Induction of TDO2 and IDO2 in Liver by High-Fat Feeding in Mice: Discrepancies with Human Obesity

Abstract

Low-grade and chronic inflammation is elicited in white adipose tissue in human obesity. The presence of inflammatory molecules leads to an increased tryptophan catabolism through the induction of indoleamine-2,3-dioxygenase-1 (IDO1). In order to characterize the mechanisms underlying this dysregulation, we have studied 2 mouse models of obesity. Unexpectedly, we did not detect any IDO1 expression in obese or lean mice adipose tissue. In a previous study, we did not find any significant difference in the liver for IDO2 and tryptophan-2,3-dioxygenase (TDO2) gene expression between normal weight and obese patients. IDO2 and TDO2 expression was increased in the liver of high-fat fed mice, but not in ob/ob mice, and was strongly correlated with hydroxysteroid-(11-beta) dehydrogenase-1 (HSD11B1) expression, an enzyme that generates active cortisol within tissues. In conclusion, despite a dysregulation of tryptophan metabolism, obese mice display discrepancies with human obesity metabolism, rendering them inappropriate for further investigations in this animal model.

Microbiota‐derived tryptophan indoles increase after gastric bypass surgery and reduce intestinal permeability in vitro and in vivo

“…In human metabolic disease, mammalian tryptophan pathway enzymes are generally upregulated, as described in Figure , but the extent to which changes in this pathway is back‐translational from human to metabolic rodent models is unclear. Intestinal IDO1 (Figure Pathway 1 to kynurenine) in HFD‐fed mice was downregulated in the present study, as reported in other tissues in DIO models . Maybe low‐grade intestinal inflammation in response to HFD does not engage IDO1 T‐cell‐mediated tolerance and antimicrobial effects .…”

“…Intestinal IDO1 (Figure 1 Pathway 1 to kynurenine) in HFD-fed mice was downregulated in the present study, as reported in other tissues in DIO models. 37,38 Maybe low-grade intestinal inflammation in response to HFD does not engage IDO1 T-cell-mediated tolerance and antimicrobial effects. 14…”

Inhibition of the aryl hydrocarbon receptor prevents Western diet-induced obesity. Model for AHR activation by kynurenine via oxidized-LDL, TLR2/4, TGFβ, and IDO1

“…Kyn levels and the ratio of Kyn to Trp, which reflects IDO1, IDO2, and/or TDO2 activities, are elevated in the plasma and adipose tissue of obese women to that in lean women (Wolowczuk et al , 2012; Favennec et al , 2015). In contrast, Kyn and Kyn/Trp plasma levels are depressed in mice on high-fat diet (Poulain-Godefroy et al , 2013); in which both species are perhaps revealing the dysregulation of TDO and IDO enzymatic activities caused by an obese state. Ido1 and Ido2 gene expression is regulated in an AHR-dependent manner (Mezrich et al , 2010) and pro-inflammatory cytokines, especially INFγ (Brandacher et al , 2007).…”

“…Ido1 −/− mice showed an even greater drop in the plasma Kyn/Trp ratio as well as a resistance to obesity (Nagano et al , 2013). Thus, IDO1, like its many roles in immune cell regulation, may be the key regulator of systemic Kyn levels in the context of obesity and obesity-associated inflammation (Watcharanurak et al , 2014), while the role of TDO2 in obesity and its regulation by glucocorticoids remain obscure (Poulain-Godefroy et al , 2013) and need to be explored further.…”

The kynurenine:tryptophan ratio as a predictor of incident type 2 diabetes mellitus in individuals with coronary artery disease

“…TDO was not found to be increased in obese individuals [ 41 ]. In contrast, a rodent model demonstrated highly upregulated TDO expression in diet-induced obesity [ 42 ]. In our cohort, plasma and urine KTR were strongly related with plasma neopterin, indicating that IFN-γ mediated IDO1 activation is a major determinant for circulating, as well as urinary, KTR levels.…”