The weight of nutrients: kynurenine metabolites in obesity and exercise

Abstract

Obesity ultimately results from an imbalance between energy intake and expenditure. However, in addition to their bioenergetic value, nutrients and their metabolites can function as important signalling molecules in energy homeostasis. Indeed, macronutrients and their metabolites can be direct regulators of metabolism through their actions on different organs. In turn, target organs can decide to use, store or transform the incoming nutrients depending on their physiological context and in coordination with other cell types. Tryptophan-kynurenine metabolites are an example of a family of compounds that can serve as systemic integrators of energy metabolism by signalling to different cell types. These include adipocytes, immune cells and muscle fibres, in addition to the well-known effects of kynurenine metabolites on the central nervous system. In the context of energy metabolism, several of the effects elicited by kynurenic acid are mediated by the G-protein-coupled receptor, GPR35. As GPR35 is expressed in tissues such as the adipose tissue, immune cells and the gastrointestinal tract, this receptor could be a potential therapeutic target for the treatment of obesity, diabetes and other metabolic diseases. In addition, metabolic disorders often coincide with states of chronic inflammation, which further highlights GPR35 as an integration node in conditions where inflammation skews metabolism. Defining the molecular interplay between different tissues in the regulation of energy homeostasis can help us understand interindividual variability in the response to nutrient intake and develop safe and efficient therapies to fight obesity and metabolic disease.

Are we close to defining a metabolomic signature of human obesity? A systematic review of metabolomics studies

“…Interestingly, alterations in the kynurenine pathway have been reported in subjects with obesity and IR (Favennec et al 2015 ), and furthermore, increased levels of both metabolites have been detected in patients with diabetic retinopathy (Munipally et al 2011 ). The higher levels of such compounds might reflect immune activation or low-grade systemic inflammation due to an increase in the enzyme indoleamine 2,3-dioxygenase (IDO) activity (Zhao et al 2016a , b ; Dadvar et al 2018 ). The increased activity of IDO has been closely related to the propagation of obesity, probably, because the reduced tryptophan mediated by IDO may reduce serotonin production and cause mood disturbances, depression, and impaired satiety ultimately leading to increased caloric uptake and obesity (Brandacher et al 2007 ).…”

Skeletal muscle PGC-1α1 reroutes kynurenine metabolism to increase energy efficiency and fatigue-resistance

“…This mechanism relies on increasing the expression of several kynurenine aminotransferases (Kats) in muscle, that clear the neurotoxic tryptophan metabolite kynurenine (Kyn) from circulation, and prevent its accumulation in the brain. Kyn accumulation in the CNS has been related to several mental health disorders 15–18 . Muscle Kats convert Kyn into kynurenic acid (Kyna) 15 , which in turn increases adipose tissue energy expenditure and promotes an anti-inflammatory phenotype of the resident immune cells 19 .…”

The Human Breast Milk Metabolome in Overweight and Obese Mothers

“…In humans, serum kynurenic acid has been positively associated with several cardio-metabolic risk factors as BMI and insulin-resistance (35,44): however, some reports in humans disagree with experimental studies where kynurenic acid was able to improve energy metabolism and inflammation in mice fed a high-fat diet and to promote weight loss (65,66). Thus, it is possible that the elevation of this metabolite in individuals with metabolic risk can represent a compensatory mechanism through which kynurenic acid could perform its beneficial action.…”