Pathogenetic Interplay Between IL-6 and Tryptophan Metabolism in an Experimental Model of Obesity.
Adipose Tissue
/ metabolism
Animals
Biomarkers
Cytokines
/ metabolism
Diet, High-Fat
Disease Models, Animal
Disease Susceptibility
Energy Metabolism
Hepatocytes
/ metabolism
Indoleamine-Pyrrole 2,3,-Dioxygenase
/ metabolism
Insulin
/ metabolism
Interleukin-6
/ metabolism
Kynurenine
/ metabolism
Male
Mice
Obesity
/ etiology
Receptors, Interleukin-6
/ metabolism
Tryptophan
/ metabolism
IL-6 receptor (IL-6R)
experimental obesity
high fat diet (HFD)
indoleamine 2, 3 dioxygenase 1 (IDO1)
tocilizumab (TCZ)
tryptophan metabolism
white adipose tissue (WAT)
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2021
2021
Historique:
received:
24
05
2021
accepted:
19
07
2021
entrez:
16
8
2021
pubmed:
17
8
2021
medline:
21
12
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34394118
doi: 10.3389/fimmu.2021.713989
pmc: PMC8361489
doi:
Substances chimiques
Biomarkers
0
Cytokines
0
Indoleamine-Pyrrole 2,3,-Dioxygenase
0
Insulin
0
Interleukin-6
0
Receptors, Interleukin-6
0
Kynurenine
343-65-7
Tryptophan
8DUH1N11BX
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
713989Informations de copyright
Copyright © 2021 Mondanelli, Albini, Orecchini, Pallotta, Belladonna, Ricci, Grohmann and Orabona.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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