Overweight and obesity

Overweight and obesity are defined by the WHO as excess fat accumulation that presents a risk to health^{( 2 )}. Obesity has become an acute focal point of research, as it is a strong risk factor for various diseases. These include CVD, diabetes, asthma, orthopaedic diseases and some forms of cancers⁽ Reference Guh, Zhang and Bansback ^{3 –} Reference Rice, Foster and Sanders ^{7 )}, not to mention the social stigma and low self-esteem that obese individuals may suffer⁽ Reference Guh, Zhang and Bansback ^{3 )}.

The rapid urbanisation and Westernisation of countries has led to consumption of larger amounts of energy with a decline in daily activity, which has resulted in rising epidemics of obesity⁽ Reference Jacobs ^{8 ,} Reference Peters, Wyatt and Donahoo ^{9 )}. According to the WHO, in 2008, over 1·4 billion adults older than 20 years of age were overweight; among them, approximately 200 million men and 300 million women were obese^{( 2 )}.

We are now aware that adipose tissue is not merely for storage of spare energy consumed but not used. Adipose tissue is a physiologically complex and highly active metabolic and endocrine organ that secretes various hormones (adipokines). These regulate the appetite in the central nervous system, as well as insulin, fatty acid levels and sex hormone precursors⁽ Reference Proietto, Galic and Oakhill ^{10 ,} Reference Guerre-Millo ^{11 )}.

Asthma

Similarly, an increase in the prevalence of asthma and allergies has been observed in recent decades^{( 12 ,} Reference Masoli, Fabian and Holt ^{13 )}. This rapid increase, with clearly observable social and demographic patterns, again suggests changes in lifestyle to be a possible explanation⁽ Reference von Hertzen and Haahtela ^{14 )}.

Since more than 300 million individuals suffer from this disease and its prevalence is increasing, the importance of studies in this field has also increased. It is often reported in children but affects all age groups⁽ Reference Vale-Pereira, Todo-Bom and Geraldes ^{15 )}.

Asthma has a very strong genetic component, and new genes contributing to its development and severity continue to be found⁽ Reference Bønnelykke, Sleiman and Nielsen ^{16 –} Reference Melén, Kho and Sharma ^{18 )}. Nevertheless, environmental, behavioural and socio-economic risk factors significantly modulate the development and course of the disease⁽ Reference Salam, Li and Langholz ^{19 ,} Reference Asher, Stewart and Mallol ^{20 )}.

Epidemiologists, after close and detailed analyses of the asthmatic spectrum, have pointed out the necessity of distinguishing not only different asthma phenotypes (different observable characteristics of the same disease) but also endotypes (different pathophysiological origins of the same disease)⁽ Reference Lötvall, Akdis and Bacharier ^{21 ,} Reference Agache, Akdis and Jutel ^{22 )}. One of the phenotypes is obesity-induced asthma⁽ Reference Farzan ^{23 )}.

Association between asthma and obesity

The parallel increase in the prevalence of obesity and asthma in childhood suggests a link between the two.

In 1986, Seidel et al. ⁽ Reference Seidell, de Groot and van Sonsbeek ^{24 )}, through a large study in Holland, showed for the first time that asthma was associated with severe obesity in women. However, it was not until 1999 when Camargo et al. ⁽ Reference Camargo, Weiss and Zhang ^{25 )} performed a prospective cohort study of 85911 women from the US Nurses’ Health Study II that evidence suggested that BMI has a strong, independent and positive association with risk of adult-onset asthma. After this, a number of publications on this topic increased and remained of strong interest to researchers and physicians.

Indeed, numerous cross-sectional⁽ Reference Black, Smith and Porter ^{26 ,} Reference Okabe, Adachi and Itazawa ^{27 )} and longitudinal studies⁽ Reference Jeong, Jung-Choi and Lee ^{28 ,} Reference Taveras, Rifas-Shiman and Camargo ^{29 )} confirmed this association. A study of 12 388 children and adolescents from the USA showed double the risk of having asthma for children with a BMI greater than or equal to the 85th percentile⁽ Reference Rodríguez, Winkleby and Ahn ^{30 )}. Another study, including 4- to 17-year-olds from the Third National Health and Nutrition Examination Survey (NHANES-III), showed an increased prevalence of asthma with increased quartile of BMI, significant for the lowest and the highest quartile. These results show a dose-dependent and U-shaped association between BMI and asthma prevalence in children⁽ Reference von Mutius, Schwartz and Neas ^{31 )}. A similar U-shaped correlation was found for adult men in a cross-sectional study of 5524 subjects included in the New York State Behavioral Risk Factor Surveillance System. In this study, women had a monotonic association, with only the higher BMI values being associated with asthma⁽ Reference Luder, Ehrlich and Lou ^{32 )}. Not all studies confirm this association. A comparative study of children performed by Guler et al. found no significant difference between asthmatic and healthy children, even when atopy was taken into account⁽ Reference Guler, Kirerleri and Ones ^{33 )}. A recent study on allergies and asthma involving eight European birth cohorts of 12 050 children found an association between the sex- and age-specific BMI trajectories during the first 6 years of life and the incidence of asthma. The rapid increase in body mass in the first 2 years of life appeared to be the strongest predictor of asthma incidence later in childhood⁽ Reference Rzehak, Wijga and Keil ^{34 )}.

Although BMI is the most common and easiest measure of adiposity, it assesses total body mass without clarifying the real contribution of fat tissue in the total mass or its distribution. There is strong evidence demonstrating that not only total body mass but also fat distribution can modify the effect of adiposity on health. Abdominal obesity is the clinical name for accumulation of fat tissue in the abdominal area, also known as central obesity; it seems to be an additional strong risk factor for co-morbidity in relation to obesity for diseases including asthma⁽ Reference Musaad, Patterson and Ericksen ^{35 )}.

Although the association appears at all ages, its relationship with regard to sex changes in proportion as individuals age, being stronger in males in childhood⁽ Reference Chen, Dong and Lin ^{36 )} and skewing towards females in adulthood⁽ Reference Chen, Dales and Tang ^{37 )}. The results of studies on the obesity-induced asthma phenotype are much more consistent when investigating adults rather than children. There is strong evidence in the literature that the phenotype of obese asthmatic is more prevalent among adult women, especially at the postmenopausal age⁽ Reference Sood, Qualls and Schuyler ^{38 ,} Reference Sood ^{39 )}. Hormonal changes related to menopause could be one factor which could explain this dimorphism, suggesting that postmenopausal oestrogen-based therapy increases the development of asthma symptoms in women⁽ Reference Troisi, Speizer and Willett ^{40 )}. The answer could also lie in fat distribution and composition. Adipokines have been shown to be more strongly associated with asthma symptoms in women than in men⁽ Reference Sood, Qualls and Schuyler ^{41 )}. This once again points toward the endocrine function of adipose tissue. Not every type of fat has the same physiological activity; ectopic fat (deposition of TAG within cells of non-adipose tissue) is more physiologically active within the viscera and skeletal muscle and produces more adipokines, which can promote asthmatic inflammation. This fat, although it exists in lower quantities in women, is more physiologically active⁽ Reference Sood ^{39 )}. This could partly be the reason for the higher prevalence of obesity-induced asthma in adult women than in men.

The situation is less clear and more difficult to explain in children. There are many inconsistencies in the reports on obesity-induced asthma amongst children⁽ Reference Chen, Dong and Lin ^{36 ,} Reference Willeboordse, van den Bersselaar and van de Kant ^{42 )}. Discrepancies may reflect differences in methodology, as there are not only various markers of obesity used but also different definitions of asthma. The mechanism justifying the higher prevalence of obesity related to asthma amongst boys is fairly unclear, but those sources reporting a stronger association amongst girls suggest similar explanations to those in adults, pointing at adipokine production⁽ Reference Sood ^{39 )} and early menarche; this is caused by increased body mass associated with higher risk for asthma⁽ Reference Varraso, Siroux and Maccario ^{43 )}. The genetic predisposition of girls toward this asthma phenotype has also been mentioned in the literature⁽ Reference Arriba-Méndez, Sanz and Isidoro-García ^{44 )}.

What comes first?

One of the many questions frequently posed in discussions on this topic is what appears first in this specific group of patients, asthma or obesity? Although the association may be bi-directional, prospective studies suggest that obesity precedes and is a risk factor for the development of asthma⁽ Reference Beuther and Sutherland ^{45 )}. However, this chicken-or-egg question is much harder to answer than it might seem, due to the difficulty of determining the exact moment when the two situations set in. What we usually treat as the onset of asthma is the moment when the first symptoms occur and when the diagnosis is made. This, however, does not mean that the pathological state leading to these symptoms or to other physiological alterations did not appear earlier. Prospective studies show that children who are diagnosed with asthma already have altered respiratory function in their infancy, which suggests that the disease might originate in the prenatal state⁽ Reference Bisgaard, Jensen and Bønnelykke ^{46 )}.

A similar situation exists with regard to obesity. We know by now that prenatal and perinatal factors such as birth weight, maternal weight gain, and diet considerably alter the risk of developing obesity later in the child’s life⁽ Reference Levin ^{47 ,} Reference Picó, Palou and Priego ^{48 )}. Moreover, the impact of the increased neonatal size on the development of asthma at the age of 7 years has been observed in a Danish cohort from the Copenhagen Prospective Study on Asthma in Childhood (COPSAC). Children developing asthma by the age of 7 years already as neonates had expressed lung function deficit and increased bronchial responsiveness⁽ Reference Sevelsted and Bisgaard ^{49 )}. As both asthma and obesity often begin before the moment of birth, claiming a causal relationship is difficult.

Lately there has been a focus on the effect of weight loss in asthmatic patients. In a study run in a private out-patients centre in Finland, two groups of obese patients with asthma participated in an 8-week, supervised weight-reduction programme, which included a very low-energy diet. Over the course of the programme, weight reduction in the intervention group of obese patients with asthma improved lung function, asthma symptoms, morbidity and health status⁽ Reference Stenius-Aarniala, Poussa and Kvarnström ^{50 )}. Studies performing a weight-loss intervention for asthmatic obese children also found that with decreased weight there is a significant improvement in asthma control, lung function and asthma-related quality of life⁽ Reference Luna-Pech, Torres-Mendoza and Luna-Pech ^{51 ,} Reference van Leeuwen, Hoogstrate and Duiverman ^{52 )}. Some authors report a decrease in systemic and airway inflammation⁽ Reference Abd El-Kader, Al-Jiffri and Ashmawy ^{53 )}, while others did not find this association⁽ Reference Jensen, Gibson and Collins ^{54 )}.

Possible links

In the literature there are several links concerning the association between asthma with obesity⁽ Reference Ali and Ulrik ^{55 )}. Epidemiological studies have shown and highlighted that the risk of developing asthma is significantly higher with a positive family history of atopic diseases, with a very significantly increased risk when there is a history of maternal atopy⁽ Reference Burke, Fesinmeyer and Reed ^{56 –} Reference Litonjua, Carey and Burge ^{58 )}. Likewise, a family history of obesity is a strong risk factor for this condition⁽ Reference Whitaker, Jarvis and Beeken ^{59 )}. This highlights the need to research the genetic contribution to obesity and related problems of asthma patients. Indeed, investigating the putative genetic background for both asthma and obesity highlighted some genes as candidates⁽ Reference Melén, Himes and Brehm ^{60 )}.This does not, however, explain the full variation of the disease and further hypotheses had to be tested to reach a deeper understanding of the phenomenon. A reverse causation was proposed as a putative mechanism contributing to increased weight amongst asthmatic children. It has been shown that inhaled steroids, a commonly prescribed medication for asthma, might have a positive dose effect on children’s weight and therefore increased medication use would cause obesity, rather than the other way around⁽ Reference Jani, Ogston and Mukhopadhyay ^{61 )}. It seems more plausible, however, that obesity precedes asthma or at least its manifestation, a hypothesis which is supported by growing evidence⁽ Reference Papoutsakis, Priftis and Drakouli ^{62 )}.

Asthma-like symptoms such as shortness of breath and wheezing could appear as the result of excess of thoracic and abdominal fat mass that mechanically restricts respiration⁽ Reference Salome, King and Berend ^{63 )}. This would stiffen the movement of the lungs and diaphragm and cause shortness of breath, oxidative stress and, as a result, reduction of resting lung volumes such as functional residual capacity⁽ Reference Brashier and Salvi ^{64 )}. It has been suggested that increased obesity is more related to non-specific (self-reported and not specific to one disease only) asthma symptoms such as dyspnoea or nocturnal awakenings and could lead to the impression of lower asthma control, unrelated to severity of inflammation⁽ Reference Sah, Teague and Demuth ^{65 )}.

There are researchers who claim that there might be an overdiagnosis of asthma amongst obese patients due to the dyspnoea resulting in mechanical restriction⁽ Reference Sah, Teague and Demuth ^{65 )} and indeed this has been shown to be true in some cases, with a substantial amount of underdiagnoses observed as well⁽ Reference van Huisstede, Castro Cabezas and van de Geijn ^{66 )}. Another study, however, showed that overdiagnosis is no more likely in cases of obesity than it is for non-obese individuals⁽ Reference Aaron, Vandemheen and Boulet ^{67 )}.

Both obesity and asthma, as described above, are conditions of affluence, and their prevalence has increased significantly over the past few decades. It has been suggested that the Westernised lifestyle played a significant role in these epidemics⁽ Reference Huneault, Mathieu and Tremblay ^{68 )}. Patterns of prevalence have increased, seeming to prove this hypothesis, since they follow the countries’ development and Westernisation⁽ Reference Douwes ^{69 ,} Reference Wang and Lim ^{70 )}. As a natural consequence of this analysis, the question arose whether the association between asthma and obesity could be explained by the existence of common risk factors due to changing environment and lifestyle. The risk factors related to the Westernised lifestyle that led to an increase in cases of obesity and asthma could also have led to the increase in the number of obese asthmatics. There are a number of common factors observed to be promoting both conditions, such as sedentary lifestyle⁽ Reference Prentice-Dunn and Prentice-Dunn ^{71 ,} Reference Konstantaki, Priftis and Antonogeorgos ^{72 )}, dietary changes⁽ Reference Myers and Allen ^{73 –} Reference Esposito, Kastorini and Panagiotakos ^{77 )}, vitamin D insufficiency due to lower exposure to sunlight⁽ Reference Olson, Maalouf and Oden ^{78 –} Reference Hollams, Hart and Holt ^{81 )} and tobacco exposure⁽ Reference Tsai, Huang and Hwang ^{82 –} Reference Ino ^{84 )}, amongst others. Westernised lifestyle increased exposure to risk factors common to these conditions and contributed to the increase in obese children’s development of asthma symptoms, as well as their experiencing them more severely and finding less success in treatment⁽ Reference Rasmussen and Hancox ^{85 –} Reference Brisbon, Plumb and Brawer ^{90 )}. Studies have been conducted worldwide examining the role of these factors in childhood obesity, related especially to asthma. Early-life exposures play a crucial role in the development of asthma and obesity. Some of the most important factors linking asthma with obesity are birth weight, both low and high⁽ Reference Sevelsted and Bisgaard ^{49 )}, and breast-feeding⁽ Reference Papoutsakis, Priftis and Drakouli ^{62 )}. In addition, poor maternal diet, low in micronutrients such as vitamins D, E and C, and maternal weight gain during pregnancy were shown to increase the chances of the offspring having asthma and/or obesity later in life⁽ Reference Morales, Rodriguez and Valvi ^{91 –} Reference Harpsøe, Basit and Bager ^{95 )}. These factors could contribute to the coexistence of these two conditions⁽ Reference Litonjua and Gold ^{86 )}; however, the evidence is rather ambiguous.

There might also be a pharmacological contribution to the increased body mass in asthmatic individuals. Evidence exists indicating that treatment with steroids, very commonly used for asthma, is associated with a higher annual body mass gain and the association might be dose-dependent⁽ Reference Jani, Ogston and Mukhopadhyay ^{61 )}.

Although these factors might indeed contribute to the association between these two conditions, one of the strongest pieces of evidence points to the physiological activity of the fat tissue. Adipokines regulate energy homeostasis through hunger and satiety control⁽ Reference Trayhurn and Bing ^{96 ,} Reference Trayhurn, Bing and Wood ^{97 )}. Some adipokines such as leptin or resistin are produced in excess in obesity⁽ Reference Muc, Todo-Bom and Mota-Pinto ^{98 )}, while others, such as adiponectin and ghrelin are reduced. This imbalance promotes pro-inflammatory responses and leads to inflammation⁽ Reference Balistreri, Caruso and Candore ^{99 –} Reference Monti, Carlson and Hunt ^{101 )}. A link between these adipokines was found in paediatric⁽ Reference Baek, Kim and Shin ^{102 )} and adult populations, with a stronger relationship observed in female, rather than male, individuals⁽ Reference Sood, Qualls and Schuyler ^{41 ,} Reference Tsaroucha, Daniil and Malli ^{103 )}. Receptors for leptin have been found in lung tissue⁽ Reference Bergen, Cherlet and Manuel ^{104 )} and various studies have observed increased concentrations of adipokines in asthmatic and allergic patients⁽ Reference Baek, Kim and Shin ^{102 ,} Reference Tsaroucha, Daniil and Malli ^{103 )}.

Most likely, the association between increased obesity amongst children with asthma is multifactorial. Surely, some part of the link can be explained by overestimation due to fat mass on the thoracic chest mimicking asthma symptoms⁽ Reference Sah, Teague and Demuth ^{65 )}; part of the weight increase may also be due to medication or decreased activity caused by exercise-induced wheezing attacks, resulting in reverse causation⁽ Reference Jani, Ogston and Mukhopadhyay ^{61 )}. There is no doubt that the endocrine role of adipose tissue (adipokines) is a strong physiological link and very plausibly could be a mechanism in causing a chain of disruption leading to inflammation and narrowing of airways⁽ Reference Muc, Todo-Bom and Mota-Pinto ^{98 ,} Reference Kim, Shin and Lee ^{105 –} Reference Loureiro, Pinto and Muc ^{107 )}. Despite existing evidence indicating that adipokines may be a plausible link between obesity and asthma, clinical studies bring inconclusive results. A case–control study, by Holguin et al. ⁽ Reference Holguin, Rojas and Brown ^{108 )}, compared the markers of inflammation and oxidation in bronchoalveolar lavage between asthmatic and healthy individuals. Despite increasing BMI being associated with the levels of airway leptin and adiponectin both in asthmatics and healthy controls, these associations were not associated with biomarkers of oxidation or inflammation.

Similarly, in a large prospective cohort study, asthma was linked with obesity only in adults, not in children, and they did not find evidence of a role for leptin or adiponectin in this association⁽ Reference Jartti, Saarikoski and Jartti ^{109 )}. No difference in leptin and adiponectin concentrations was found between asthmatics and controls in the study by Jang et al. ⁽ Reference Jang, Kim and Park ^{110 )}; however, the leptin:adiponectin ratio was correlated with BMI in asthmatics.

Leptin plays an additional role; it not only works as a hormone, as described above, it also works⁽ Reference Monti, Carlson and Hunt ^{101 )} as a neurotransmitter in the hypothalamus⁽ Reference Münzberg and Myers ^{111 )}. It was recently shown that leptin acts on the parasympathetic nervous system, which is responsible for the regulation of homeostasis, through the inhibition of the action of acetylcholine on the muscarinic acetylcholine receptor M3R. These receptors mediate the bronchoconstriction in response to acetylcholine and its other antagonists and control the dilation of the airways⁽ Reference Arteaga-Solis, Zee and Emala ^{112 )}. Moreover, leptin-mediated acetylcholine imbalance can cause an increase in the T helper (Th) 2 cells and a decrease of Th1, which can cause the state of allergic inflammation⁽ Reference Nizri, Fey-Tur-Sinai and Lory ^{113 )}.

Many neuropeptides which regulate appetite and satiety play an important role in asthmatic and allergic inflammation and are in metabolic interaction with leptin⁽ Reference Dhillon, Ge and Minter ^{114 )}. Human and animal studies suggest that adiposity-induced leptin increase and subsequent leptin resistance would affect these transmitters, causing or worsening asthma symptoms. This relates both to orexigenic neuropeptides such as neuropeptide Y⁽ Reference Dhillon, Ge and Minter ^{114 –} Reference Lee, Verma and Simonds ^{120 )}, endocannabinoids⁽ Reference Di Marzo ^{121 ,} Reference Pini, Mannaioni and Pellegrini-Giampietro ^{122 )}, endogenous opioids⁽ Reference Vucetic, Kimmel and Reyes ^{123 –} Reference Groneberg and Fischer ^{126 )}; and anorexigenic neuropeptides such as tachykinins and its most studied members substance P⁽ Reference Karagiannides, Bakirtzi and Kokkotou ^{127 –} Reference Ramalho, Almeida and Beltrão ^{132 )}, α-melanocyte-stimulating hormone⁽ Reference Baltazi, Katsiki and Savopoulos ^{133 –} Reference Faulkner, Dowling and Stuart ^{135 )}, corticotropin-releasing factor⁽ Reference Sharma and Banerji ^{136 –} Reference Sy, Ko and Chu ^{141 )} and serotonin⁽ Reference Hodge, Bunting and Carr ^{142 –} Reference Oury and Karsenty ^{150 )}. Altogether, it suggests that these peptides can modulate asthmatic inflammation among obese patients. Despite clinical discrepancies, leptin seems to play an important role in this neuro-immune crosstalk between adipose tissue and pathogenesis of asthma. It might be a potential target for treatment and a key element for understanding the complex problem of obesity-induced asthma.

Obesity-induced asthma phenotype

Obesity-induced asthma has been proposed as one of many distinctive asthma phenotypes⁽ Reference Farzan ^{23 ,} Reference Jensen, Collins and Gibson ^{151 –} Reference Lang, Hossain and Dixon ^{153 )}. Classification of obesity-induced asthma as a distinct phenotype means that this group of asthmatics have a distinct clinical and immunological profile that differs from other phenotypes. As mentioned above, this particular type of asthma seems to be more common amongst adult women, is more likely to be non-atopic and is characterised by a later onset⁽ Reference Farzan ^{23 )}. A childhood obesity-induced asthma phenotype has also been proposed⁽ Reference Jensen, Collins and Gibson ^{151 )}. It is generally characterised by primary and predominantly atopic asthma and the severity of asthma in this phenotype is increased by the presence of obesity⁽ Reference Rasmussen and Hancox ^{85 )}. It has also been suggested that obesity has even more effect on lung function for children than it does for adults⁽ Reference Lang, Hossain and Dixon ^{153 )}. As in the case of adults, amongst children too, obesity is more closely related to non-atopic asthma⁽ Reference Visness, London and Daniels ^{154 )}. Similarly, it has also been observed that obese children have a lower response to treatment with inhaled steroids and are at a higher risk of emergency hospitalisations than asthmatics with normal weight⁽ Reference Forno, Lescher and Strunk ^{155 )}. Obese children also tend to have lower disease control, higher severity of symptoms and more exacerbations⁽ Reference Quinto, Zuraw and Poon ^{156 )}. Moreover, obese asthmatic children were shown to have a Th1 polarisation rather than the typical atopic Th2 immunological profile⁽ Reference Rastogi, Canfield and Andrade ^{157 )}. Interestingly, it has been shown that obese children might respond differently to environmental triggers, and traffic exposure to polycyclic aromatic hydrocarbons is more likely to cause asthma in obese children than those with normal weight⁽ Reference Jung, Perzanowski and Rundle ^{158 )}.

Nevertheless, even within the obesity-induced asthma phenotype, heterogeneity can be observed in the clinical characteristics of patients and corresponding differences in their treatment approach⁽ Reference Sutherland, Goleva and King ^{152 )}. A strong focus was placed on describing the clinical profile of these individuals.