The pathway associating IFNAR signaling and free fatty acid metabolism in obese children may be important. The role of free fatty acids has been reported in several metabolomic studies in childhood asthma [23,25]. However, there is still controversy in regard to the associations with long-term outcomes (i.e., asthma) [10,84]. Till now, the evidence shows that decreased peripheral blood n-3 long-chain fatty acid levels are associated with an increased risk for obesity-related asthma [85]. However, sparse evidence shows that interventions with n-6 long-chain fatty acids may be associated with increased airway inflammation [86,87]. These ostensibly controversial findings can be possibly explained by the timing, sensitivity of measurement tools, or possible interactions with other measured metabolites but need to be further elucidated.

In contrast to the evidence around the role of polyunsaturated long-chain fatty acids, data from observational studies and experimental models investigating the role of short-chain fatty acids point consistently toward a protective role in childhood asthma [88]. However, evidence around their role in obesity-related childhood asthma is missing. Short-chain fatty acids are synthesized by gut microbiota through the fermentation of undigested carbohydrates and dietary fibers in the gastrointestinal tract [89]. Observational studies show that decreased levels of short-chain fatty acids are associated with increased asthma severity [10]. Additionally, reduced secretion of short-chain fatty acids (e.g., acetate, propionate, and butyrate) secondary to gut microbiome changes is associated with an increased risk of childhood asthma development [90]. Although the protective role of short-chain fatty acid supplementation is yet to be confirmed, mouse models of short-chain fatty acid supplementation show a protective effect on asthma development in the offspring [91]. These findings are also supported by observational data associating a reduced fecal level of short-chain fatty acids during pregnancy with an increased risk of asthma development. Recent in vivo pre-clinical data also indicate protection against rhinovirus-induced respiratory tract infections (i.e., the most common trigger of asthma exacerbations) following intranasal administration of short-chain fatty acids. However, this study does not focus on obesity-driven airway inflammation [92].

In addition to fatty acid metabolism pathways, there are observational studies that associate blood ketone levels, amino acid metabolism, and control of hepatic glucose release with obesity-related asthma development in children and adults [93,94]. More specifically, past observational studies have shown that increased energy demands and hypoxia (i.e., in asthma) are associated with an increase in the consumption of ketone bodies [25]. There are two main ketone bodies, acetoacetate, and beta-hydroxybutyrate, being detected at lower levels in obese children with asthma compared to controls.

In regard to amino acid metabolism, lower levels of plasma histidine and glutamine have been associated with increased asthma incidence [25]. Histidine is an essential amino acid [95]. Lower histidine levels have also been detected in obese women without asthma [96]. In female animal models, supplementation with histidine has been shown to impact weight increase and improve airway inflammation and oxidative inflammatory responses driven by adipose tissue [97].

In addition, a higher prevalence of insulin resistance and consequent hyperglycemia has been reported in obese asthmatic children [93]. Past studies have shown that impaired insulin secretion during the first years of life has been related to an increased risk of asthma development [98]. Several studies report that insulin resistance, in combination with other factors (e.g., abdominal fat and metabolic syndrome) [93], is associated with reduced lung function in asthmatic and non-asthmatic children. Interestingly, these studies in the general adult population show that insulin resistance is associated with an obstructive rather than restrictive (i.e., obesity-related) decline in lung function.

The pathophysiologic mechanisms underlying these findings are poorly understood. Mechanistic studies have shown that airway smooth muscle (ASM) cells express insulin receptors and develop a pro-contractile phenotype when exposed to high levels of insulin [99]. Based on these findings, the reported associations between insulin resistance and asthma may be enhanced by obesity and that glucose regulation pathways may help subtyping obesity-related asthma in childhood.

In conclusion, metabolic pathways may explain a large part of obesity-related asthma pathophysiology in children [23,25,41,42,65,100]. Although levels of other metabolites, including urinary prostaglandin D2 and urinary leukotriene E4, have been associated with increased prevalence of childhood asthma, there is no evidence related to associations with obesity-related asthma prevalence [101]. The metabolomics studies that have reported associations between childhood and adult asthma and obesity are depicted in Table 1, and the main metabolic profiles are shown in Figure 2. Both fatty acid metabolism and glucose regulation pathways merit further investigation, ideally in integration with other “omic” data so that asthma endotypes can be better described.