1. Introduction

Obesity has become a real pandemic and is a major public health concern; the World Health Organization estimates that in 2020 there were 39 million overweight or obese children under the age of five years, and that in 2016 there were over 340 million overweight or obese children and teenagers aged 5–19. The WHO additionally stated that there had been an almost threefold increase in worldwide obesity since 1975 ^[1], although in some countries that increasing trend has levelled off in the last 10 years ^[2]. The high prevalence of overweight and obesity is observed at young ages, such as from 2–7 years old; overall, the pooled prevalence estimate regarding overweight/obesity in European children (aged 2–7 years) for the years 2006–2016 was 17.9% (95% CI: 15.8–20.0), whilst the pooled prevalence estimate of obesity was 5.3% (95% CI: 4.5–6.1) ^[3]. It is also important to recall that there is a clear correlation between childhood or teenage BMI and adult BMI2 and, so it can be stated that it is very probable that the obese child or teenager continues to be obese at adult age; thus the consequences of childhood obesity on public health will remain for many years.

On the other hand, asthma is the most frequent chronic childhood disease: the mean worldwide symptom prevalence of current wheezing in the last 12 months is about 13% in adolescents (13–14 years) and 11% in children (6–7 years) ^[4]. It is thus not uncommon for these two prevalent diseases to coincide in a considerable number of children; if the prevalence remained the same as in the general population there should be approximately 2% of obese, asthmatic children. If asthma favoured the development of obesity or vice versa, then this figure would have to be even higher.

Numerous cross-sectional and cohort studies have shown an association between obesity or overweight and asthma [5,6,7,8,9,10,11,12,13,14]^{[5][6][7][8][9][10][11][12][13][14]}. Longitudinal studies have shown an increase in the risk of persistent wheeze among those children who are within the uppermost quintile of increase in BMI in the last year with respect to those children who are within the third quintile ^[10] and the proportion of children who develop asthma is greater among those who stayed in the 85 percentile or higher of BMI during the follow-up of around 14 years ^[15]. However, one very broad study that included 16 European cohorts found that it was asthma that increased the risk of obesity (hazard ratio (HR) 1.87 (95% CI 1.32; 2.64)) ^[16]. Physiopathological mechanisms can be imagined that explain both directions in this relationship; thus, asthmatic children generally carry out less exercise and receive treatments that increase their appetite and weight, so they become at risk of developing obesity; on the other hand, obesity is a process that presents a subclinical inflammation, in which there are endocrine alterations and, furthermore respiratory function changes, all of which could affect the respiratory tree, developing asthma. It is probable that this is a two-way street and, in any case, causes a worsening in the child’s quality of life ^[17] and asthma severity: they suffer from more hospitalisations, more admittance to intensive care units and use more medication ^[18]. BMI is an independent risk factor for severe asthma (odd ratio (OR) = 1.12; 95% CI: 1.05–1.21) compared to suffering from moderate asthma, mild asthma or not suffering from asthma ^[19]. In a total of slightly more than 100,000 hospitalisations due to asthma in children aged between two and 18 years, it was shown that obesity was a risk factor for the need for mechanical ventilation (OR = 1.59; 95% CI: 1.28–1.99) ^[20]. Conversely, a worse bronchodilatory response to albuterol has been shown; the risk of not having a bronchodilatory response is significantly higher among obese children and teenagers independently of age, gender, ethnicity, base lung function and prior controlling treatment (OR, 1.24; 95% CI, 1.03–1.49) ^[21]. Moreover, a worse response to budesonide has been described among obese patients in terms of lung function but also in the number of visits to the emergency room and hospitalisations due to asthma ^[22].

2. Consequences of Obesity on the Respiratory Apparatus

Obesity associates a non-TH2 subclinical inflammatory state induced by the infiltration of M1-type macrophages capable of liberating pro-inflammatory cytokines such as IFN-γ, IL-6, TNF-α, IL-1β and monocyte chemotactic peptide (MCP)-1 ^[23]. It has been shown that in obese adults with asthma, the number of M1 macrophages in visceral fat is correlated with the body mass index (BMI) ^[24]. Thus, obese people generally show elevated TH1-type cytokines with respect to their healthy peers, and this difference has also been shown when asthmatic obese people are compared to non-obese asthmatics ^[25]; for example it has been found that in asthmatic children, those who are obese, with respect to those who are not obese, have significantly higher values of IFN-γ and lower values of IL-4, which speaks in favour of this TH1 imbalance, as opposed to TH2 in the obese ^[26].

A recent study found, on this occasion in children, new evidence of the transcriptome of CD4+ T cells derived from asthmatic obese children being different from that of CD4+ T cells from normal weight asthmatic children; specifically several genes associated with the small GTP-binding protein CDC42, which plays a role in T-cell activation, were upregulated in T cells from obese asthmatic children. Expression of genes downstream of CDC42 as MLK3 and PLD1, in the MAPK and mTOR pathways, respectively, was upregulated in TH cells from obese asthmatic patients, thereby suggesting that the pathways activated distal to CDC42 may play a role in the non-atopic TH1 immune responses observed in obese asthmatic children and, additionally, that Log10 transformed CDC42EP4 and DOCK5 gene counts were inversely correlated with the FEV1/FVC ratio, but only in obese asthmatic children [31]^[27].

In the obese patient’s adipose tissue, the majority of the macrophages that infiltrate are M1 type, which produce inflammatory cytokines such as IL1-β, IL-6 and IL-15 that act on naïve T cell receptors, inducing the differentiation on TH17 lymphocytes. These TH17 lymphocytes, activated by IL23, also secreted by M1 macrophages in turn liberate, IL-17A, IL-17F, IL-21 and IL-22. The liberation of IL-17A closes the circle because it activates M1 macrophages and dendritic cells that reinitiate the liberation of those same cytokines [32]^[28]. The IL-17 has been found to be elevated in adult asthmatic obese patients compared to overweight asthmatics and thin asthmatics, in both plasma as well as in sputum and the levels of IL-17 in sputum are correlated with the presence of neutrophils in the sputum (r = 0.353; p = 0.002) and with FEV1 (r = –0.47; p < 0.001) [33]^[29]. The hypothesis has been put forward that non-atopic asthmatic obese patients could have a hypomethylation of the THFA promoting genes in M1 macrophages and the IL-17A promoting genes in TH17 lymphocytes; the result of such a genetic overexpression would be the elevation of TNF-α and of IL-17A [34]^[30]. In children with central obesity, higher percentages of Th17 cells have been found than in children from the control group [35]^[31] and it was also shown that, after Ionomycin stimulated peripheral blood mononuclear cells, there is a significant increase in TH17 cells (34.7 ± 1.54% vs. 25.4 ± 2.38%; p = 0.0023) in obese children without asthma, allergic rhinitis, atopic dermatitis nor autoimmune diseases, compared to the non-obese controls. This increase correlates with BMI (r = 0.42; p = 0.0005) and the relative mRNA expression of RORC ( p = 0.013) and IL-17A ( p = 0.014) were both upregulated in the overweight children compared to those who were not overweight [36]^[32].

There would also appear to be a relationship of dysanapsis with the genetic regulation of the ways regulating the TH1 expression: the study by Rastogi et al. [31]^[27] identified that the CDC42 way is upregulated in the TH cells of obese asthmatic children and that the expression of the CDC42EP4 and DOCK5 genes, implicated in said way, are inversely correlated with the FVE1/FVC ratio only in obese asthmatic children, but not in non-obese asthmatic children. This suggests a role for this way in the TH1 non-atopic systemic inflammation and the changes in lung function found in patients with asthma related to obesity.

3. The Role of Adipokines and Insulin Resistance

The possible role played by cytokines liberated by the adipose tissue has been studied, especially the role of leptin, with contradictory results. Guler et al. [57]^[33] in 102 asthmatic patients versus 33 healthy controls, found that leptin was a predictive factor for asthma (OR = 1.98; 95% CI: 1.10–3.55). However, the study by Kim et al. [58]^[34] found resistin to be a predictive factor for asthma (Log resistin OR = 0.587; 95% CI: 0.35–0.98) but not leptin (Log leptin OR = 0.94; 95% CI: 0.65–1.35) which, however, did correlate inversely with FEV1 and FEF25-75. Other authors also found no relationship between leptin and asthma [59,60]^[35][36]. A metanalysis published in 2017 [61]^[37] found asthma diagnosis to be associated with elevated levels of leptin in adults (standardised difference in means = 1.37, 95% CI 0.62 to 2.13, p < 0.001) and in children (standardised difference in means = 0.30, 95% CI 0.01 to 0.59, p = 0.042) and low levels of adiponectin in adults, but not in children. More recently, it has been published that leptin is not only a risk factor for asthma (OR = 1.06; 95% CI: 0.28–1.31) but that it is positively related with its severity, whilst it is inversely related with the adiponectin levels [62]^[38]. Moreover, those children from obese mothers whose cord blood leptin levels are elevated, have a greater risk of asthma at three years of age (OR = 1.30; 95% CI: 1.1–1.55) [63]^[39]. The mechanism by which the adipokines could have a role in the pathogenesis of asthma is not clearly defined; on the one hand, it has been suggested that it participates in the TH1-type inflammation since it correlates with the levels of IFN- γ and it has been described that in the presence of high leptin levels, only asthmatic obese children exhibited a TH1 polarisation with elevated IFN-γ levels and more severe asthma ^[26]. It may also have a role in altering the lung function [58,62]^[34][38]. Finally, it has recently been described that the polymorphism rs13228377 of the leptin gene is associated with higher levels of leptin in serum in asthma and those two variables (polymorphism + elevation in leptin) have a high predictive value for asthma risk (OR = 17.5, predictive accuracy 83.9%), although the authors themselves recognise the limitation of the scant sample [64]^[40]. In addition, it has been described that the single nucleotide polymorphisms (SNPs) of the leptin and adiponectin genes have a protective effect for asthma, but that that effect is lost in obese individuals [65]^[41].

A known consequence of obesity is the development of insulin resistance, and this circumstance has also been analysed in relation with asthma. Thus in 2007, a cross-sectional study of 415 obese teenagers (146 asthmatic and 269 non-asthmatic) with a mean BMI above 30 in both groups, described that insulin resistance, measured by homeostasis model assessment (HOMA), is a risk factor for asthma, with an OR of 4.1 [66]^[42]. Some years later, 21 asthmatics and 10 non-asthmatics aged between six and 17.9 years, who were not obese (mean BMI z-score: 0.15 and −0.19, respectively) were studied, and statistically significant differences were also found between both groups (HOMA: 0.7 ± 0.3 in the control group vs. 1.7 ± 1.4 in the asthmatic group; p < 0.01) and in addition there were 0% with HOMA-IR ≥ 1.77 in the control group and 42.8% in the asthmatic group; p = 0.05) [67]^[43]. In a prospective study that recruited 153 children aged between six and 15 years of age, 56 asthmatics and 97 non-asthmatics, all of whom were obese (BMI ≥ 95 percentile) the authors found that although there were no differences in the mean values of HOMA between both groups (2.25 (0.42–4.45) as opposed to 2.03 (0.28–4.97); p = 0.205), having a HOMA value ≥2.22 was a risk factor for allergic asthma (OR = 2.36; 95% CI: 1.01–5.49) [68]^[44]. In 2015, a cross-sectional study was published that used data from 1429 teenagers aged between 12 and 17 years who had been recruited in the National Health and Nutrition Examination Survey of 2007–2010. With this large sample, the authors found no statistically significant differences in the HOMA-IR of asthmatics and non-asthmatics (3.90 ± 0.55 vs. 3.24 ± 0.11, respectively; p = 0.24). However, insulin resistance was associated with worse lung function among the overweight and obese patients (FEV1: −34.32 mL (−50.99 to −17.66); p < 0.01 and FVC −42.28 mL (−63.22 to −21.35); p < 0.01). Furthermore, they showed that among the teenagers with HOMA-IR > 3.0, the increase of one point in the BMI z-score was accompanied by a loss of 70 mL in FEV1 ( p for interaction= 0.0006) and by a significant decline in FEV1/FVC ( p for interaction= 0.02), which did not happen in the insulin-resistant patients; therefore the synergic action of obesity and insulin resistance could contribute to the dysanapsis and thus to the development of asthma or, at least, to worsen it [69]^[45]. That result is thereby very interesting since it was published shortly after a study carried out on mice in which it was shown that insulin administered intranasally produced bronchial hyperreactivity and increased the depositing of collagen in the lungs [70]^[46]. However, a very broad cross-sectional study has been published recently using the data of no fewer than 11,662 children aged between three and 11 years, and of 12,179 teenagers from 12 to 19 years old. In the study, some 3703 asthmatics and 20,138 non-asthmatics were identified in the United States National Health and Nutrition Examination Survey database between 1999 and 2012. That study found no relationship between HOMA > 3 and asthma diagnosis [71]^[47], although it did not analyse the synergic action of obesity + insulin resistance that Forno et al. had found [69]^[45]. Nevertheless, all those studies are cross-sectional, so it is not possible to establish a causal relationship between obesity, insulin resistance and asthma. Cohort studies are required that analyse how the development of obesity affects the respiratory apparatus to produce asthma. Holguin et al. [72]^[48] described that, in the adult, there are two phenotypes of asthma, related with obesity, depending on the age of its onset. One group starts with asthma early on (before the age of 12 years) and presents more severe asthma, they are often atopic and there is an association between an increase in BMI and asthma duration. This suggests to the authors that in the early-onset patients, the asthma severity increases in the asthmatics who become obese whilst in those subjects who have late onset, the obesity is more likely to have a role in causing the asthma and its severity. In children it is probable that we also find both groups; some in whom obesity causes inflammatory and lung function changes and the clinical signs of asthma appear and, on the other hand, asthmatics who when they become obese, their asthma worsens. A phenotype that is independent of those related to puberty has also been described; Castro et al. ^[11] described, in the Tucson cohort, that girls who become obese between the ages of six and 11 years have a greater risk of developing asthma between 11 and 13 years than those whose weight remains normal (OR = 6.8; 95% CI: 2.4–19.4). Some years later, the same author related that phenotype to early menarche and defined it as that which affects obese girls whose menarche occurs under the age of 12 [73]^[49]; a phenotype confirmed recently by Chen et al. [74]^[50] who found that the synergic effect of early puberty and obesity is a risk factor for developing asthma between 12 and 17 years of age (OR = 1.08; 95% CI: 1.04–1.11).

Obesity is currently a first-degree public health problem in the whole world due to its growing incidence. Comorbidity of two very prevalent conditions such as asthma and obesity is not rare. The role of obesity on the inception of asthma and on its severity has attracted much attention during the recent years. It is reasonable to try and find common epidemiological and therapeutic targets which might be common to both diseases. We have learned that obesity is a much more complicated condition than just the collection of fat tissue and causes a state of low-grade inflammation in which insulin resistance and increased leptin levels probably play a role. Both circumstances possibly alter the developing infant lung, after provoking a non-harmonic growth of lung size and lung airway (dysanapsis) which might be the cause of a specific asthma phenotype. Nevertheless, dysanapsis has clinical consequences and would aggravate the condition in asthmatic children. Reducing the incidence of obesity would most probably reduce not only new asthma cases but also severe asthma prevalence.