Obesity‐related dysregulation of the Tryptophan–Kynurenine metabolism: Role of age and parameters of the metabolic syndrome

Abstract

Objective: Obesity-related immune mediated systemic inflammation was associated with the development of the metabolic syndrome by induction of the tryptophan (TRP)-kynurenine (KYN) pathway. The study aimed to assess whether this holds true across the lifespan from juvenility to adulthood. Design and Methods: Five hundred twenty-seven participants aged between 10 and 65 years were analyzed. Standard anthropometric measures, carotid ultrasound, and laboratory analysis including interleukin-6, ultra-sensitive C-reactive protein, lipids, glucose metabolism, neopterin, TRP, KYN levels, and the KYN=TRP ratio were performed. Results: Overweight=obese (ow=ob) adults had significantly increased KYN serum levels and a significantly increased KYN=TRP ratio. In sharp contrast, ow=ob juvenile males aged 18 years showed decreased, females similar KYN and KYN=TRP ratio in comparison to their control counterparts. Also, adult ow=ob subjects with metabolic syndrome showed markedly increased KYN=TRP ratios contrary to decreased KYN=TRP ratios in ow=ob juveniles. Abdominal fat content, characterized by age normalized waist circumference, and not body mass index, had the strongest effect for an increase of the KYN=TRP ratio in adults. Conclusions: TRP metabolism and obesity-related immune mediated inflammation differs markedly between juveniles and adults. While childhood obesity seems to be dominated by a Th2-driven activation, an accelerated production of Th1-type cytokines may pave the way for later atherosclerotic endpoints.

Activation of the tryptophan/serotonin pathway is associated with severity and predicts outcomes in pneumonia: results of a long-term cohort study

“…These findings are in line with current research and are possibly explained by chronic inflammation [41,42].…”

Alterations of plasma metabolite profiles related to adipose tissue distribution and cardiometabolic risk

“…PCA showed that altered plasma levels of AA and some of their metabolites, such as kynurenine (Kyn) and C5 acylcarnitine, are associated with many adiposity markers, as reported by other groups (3,24,33,42,44). One other study had examined associations between levels of glutamine, leucine, isoleucine, phenylalanine, and tyrosine and visceral obesity (25).…”

“…Evidence suggests that ceramide concentrations are associated with insulin resistance (12,21,46). The ratio of kynurenine to tryptophan levels (Kyn/Trp), an increasingly recognized marker of inflammation and metabolic alterations, has been shown to be high in adult overweight or obese individuals (24,53), and also appears to be related to waist circumference independent of age (24).…”

Role of Adiposity-Driven Inflammation in Depressive Morbidity

“…Interestingly, the recent finding that adipokines with potent anti-inflammatory properties (eg, adiponectin) have a role in the antidepressant effects of the NMDA receptor antagonist ketamine further supports the notion that inflammationinduced alterations of glutamatergic neurotransmission may contribute to the development of obesity-related depressive comorbidities (Machado-Vieira et al, 2016). Although activation of the kynurenine pathway has been primarily reported to represent a key component in the initiation and propagation of obesity and related medical complications, including CVD and the metabolic syndrome (Mangge et al, 2014), it is thus also possible that it contributes to the development of depressive comorbidities, notably through neurotoxic effects of kynurenine metabolites. The hippocampal atrophy found in obese subjects in comparison with healthy controls is in favor of this assumption (Fotuhi et al, 2012).…”