrl-/- mice showed exacerbated disease symptoms, and higher levels of chemoattractant and pro-inflammatory cytokines in the colon. Overall, these data demonstrated that ghrelin deficiency is associated with gut barrier dysfunction, alterations in microbially derived tryptophan metabolites, and increased susceptibility to colitis. These data suggested that endogenous ghrelin contributes to maintaining a healthy host-microbe environment, ultimately impacting on brain function.

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Pathogenetic Interplay Between IL-6 and Tryptophan Metabolism in an Experimental Model of Obesity.

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