Obesity and allergic diseases are both significant public health issues. Obesity in children is defined by a body mass index (BMI) above the 95th percentile for age and sex, while overweight is defined by a BMI between the 85th and 95th percentile for age and sex [1]. In Europe, the prevalence of obesity is rising in almost all countries; in some of these, it has nearly doubled in the last four decades ^[2][3][2,3]. At the same time, the prevalence of allergic diseases, such as allergic rhinitis (AR), atopic dermatitis (AD), bronchial asthma (BA), food allergies (FA), and chronic urticaria (CU), is also increasing considerably. AR is the most common allergic disease, affecting 10 to 30 percent of children and adults in the United States and other industrialized countries [4]. AD affects up to 12% of children and 7.2% of adults, leading to high healthcare use [5]. BA is one of the most common chronic diseases in childhood, with a prevalence of 6% to 9% and an incidence that is continuously increasing worldwide [6]. Regarding FA, the prevalence is 6.7% in the USA [7]. Up to 1% of the population in the USA and Europe suffer from chronic urticaria during their lifetime. Both children and adults can develop CU, but it is more common in adults [8]. There is rising epidemiological evidence that obesity increases the risk of allergic diseases, particularly asthma ^[9][10][9,10]. Studies in monozygotic and heterozygotic twins suggest that eight percent of the genetic component of obesity is shared with asthma [11]. In addition, it is known from several studies that children of mothers with atopy are at greater risk of developing atopy themselves [12]. Allergic diseases result from the interaction between genetic and environmental factors, which may aggravate the susceptibility to allergic diseases through epigenetic modification. Specifically, obesity represents an environmental factor involved in immunological changes resulting in switching the immune system toward a Th2-cytokine profile and a high risk of allergy [12]. In addition, intrauterine exposure to tobacco smoke seems to play a role in developing obesity and asthma in adult life. Penn and colleagues demonstrated that tobacco smoking exposure in mice during fetal life exacerbates subsequent adult responses to initial allergen exposure by increasing bronchial hyperactivity [13]. The studies on the association between obesity and atopy, however, have conflicting results. Some data indicate the correlation of a higher BMI with an increased prevalence of atopy ^[14][15][14,15], while others show a lack of relation between the serum IgE level and blood eosinophil percentage with obesity ^[16][17][16,17]. Some recent evidence has also suggested the role of obesity in developing chronic rhinosinusitis (CRS) with nasal polyposis ^[18][19][18,19]. However, the effect of obesity on sino-nasal inflammation remains controversial ^[20][21][20,21].

2. Obesity and Asthma

Epidemiological studies have demonstrated the connection between asthma and obesity. Although the relationship between asthma and obesity remains not fully explained from a pathophysiological point of view, it has been demonstrated that obesity is a risk factor for asthma ^{[9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]}[9,10,11,12,13,14,15,16,17,18,19,20,21,22,23]. Rönmark and colleagues found that obesity increased the risk of asthma by 2.7-fold and the risk of being overweight by 2-fold compared with patients of normal weight [24]. A meta-analysis including six prospective studies found that obese children have a two-fold higher risk for asthma than normal-weight children [25]. The link between asthma and obesity can be explained partly by mechanical factors and partly by the chronic low-grade inflammation accompanying obesity. In some patients, obesity precedes asthma; in others, asthma precedes obesity, suggesting that asthma or asthma treatment may also be a risk factor for obesity ^[26][27][26,27]. Asthma occurs more frequently in obese patients, who tend to have more symptoms, increased asthma severity, healthcare use, and worse quality of life ^[28][29][28,29]. Different studies suggest that asthma in obese patients may differ from the classical phenotype of the disease, showing a non-Th2-mediated response. Asthma exacerbations in obese subjects frequently present a reduced response to standard medications ^{[16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]}[16,17,18,19,20,21,22,23,24,25,26,27,28,29,30]. This severe asthma phenotype characterized patients, predominantly females, without eosinophilic airway inflammation [31]. Lessard and colleagues found a significant inverse correlation between the percentage of eosinophils in induced sputum and BMI and waist circumference [16]. This may suggest a role of abdominal fat in the noneosinophilic inflammation of the airway, typical of obese subjects. Several studies have focused on the relationship between BMI and exhaled nitric oxide (eNO), a measure of airway inflammation, with conflicting results. Some authors describe a positive association between eNo concentration and BMI, concluding that eNO can be a systemic link between airway inflammation and obesity [32]. Other studies show a negative correlation between BMI and eNO in obese patients with asthma [33]. Several factors related to obesity likely contribute to the increased risk of asthma in children, but the exact pathogenetic mechanism is still unknown. A lot of factors seem to be involved, primarily, dietary factors. Diets rich in sugar and saturated fatty acids and low in fiber and antioxidants increase the risk of obesity and respiratory symptoms [34]. Low vitamin D levels may also contribute to the risk of asthma in obese patients [35]. Dyslipidemia and insulin resistance are associated with impaired forced vital capacity (FVC) and asthma severity. Insulin is a trophic stimulus for low airway smooth muscle cells; it induces laminin production, leading to muscle hypertrophy. It also enhances airway hyperreactivity via stimulating parasympathetic innervation, thus promoting airway obstruction [36]. High levels of total cholesterol (TC) and low-density lipoprotein (LDL) are more common in obese asthmatic children and are associated with lower lung function [37]. The exact mechanism by which dyslipidemia acts on pulmonary function is not yet known. Maternal obesity before and during pregnancy also appears to play a role in children’s subsequent asthma development. McDonald and colleagues deepened a murine model to investigate the effect of maternal diet on adult offspring bronchial hyperactivity. They found that a diet rich in saturated fatty acids during pregnancy plays a key role in developing airway hyperactivity [38]. The higher risk of allergic reactions in children of obese mothers seems to depend on the increased production of inflammatory cytokines induced by excess adipose tissue. Such changes are likely to result from long-lasting changes in miR-155 and miR-133b expression [39]. Secondly, environmental factors: different studies suggest that exposure to air pollution and passive tobacco smoking are independent risk factors for the development of both asthma ^[40][41][40,41] and obesity in children ^[42][43][42,43]. Thirdly, impaired lung growth: children with obesity have an incongruence between the development of the lungs and the airway. They have increased lung volume relative to airway caliber (“dysanapsis”), reflected by a lower ratio of forced expiratory volume in one second to forced vital capacity (FEV1/FVC), despite normal values for FEV1 and FVC. Dysanapsis is associated with airflow reduction, increased asthma exacerbations, and the use of systemic glucocorticoids in obese children [44]. Fourthly, mechanical factors: obesity causes substantial changes to the mechanics of the lungs and chest wall, and these mechanical changes cause asthma and asthma-like symptoms such as dyspnea, wheezing, and airway hyperresponsiveness. Excess fat mass in the chest wall and abdomen reduces the functional residual capacity of the lung (FRC) [37]. It is also associated with both reduced forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) ^{[37][38][39][40][41][42][43][44][45]}[37,38,39,40,41,42,43,44,45]. Low tidal volume breaths due to thoracic and abdominal fat excess lead to low lung volumes [46], causing alveolar hypoventilation and an increase in airway resistance [47]. These events, in turn, cause airway hyperresponsiveness, resulting in higher respiratory rates and increased work when breathing. The respiratory system compliance is also reduced, mainly due to the increased elastic resistance of the chest wall [48]. Together, these modifications cause a stiffening of the airway smooth muscle in obese subjects, leading to narrowed airways and a reduced broncho-dilatory effect [49]. Fifthly, the immune cell function: traditionally, asthma and other atopic diseases are associated with T-helper 2 cellular inflammation with elevated levels of IgE and eosinophils. Adaptive and innate immune cell functions are altered in obesity. Several studies show the suppression of Th2 lymphocyte function in obese patients ^[50][51][50,51]. Obesity polarizes the immune response toward Th1 rather than the classical Th2 ^[52][53][52,53]. Other studies show a polarization toward Th17 immune response in obese patients. Visceral inflammation with increased proinflammatory macrophages (M1) also occurs in obese asthmatics and may determine systemic inflammation and asthma severity [54]. In obese subjects, oxidative stress, products of cell necrosis, and the overload of free fatty acids lead to polarization toward an M1 phenotype, while the anti-inflammatory M2 macrophages are reduced [55]. M1 macrophages induce airway obstruction in obese patients [56]. Eosinophil function is also altered by obesity. While submucosal eosinophils are increased in obese patients with asthma compared to lean subjects, eosinophils in peripheral blood and sputum are not raised with obesity [57]. All these aspects could explain why current asthma medications, including corticosteroids, leukotriene inhibitors, and biological agents against Th2 response and eosinophils, are less effective for obese asthmatic patients [37]. Lastly, the adipose tissue mediators: adipose tissue is recognized as an active endocrine organ that can affect the function of other organs and as an important source of proinflammatory cytokines, chemokine, and growth factors ^[58][59][58,59]. Excess adiposity is associated with increased production of inflammatory cytokines (IL-6, IL-1ß, and TNF-alpha), leading to low-grade systemic inflammation and increased risk of asthma exacerbations ^{[12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60]}[12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60]. High levels of circulating IL-6 are associated with poor asthma control [61], and markers of inflammation, like C reactive protein (CRP) and fibrinogen, are increased in patients with asthma and obesity compared with those with asthma alone ^{[12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50]}[12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50]. In recent years, several adipose tissue-derived cytokines have been characterized, the so-called adipokines (leptin, adiponectin, and resistin). Adipokines play a crucial role in energy homeostasis and inflammatory and immune response, most often promoting inflammation [55]. Leptin and resistin are proinflammatory, while adiponectin has mainly anti-inflammatory properties [62]. Leptin levels are positively correlated with adipose tissue mass, and leptin is therefore considered one of the factors explaining the connection between obesity and asthma [58]. The prominent role of leptin is the suppression of food intake via inhibiting hypothalamic nuclei that stimulate hunger and stimulation of those which induce satiety. Nevertheless, obese patients develop leptin resistance with a decreased sensitivity to anorexinergic stimuli. Leptin loss of function leads to hyperphagia, rapid weight gain, and insulin resistance [63]. Leptin also has immunomodulatory activities, stimulating neutrophil activation and chemotaxis, oxygen radical release, and the survival of macrophages, eosinophils, basophils, and natural killer cells [55]. IL6 and leptin downregulate the activity of regulatory T-lymphocytes (Tregs), decreasing immunological tolerance to antigens and thus increasing the risk of allergies and other immune-mediated diseases [12]. Adiponectin has anti-inflammatory properties and is associated with a lower risk of asthma, independent of BMI ^{[59][60][61][62][63][64]}[59,60,61,62,63,64]. In macrophages, adiponectin promotes M2 phenotype polarization, TNF-alpha secretion reduction, and scavenger activity enhancement. Moreover, it stimulates the release of IL-10, one of the major anti-inflammatory cytokines, that plays a central role in regulating the immune response and improving insulin sensitivity [55]. Obesity is associated with lower adiponectin levels and an increased risk of cardiovascular diseases [65]. Resistin is mainly secreted by monocytes and macrophages, while a small fraction derives from adipocytes. The role of resistin in obesity and asthma remains unclear; there are only a few publications on this topic with conflicting results. Some studies found higher resistin levels in asthmatics, and its levels correlated with worse disease control [66], while other authors suggested a protective role of resistin against asthma [67]. In conclusion, adipokines are central to the link between obesity and altered immune response, leading to low-grade systemic inflammation and reduced immune tolerance. Weight loss after lifestyle intervention trials effectively reduces serum inflammatory markers and insulin resistance in obese children and adolescents, leading to better asthma control, lung function indices, and quality of life ^{[37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68]}[37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68]. In conclusion, obesity may be associated with an asthma phenotype less responsive to classical anti-inflammatory treatment. In this context, a more useful intervention is to act on the reduction in body weight. Weight loss at any time in the individual’s lifespan has been associated with improved asthma symptoms and quality of life [37].