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Association between obesity and asthma – epidemiology, pathophysiology and clinical profile

Published online by Cambridge University Press:  12 August 2016

Magdalena Muc ,
Anabela Mota-Pinto Open the ORCID record for Anabela Mota-Pinto [Opens in a new window]  and
Cristina Padez Open the ORCID record for Cristina Padez [Opens in a new window]
Magdalena Muc*
Affiliation:
CIAS – Research Centre for Anthropology and Health, Department of Life Sciences, University of Coimbra, Calçada Martim de Freitas, 3000-456, Coimbra, Portugal Department of Clinical Sciences, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK
Anabela Mota-Pinto
Affiliation:
General Pathology Laboratory, Faculty of Medicine, University of Coimbra, Rua Larga, 3004-504, Coimbra, Portugal
Cristina Padez
Affiliation:
CIAS – Research Centre for Anthropology and Health, Department of Life Sciences, University of Coimbra, Calçada Martim de Freitas, 3000-456, Coimbra, Portugal
*
*Corresponding author: Magdalena Muc da Encarnação, email [email protected]
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Abstract

Obesity is a risk factor for asthma, and obese asthmatics have lower disease control and increased symptom severity. Several putative links have been proposed, including genetics, mechanical restriction of the chest and the intake of corticosteroids. The most consistent evidence, however, comes from studies of cytokines produced by the adipose tissue called adipokines. Adipokine imbalance is associated with both proinflammatory status and asthma. Although reverse causation has been proposed, it is now acknowledged that obesity precedes asthma symptoms. Nevertheless, prenatal origins of both conditions complicate the search for causality. There is a confirmed role of neuro-immune cross-talk mediating obesity-induced asthma, with leptin playing a key role in these processes. Obesity-induced asthma is now considered a distinct asthma phenotype. In fact, it is one of the most important determinants of asthma phenotypes. Two main subphenotypes have been distinguished. The first phenotype, which affects adult women, is characterised by later onset and is more likely to be non-atopic. The childhood obesity-induced asthma phenotype is characterised by primary and predominantly atopic asthma. In obesity-induced asthma, the immune responses are shifted towards T helper (Th) 1 polarisation rather than the typical atopic Th2 immunological profile. Moreover, obese asthmatics might respond differently to environmental triggers. The high cost of treatment of obesity-related asthma, and the burden it causes for the patients and their families call for urgent intervention. Phenotype-specific approaches seem to be crucial for the success of prevention and treatment.

Keywords

ObesityOverweightAsthmaPhenotypesObesity-induced asthma
Type
Review Article
Information
Nutrition Research Reviews , Volume 29 , Issue 2 , December 2016 , pp. 194 - 201
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Copyright
Copyright © The Authors 2016 

Introduction

Obesity and asthma are conditions that have been increasing in recent decades. This sudden increase is most probably caused by the shift towards the Westernised lifestyle and rapid urbanisation. Strong association has been found between asthma and obesity and it has been shown that obesity increases the risk of asthma( Reference Van Cleave, Gortmaker and Perrin 1 ). The large and pathologically specific group of obese patients with asthma has attracted the attention of scientists and medical doctors worldwide. The present review explores the complex association between the two conditions, with focus on their epidemiology, but also involving the pathophysiology and clinical aspects, which can serve for the creation of the personalised, tailor-made intervention and prevention initiatives for severely affected patients.

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.

Conclusion

Despite the growing evidence for the asthma–obesity association, there is no consensus on causality and mechanism. Regardless of what the links of mechanism and causality are between the two conditions, the fact is that obesity is related to higher hospitalisation rates for asthma as well as higher doses of medications required for control of the disease; it seems to be a dose-dependent association( Reference Quinto, Zuraw and Poon 156 ). Increasing numbers of obese individuals will result in an increased prevalence of obesity-induced asthma in adult and paediatric populations. For obese patients with asthma and their families this equals higher medication costs and a more difficult and less effective treatment, which constitutes a heavy burden and results in the lowering of their quality of life. Moreover, this problem is related to increased economic costs for public health systems as well. To avoid these issues, prevention and lifestyle secondary and primary weight-loss interventions are of great importance. As the phenotype of asthma, associated with obesity, seems to be a specific condition, it is necessary to study it independently. This distinct phenotype may be characterised by different environmental, socio-economic and family risk factors than for non-obese asthmatics and non-asthmatic obese children. An in-depth knowledge of the risk factors for the development of obesity-induced asthma is essential in order to design effective, evidence-based prevention and intervention programmes.

Acknowledgements

The authors would like to thank Mr Andrew Morgan and Mrs Amelia Stein for providing English proofreading of this text.

The Portuguese Foundation for Science and Technology (FTC) supported the present review (grant no. SFRH/BD/66877/2009).

M. M. carried out the literature search and wrote the review paper. C. P. provided expertise on obesity and nutrition and A. M. P. provided expertise on asthma and inflammation. Both C. P. and A. M. P. revised and constructed the paper together with M. M.

There are no potential conflicts of interest.

References

1. Van Cleave, J, Gortmaker, SL & Perrin, JM (2010) Dynamics of obesity and chronic health conditions among children and youth. JAMA 303, 623–630.CrossRefGoogle ScholarPubMed
2. World Health Organization (2013) Obesity and overweight. Fact sheet no. 311. http://www.who.int/mediacentre/factsheets/fs311/en/ (accessed January 2014).Google Scholar
3. Guh, DP, Zhang, W, Bansback, N, et al. (2009) The incidence of co-morbidities related to obesity and overweight: a systematic review and meta-analysis. BMC Public Health 9, 88.CrossRefGoogle ScholarPubMed
4. Park, MH, Falconer, C, Viner, RM, et al. (2012) The impact of childhood obesity on morbidity and mortality in adulthood: a systematic review. Obes Rev 13, 985–1000.Google Scholar
5. Hursting, SD (2014) Obesity, energy balance, and cancer: a mechanistic perspective. Cancer Treat Res 159, 21–33.Google Scholar
6. Liu, P-C, Kieckhefer, GM & Gau, B-S (2013) A systematic review of the association between obesity and asthma in children. J Adv Nurs 69, 1446–1465.CrossRefGoogle ScholarPubMed
7. Rice, TB, Foster, GD, Sanders, MH, et al. (2012) The relationship between obstructive sleep apnea and self-reported stroke or coronary heart disease in overweight and obese adults with type 2 diabetes mellitus. Sleep 35, 1293–1298.Google ScholarPubMed
8. Jacobs, DRJ (2006) Fast food and sedentary lifestyle: a combination that leads to obesity. Am J Clin Nutr 83, 189–190.Google Scholar
9. Peters, JC, Wyatt, HR, Donahoo, WT, et al. (2002) From instinct to intellect: the challenge of maintaining healthy weight in the modern world. Obes Rev 3, 69–74.Google Scholar
10. Proietto, J, Galic, S, Oakhill, JS, et al. (2010) Adipose tissue as an endocrine organ. Mol Cell Endocrinol 316, 129–139.Google Scholar
11. Guerre-Millo, M (2004) Adipose tissue and adipokines: for better or worse. Diabetes Metab 30, 13–19.Google Scholar
12. World Allergy Organization (2011) White Book on Allergy [R Pawankar, GW Canonica, ST Holgate and RF Lockey, editors]. Milwaukee, WI: World Allergy Organization.Google Scholar
13. Masoli, M, Fabian, D, Holt, S, et al. (2004) The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy 59, 469–478.CrossRefGoogle ScholarPubMed
14. von Hertzen, LC & Haahtela, T (2004) Asthma and atopy – the price of affluence? Allergy 59, 124–137.Google Scholar
15. Vale-Pereira, S, Todo-Bom, A, Geraldes, L, et al. (2011) FoxP3, GATA-3 and T-bet expression in elderly asthma. Clin Exp Allergy 41, 490–496.Google Scholar
16. Bønnelykke, K, Sleiman, P, Nielsen, K, et al. (2013) A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations. Nat Genet 46, 51–55.CrossRefGoogle ScholarPubMed
17. Ober, C & Yao, T-C (2011) The genetics of asthma and allergic disease: a 21st century perspective. Immunol Rev 242, 10–30.CrossRefGoogle ScholarPubMed
18. Melén, E, Kho, AT, Sharma, S, et al. (2011) Expression analysis of asthma candidate genes during human and murine lung development. Respir Res 12, 86.CrossRefGoogle ScholarPubMed
19. Salam, MT, Li, Y-F, Langholz, B, et al. (2004) Early-life environmental risk factors for asthma: findings from the Children’s Health Study. Environ Health Perspect 112, 760–765.CrossRefGoogle ScholarPubMed
20. Asher, MI, Stewart, AW, Mallol, J, et al. (2010) Which population level environmental factors are associated with asthma, rhinoconjunctivitis and eczema? Review of the ecological analyses of ISAAC Phase One. Respir Res 11, 8.Google Scholar
21. Lötvall, J, Akdis, CA, Bacharier, LB, et al. (2011) Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol 127, 355–360.CrossRefGoogle ScholarPubMed
22. Agache, I, Akdis, C, Jutel, M, et al. (2012) Untangling asthma phenotypes and endotypes. Allergy 67, 835–846.Google Scholar
23. Farzan, S (2013) The asthma phenotype in the obese: distinct or otherwise? J Allergy 2013, 602908.CrossRefGoogle ScholarPubMed
24. Seidell, JC, de Groot, LC, van Sonsbeek, JL, et al. (1986) Associations of moderate and severe overweight with self-reported illness and medical care in Dutch adults. Am J Public Health 76, 264–269.Google Scholar
25. Camargo, CA, Weiss, ST, Zhang, S, et al. (1999) Prospective study of body mass index, weight change, and risk of adult-onset asthma in women. Arch Intern Med 159, 2582–2588.Google Scholar
26. Black, MH, Smith, N, Porter, AH, et al. (2012) Higher prevalence of obesity among children with asthma. Obesity (Silver Spring) 20, 1041–1047.Google Scholar
27. Okabe, Y, Adachi, Y, Itazawa, T, et al. (2012) Association between obesity and asthma in Japanese preschool children. Pediatr Allergy Immunol 23, 550–555.Google Scholar
28. Jeong, Y, Jung-Choi, K, Lee, JH, et al. (2010) Body weight at birth and at age three and respiratory illness in preschool children. J Prev Med Public Health 43, 369–376.Google Scholar
29. Taveras, EM, Rifas-Shiman, SL, Camargo, CA, et al. (2008) Higher adiposity in infancy associated with recurrent wheeze in a prospective cohort of children. J Allergy Clin Immunol 121, 1161–1166.e3.Google Scholar
30. Rodríguez, MA, Winkleby, MA, Ahn, D, et al. (2002) Identification of population subgroups of children and adolescents with high asthma prevalence: findings from the Third National Health and Nutrition Examination Survey. Arch Pediatr Adolesc Med 156, 269–275.Google Scholar
31. von Mutius, E, Schwartz, J, Neas, LM, et al. (2001) Relation of body mass index to asthma and atopy in children: the National Health and Nutrition Examination Study III. Thorax 56, 835–838.Google Scholar
32. Luder, E, Ehrlich, RI, Lou, WYW, et al. (2004) Body mass index and the risk of asthma in adults. Respir Med 98, 29–37.Google Scholar
33. Guler, N, Kirerleri, E, Ones, U, et al. (2004) Leptin: does it have any role in childhood asthma? J Allergy Clin Immunol 114, 254–259.Google Scholar
34. Rzehak, P, Wijga, AH, Keil, T, et al. (2013) Body mass index trajectory classes and incident asthma in childhood: results from 8 European birth cohorts – a Global Allergy and Asthma European Network initiative. J Allergy Clin Immunol 131, 1528–1536.Google Scholar
35. Musaad, SMA, Patterson, T, Ericksen, M, et al. (2009) Comparison of anthropometric measures of obesity in childhood allergic asthma: central obesity is most relevant. J Allergy Clin Immunol 123, 1321–1327.e12.CrossRefGoogle ScholarPubMed
36. Chen, YC, Dong, GH, Lin, KC, et al. (2013) Gender difference of childhood overweight and obesity in predicting the risk of incident asthma: a systematic review and meta-analysis. Obes Rev 14, 222–231.CrossRefGoogle ScholarPubMed
37. Chen, Y, Dales, R, Tang, M, et al. (2002) Obesity may increase the incidence of asthma in women but not in men: longitudinal observations from the Canadian National Population Health Surveys. Am J Epidemiol 155, 191–197.CrossRefGoogle Scholar
38. Sood, A, Qualls, C, Schuyler, M, et al. (2013) Adult-onset asthma becomes the dominant phenotype among women by age 40 years. The longitudinal CARDIA study. Ann Am Thorac Soc 10, 188–197.CrossRefGoogle ScholarPubMed
39. Sood, A (2011) Sex differences: implications for the obesity–asthma association. Exerc Sport Sci Rev 39, 48–56.Google Scholar
40. Troisi, RJ, Speizer, FE, Willett, WC, et al. (1995) Menopause, postmenopausal estrogen preparations, and the risk of adult-onset asthma. A prospective cohort study. Am J Respir Crit Care Med 152, 1183–1188.CrossRefGoogle ScholarPubMed
41. Sood, A, Qualls, C, Schuyler, M, et al. (2012) Low serum adiponectin predicts future risk for asthma in women. Am J Respir Crit Care Med 186, 41–47.Google Scholar
42. Willeboordse, M, van den Bersselaar, DLCM, van de Kant, KDG, et al. (2013) Sex differences in the relationship between asthma and overweight in Dutch children: a survey study. PLOS ONE 8, e77574.Google Scholar
43. Varraso, R, Siroux, V, Maccario, J, et al. (2005) Asthma severity is associated with body mass index and early menarche in women. Am J Respir Crit Care Med 171, 334–339.Google Scholar
44. Arriba-Méndez, S, Sanz, C, Isidoro-García, M, et al. (2008) Analysis of 927T>C CYSLTR1 and -444A>C LTC4S polymorphisms in children with asthma. Allergol Immunopathol (Madr) 36, 259–263.CrossRefGoogle Scholar
45. Beuther, DA & Sutherland, ER (2007) Overweight, obesity, and incident asthma: a meta-analysis of prospective epidemiologic studies. Am J Respir Crit Care Med 175, 661–666.Google Scholar
46. Bisgaard, H, Jensen, SM & Bønnelykke, K (2012) Interaction between asthma and lung function growth in early life. Am J Respir Crit Care Med 185, 1183–1189.Google Scholar
47. Levin, BE (2007) Critical importance of the perinatal period in the development of obesity. In Treatment of the Obese Patient, pp. 99–119. Contemporary Endocrinology series [RF Kushner and DH Bessesen, editors]. Totowa, NJ: Humana Press.Google Scholar
48. Picó, C, Palou, M, Priego, T, et al. (2012) Metabolic programming of obesity by energy restriction during the perinatal period: different outcomes depending on gender and period, type and severity of restriction. Front Physiol 3, 436.Google Scholar
49. Sevelsted, A & Bisgaard, H (2012) Neonatal size in term children is associated with asthma at age 7, but not with atopic dermatitis or allergic sensitization. Allergy 67, 670–675.Google Scholar
50. Stenius-Aarniala, B, Poussa, T, Kvarnström, J, et al. (2000) Immediate and long term effects of weight reduction in obese people with asthma: randomised controlled study. BMJ 320, 827–832.Google Scholar
51. Luna-Pech, JA, Torres-Mendoza, BM, Luna-Pech, JA, et al. (2014) Normocaloric diet improves asthma-related quality of life in obese pubertal adolescents. Int Arch Allergy Immunol 163, 252–258.Google Scholar
52. van Leeuwen, JC, Hoogstrate, M, Duiverman, EJ, et al. (2014) Effects of dietary induced weight loss on exercise-induced bronchoconstriction in overweight and obese children. Pediatr Pulmonol 49, 1155–1161.Google Scholar
53. Abd El-Kader, MS, Al-Jiffri, O & Ashmawy, EM (2013) Impact of weight loss on markers of systemic inflammation in obese Saudi children with asthma. Afr Health Sci 13, 682–688.Google Scholar
54. Jensen, ME, Gibson, PG, Collins, CE, et al. (2013) Diet-induced weight loss in obese children with asthma: a randomized controlled trial. Clin Exp Allergy 43, 775–784.Google Scholar
55. Ali, Z & Ulrik, CS (2013) Obesity and asthma: a coincidence or a causal relationship? A systematic review. Respir Med 107, 1287–1300.CrossRefGoogle ScholarPubMed
56. Burke, W, Fesinmeyer, M, Reed, K, et al. (2003) Family history as a predictor of asthma risk. Am J Prev Med 24, 160–169.CrossRefGoogle ScholarPubMed
57. Bjerg, A, Hedman, L, Perzanowski, MS, et al. (2007) Family history of asthma and atopy: in-depth analyses of the impact on asthma and wheeze in 7- to 8-year-old children. Pediatrics 120, 741–748.Google Scholar
58. Litonjua, AA, Carey, VJ, Burge, HA, et al. (1998) Parental history and the risk for childhood asthma. Does mother confer more risk than father? Am J Respir Crit Care Med 158, 176–181.Google Scholar
59. Whitaker, KL, Jarvis, MJ, Beeken, RJ, et al. (2010) Comparing maternal and paternal intergenerational transmission of obesity risk in a large population-based sample. Am J Clin Nutr 91, 1560–1567.Google Scholar
60. Melén, E, Himes, BE, Brehm, JM, et al. (2010) Analyses of shared genetic factors between asthma and obesity in children. J Allergy Clin Immunol 126, 631–637.e1–8.Google Scholar
61. Jani, M, Ogston, S & Mukhopadhyay, S (2005) Annual increase in body mass index in children with asthma on higher doses of inhaled steroids. J Pediatr 147, 549–551.CrossRefGoogle ScholarPubMed
62. Papoutsakis, C, Priftis, KN, Drakouli, M, et al. (2013) Childhood overweight/obesity and asthma: is there a link? A systematic review of recent epidemiologic evidence. J Acad Nutr Diet 113, 77–105.Google Scholar
63. Salome, CM, King, GG & Berend, N (2013) Effects of obesity on lung function. In Obesity and Lung Disease, pp. 1–20 [AE Dixon and EM Clerisme-Beaty, editors]. Totowa, NJ: Humana Press.Google Scholar
64. Brashier, B & Salvi, S (2013) Obesity and asthma: physiological perspective. J Allergy 2013, 198068.Google Scholar
65. Sah, PK, Teague, WG, Demuth, KA, et al. (2013) Poor asthma control in obese children may be overestimated because of enhanced perception of dyspnea. J Allergy Clin Immunol Pract 1, 39–45.e2.Google Scholar
66. van Huisstede, A, Castro Cabezas, M, van de Geijn, G-JM, et al. (2013) Underdiagnosis and overdiagnosis of asthma in the morbidly obese. Respir Med 107, 1356–1364.Google Scholar
67. Aaron, SD, Vandemheen, KL, Boulet, L-P, et al. (2008) Overdiagnosis of asthma in obese and nonobese adults. CMAJ 179, 1121–1131.Google Scholar
68. Huneault, L, Mathieu, M-È & Tremblay, A (2011) Globalization and modernization: an obesogenic combination. Obes Rev 12, e64–e72.CrossRefGoogle ScholarPubMed
69. Douwes, J (2002) Asthma and the Westernization “package”. Int J Epidemiol 31, 1098–1102.Google Scholar
70. Wang, Y & Lim, H (2012) The global childhood obesity epidemic and the association between socio-economic status and childhood obesity. Int Rev Psychiatry 24, 176–188.Google Scholar
71. Prentice-Dunn, H & Prentice-Dunn, S (2012) Physical activity, sedentary behavior, and childhood obesity: a review of cross-sectional studies. Psychol Health Med 17, 255–273.Google Scholar
72. Konstantaki, E, Priftis, KN, Antonogeorgos, G, et al. (2014) The association of sedentary lifestyle with childhood asthma. The role of nurse as educator. Allergol Immunopathol (Madr) 42, 609–615.Google Scholar
73. Myers, JL & Allen, JC (2011) Nutrition and inflammation: insights on dietary pattern, obesity, and asthma. Am J Lifestyle Med 6, 14–17.Google Scholar
74. Sexton, P, Black, P, Metcalf, P, et al. (2013) Influence of Mediterranean diet on asthma symptoms, lung function, and systemic inflammation: a randomized controlled trial. J Asthma 50, 75–81.Google Scholar
75. Patterson, E, Wall, R, Fitzgerald, GF, et al. (2012) Health implications of high dietary omega-6 polyunsaturated fatty acids. J Nutr Metab 2012, 539426.Google Scholar
76. Popkin, BM, Adair, LS & Ng, SW (2012) Global nutrition transition and the pandemic of obesity in developing countries. Nutr Rev 70, 3–21.Google Scholar
77. Esposito, K, Kastorini, C-M, Panagiotakos, DB, et al. (2011) Mediterranean diet and weight loss: meta-analysis of randomized controlled trials. Metab Syndr Relat Disord 9, 1–12.Google Scholar
78. Olson, ML, Maalouf, NM, Oden, JD, et al. (2012) Vitamin D deficiency in obese children and its relationship to glucose homeostasis. J Clin Endocrinol Metab 97, 279–285.Google Scholar
79. Foss, YJ (2009) Vitamin D deficiency is the cause of common obesity. Med Hypotheses 72, 314–321.Google Scholar
80. Sutherland, ER, Goleva, E, Jackson, LP, et al. (2010) Vitamin D levels, lung function, and steroid response in adult asthma. Am J Respir Crit Care Med 181, 699–704.Google Scholar
81. Hollams, EM, Hart, PH, Holt, BJ, et al. (2011) Vitamin D and atopy and asthma phenotypes in children: a longitudinal cohort study. Eur Respir J 38, 1320–1327.CrossRefGoogle ScholarPubMed
82. Tsai, C-H, Huang, J-H, Hwang, B-F, et al. (2010) Household environmental tobacco smoke and risks of asthma, wheeze and bronchitic symptoms among children in Taiwan. Respir Res 11, 11.Google Scholar
83. Neuman, Å, Hohmann, C, Orsini, N, et al. (2012) Maternal smoking in pregnancy and asthma in preschool children: a pooled analysis of eight birth cohorts. Am J Respir Crit Care Med 186, 1037–1043.Google Scholar
84. Ino, T (2010) Maternal smoking during pregnancy and offspring obesity: meta-analysis. Pediatr Int 52, 94–99.Google Scholar
85. Rasmussen, F & Hancox, RJ (2014) Mechanisms of obesity in asthma. Curr Opin Allergy Clin Immunol 14, 35–43.Google Scholar
86. Litonjua, AA & Gold, DR (2008) Asthma and obesity: common early-life influences in the inception of disease. J Allergy Clin Immunol 121, 1075–1084; quiz 1085–1086.CrossRefGoogle ScholarPubMed
87. Oddy, WH, Sherriff, JL, de Klerk, NH, et al. (2004) The relation of breastfeeding and body mass index to asthma and atopy in children: a prospective cohort study to age 6 years. Am J Public Health 94, 1531–1537.Google Scholar
88. Suglia, SF, Chambers, EC, Rosario, A, et al. (2011) Asthma and obesity in three-year-old urban children: role of sex and home environment. J Pediatr 159, 14–20.e1.Google Scholar
89. Chen, Y-C, Tu, YK, Huang, KC, et al. (2014) Pathway from central obesity to childhood asthma. Physical fitness and sedentary time are leading factors. Am J Respir Crit Care Med 189, 1194–1203.CrossRefGoogle ScholarPubMed
90. Brisbon, N, Plumb, J, Brawer, R, et al. (2005) The asthma and obesity epidemics: the role played by the built environment – a public health perspective. J Allergy Clin Immunol 115, 1024–1028.Google Scholar
91. Morales, E, Rodriguez, A, Valvi, D, et al. (2015) Deficit of vitamin D in pregnancy and growth and overweight in the offspring. Int J Obes (Lond) 39, 61–68.CrossRefGoogle ScholarPubMed
92. Laitinen, J, Jääskeläinen, A, Hartikainen, AL, et al. (2012) Maternal weight gain during the first half of pregnancy and offspring obesity at 16 years: a prospective cohort study. BJOG 119, 716–723.Google Scholar
93. Maslova, E, Hansen, S, Jensen, CB, et al. (2013) Vitamin D intake in mid-pregnancy and child allergic disease – a prospective study in 44,825 Danish mother–child pairs. BMC Pregnancy Childbirth 13, 199.Google Scholar
94. Allan, KM, Prabhu, N, Craig, LC, et al. (2015) Maternal vitamin D and E intakes during pregnancy are associated with asthma in children. Eur Respir J 45, 1027–1036.Google Scholar
95. Harpsøe, MC, Basit, S, Bager, P, et al. (2013) Maternal obesity, gestational weight gain, and risk of asthma and atopic disease in offspring: a study within the Danish National Birth Cohort. J Allergy Clin Immunol 131, 1033–1040.Google Scholar
96. Trayhurn, P & Bing, C (2006) Appetite and energy balance signals from adipocytes. Philos Trans R Soc Lond B Biol Sci 361, 1237–1249.Google Scholar
97. Trayhurn, P, Bing, C & Wood, IS (2006) Adipose tissue and adipokines – energy regulation from the human perspective. J Nutr 136, 7 Suppl., 1935S–1939S.Google Scholar
98. Muc, M, Todo-Bom, A, Mota-Pinto, A, et al. (2014) Leptin and resistin in overweight patients with and without asthma. Allergol Immunopathol (Madr) 42, 415–421.Google Scholar
99. Balistreri, CR, Caruso, C & Candore, G (2010) The role of adipose tissue and adipokines in obesity-related inflammatory diseases. Mediators Inflamm 2010, 802078.Google Scholar
100. Maury, E & Brichard, SM (2010) Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome. Mol Cell Endocrinol 314, 1–16.Google Scholar
101. Monti, V, Carlson, JJ, Hunt, SC, et al. (2006) Relationship of ghrelin and leptin hormones with body mass index and waist circumference in a random sample of adults. J Am Diet Assoc 106, 822–828; quiz 829–830.CrossRefGoogle Scholar
102. Baek, H-S, Kim, YD, Shin, JH, et al. (2011) Serum leptin and adiponectin levels correlate with exercise-induced bronchoconstriction in children with asthma. Ann Allergy, Asthma Immunol 107, 14–21.Google Scholar
103. Tsaroucha, A, Daniil, Z, Malli, F, et al. (2013) Leptin, adiponectin, and ghrelin levels in female patients with asthma during stable and exacerbation periods. J Asthma 50, 188–197.Google Scholar
104. Bergen, HT, Cherlet, TC, Manuel, P, et al. (2002) Identification of leptin receptors in lung and isolated fetal type II cells. Am J Respir Cell Mol Biol 27, 71–77.Google Scholar
105. Kim, KW, Shin, YH, Lee, KE, et al. (2008) Relationship between adipokines and manifestations of childhood asthma. Pediatr Allergy Immunol 19, 535–540.Google Scholar
106. Yuksel, H, Sogut, A, Yilmaz, O, et al. (2012) Role of adipokines and hormones of obesity in childhood asthma. Allergy Asthma Immunol Res 4, 98–103.Google Scholar
107. Loureiro, C, Pinto, AM, Muc, M, et al. (2012) Valores de resistina, adiponectina e leptina em doentes com asma e excesso de peso (Values of resistin, adiponectin and leptin in patients with asthma and overweight). Rev Port Imunoalergologia 20, 121–128.Google Scholar
108. Holguin, F, Rojas, M, Brown, LA, et al. (2011) Airway and plasma leptin and adiponectin in lean and obese asthmatics and controls. J Asthma 48, 217–223.Google Scholar
109. Jartti, T, Saarikoski, L, Jartti, L, et al. (2009) Obesity, adipokines and asthma. Allergy 64, 770–777.Google Scholar
110. Jang, A-S, Kim, TH, Park, JS, et al. (2009) Association of serum leptin and adiponectin with obesity in asthmatics. J Asthma 46, 59–63.Google Scholar
111. Münzberg, H & Myers, MG (2005) Molecular and anatomical determinants of central leptin resistance. Nat Neurosci 8, 566–570.Google Scholar
112. Arteaga-Solis, E, Zee, T, Emala, CW, et al. (2013) Inhibition of leptin regulation of parasympathetic signaling as a cause of extreme body weight-associated asthma. Cell Metab 17, 35–48.Google Scholar
113. Nizri, E, Fey-Tur-Sinai, M, Lory, O, et al. (2009) Activation of the cholinergic anti-inflammatory system by nicotine attenuates neuroinflammation via suppression of Th1 and Th17 responses. J Immunol 183, 6681–6688.Google Scholar
114. Dhillon, H, Ge, YL, Minter, R, et al. (2000) Long-term differential modulation of genes encoding orexigenic and anorexigenic peptides by leptin delivered by rAAV vector in ob/ob mice. Regul Pept 92, 97–105.Google Scholar
115. Zhang, W, Cline, MA & Gilbert, ER (2014) Hypothalamus–adipose tissue crosstalk: neuropeptide Y and the regulation of energy metabolism. Nutr Metab (Lond) 11, 27.Google Scholar
116. Buttari, B, Profumo, E, Domenici, G, et al. (2014) Neuropeptide Y induces potent migration of human immature dendritic cells and promotes a Th2 polarization. FASEB J 28, 3038–3049.Google Scholar
117. Makinde, TO, Steininger, R & Agrawal, DK (2013) NPY and NPY receptors in airway structural and inflammatory cells in allergic asthma. Exp Mol Pathol 94, 45–50.Google Scholar
118. Macia, L, Rao, PT, Wheway, J, et al. (2011) Y1 signalling has a critical role in allergic airway inflammation. Immunol Cell Biol 89, 882–888.Google Scholar
119. Mutschler, J, Abbruzzese, E, Wiedemann, K, et al. (2013) Functional polymorphism in the neuropeptide Y gene promoter (rs16147) is associated with serum leptin levels and waist-hip ratio in women. Ann Nutr Metab 62, 271–276.Google Scholar
120. Lee, SJ, Verma, S, Simonds, SE, et al. (2013) Leptin stimulates neuropeptide Y and cocaine amphetamine-regulated transcript coexpressing neuronal activity in the dorsomedial hypothalamus in diet-induced obese mice. J Neurosci 33, 15306–15317.CrossRefGoogle ScholarPubMed
121. Di Marzo, V (2011) Endocannabinoids: an appetite for fat. Proc Natl Acad Sci U S A 108, 12567–12568.Google Scholar
122. Pini, A, Mannaioni, G, Pellegrini-Giampietro, D, et al. (2012) The role of cannabinoids in inflammatory modulation of allergic respiratory disorders, inflammatory pain and ischemic stroke. Curr Drug Targets 13, 984–993.Google Scholar
123. Vucetic, Z, Kimmel, J & Reyes, TM (2011) Chronic high-fat diet drives postnatal epigenetic regulation of μ-opioid receptor in the brain. Neuropsychopharmacology 36, 1199–1206.Google Scholar
124. Czyzyk, TA, Romero-Picó, A, Pintar, J, et al. (2012) Mice lacking δ-opioid receptors resist the development of diet-induced obesity. FASEB J 26, 3483–3492.CrossRefGoogle ScholarPubMed
125. Lim, G, Kim, H, McCabe, MF, et al. (2014) A leptin-mediated central mechanism in analgesia-enhanced opioid reward in rats. J Neurosci 34, 9779–9788.Google Scholar
126. Groneberg, DA & Fischer, A (2001) Endogenous opioids as mediators of asthma. Pulm Pharmacol Ther 14, 383–389.Google Scholar
127. Karagiannides, I, Bakirtzi, K, Kokkotou, E, et al. (2011) Role of substance P in the regulation of glucose metabolism via insulin signaling-associated pathways. Endocrinology 152, 4571–4580.Google Scholar
128. Fu, J, Liu, B, Liu, P, et al. (2011) Substance P is associated with the development of obesity, chronic inflammation and type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes 119, 177–181.Google Scholar
129. Sismanopoulos, N, Delivanis, D, Mavrommati, D, et al. (2013) Do mast cells link obesity and asthma? Allergy 68, 8–15.Google Scholar
130. Ramalho, R, Almeida, J, Fernandes, R, et al. (2013) Neurokinin-1 receptor, a new modulator of lymphangiogenesis in obese-asthma phenotype. Life Sci 93, 169–177.Google Scholar
131. Ramalho, R, Almeida, J, Beltrão, M, et al. (2012) Neurogenic inflammation in allergen-challenged obese mice: a missing link in the obesity–asthma association? Exp Lung Res 38, 316–324.Google Scholar
132. Ramalho, R, Almeida, J, Beltrão, M, et al. (2013) Substance P antagonist improves both obesity and asthma in a mouse model. Allergy 68, 48–54.Google Scholar
133. Baltazi, M, Katsiki, N, Savopoulos, C, et al. (2011) Plasma neuropeptide Y (NPY) and α-melanocyte stimulating hormone (a-MSH) levels in patients with or without hypertension and/or obesity: a pilot study. Am J Cardiovasc Dis 1, 48–59.Google Scholar
134. Cyr, NE, Toorie, AM, Steger, JS, et al. (2013) Mechanisms by which the orexigen NPY regulates anorexigenic α-MSH and TRH. Am J Physiol Endocrinol Metab 304, E640–E650.CrossRefGoogle ScholarPubMed
135. Faulkner, LD, Dowling, AR, Stuart, RC, et al. (2015) Reduced melanocortin production causes sexual dysfunction in male mice with POMC neuronal insulin and leptin insensitivity. Endocrinology 156, 1372–1385.Google Scholar
136. Sharma, R & Banerji, MA (2012) Corticotropin releasing factor (CRF) and obesity. Maturitas 72, 1–3.Google Scholar
137. George, SA, Khan, S, Briggs, H, et al. (2010) CRH-stimulated cortisol release and food intake in healthy, non-obese adults. Psychoneuroendocrinology 35, 607–612.Google Scholar
138. Fahlbusch, FB, Ruebner, M, Volkert, G, et al. (2012) Corticotropin-releasing hormone stimulates expression of leptin, 11β-HSD2 and syncytin-1 in primary human trophoblasts. Reprod Biol Endocrinol 10, 80.Google Scholar
139. Harris, RBS (2010) Leptin responsiveness of mice deficient in corticotrophin-releasing hormone receptor type 2. Neuroendocrinology 92, 198–206.Google Scholar
140. Poon, AH, Tantisira, KG, Litonjua, AA, et al. (2008) Association of corticotropin-releasing hormone receptor-2 genetic variants with acute bronchodilator response in asthma. Pharmacogenet Genomics 18, 373–382.Google Scholar
141. Sy, HY, Ko, FWS, Chu, HY, et al. (2012) Asthma and bronchodilator responsiveness are associated with polymorphic markers of ARG1, CRHR2 and chromosome 17q21. Pharmacogenet Genomics 22, 517–524.Google Scholar
142. Hodge, S, Bunting, BP, Carr, E, et al. (2012) Obesity, whole blood serotonin and sex differences in healthy volunteers. Obes Facts 5, 399–407.Google Scholar
143. Hurren, KM & Berlie, HD (2011) Lorcaserin: an investigational serotonin 2C agonist for weight loss. Am J Health Syst Pharm 68, 2029–2037.Google Scholar
144. Moore, BD, Hyde, D, Miller, L, et al. (2012) Allergen and ozone exacerbate serotonin-induced increases in airway smooth muscle contraction in a model of childhood asthma. Respiration 83, 529–542.Google Scholar
145. Moore, BD, Hyde, DM, Miller, LA, et al. (2014) Persistence of serotonergic enhancement of airway response in a model of childhood asthma. Am J Respir Cell Mol Biol 51, 77–85.Google Scholar
146. Young, SN (2013) Elevated incidence of suicide in people living at altitude, smokers and patients with chronic obstructive pulmonary disease and asthma: possible role of hypoxia causing decreased serotonin synthesis. J Psychiatry Neurosci 38, 423–426.Google Scholar
147. Walther, DJ, Peter, JU, Winter, S, et al. (2003) Serotonylation of small GTPases is a signal transduction pathway that triggers platelet α-granule release. Cell 115, 851–862.Google Scholar
148. Shajib, MS & Khan, WI (2015) The role of serotonin and its receptors in activation of immune responses and inflammation. Acta Physiol (Oxf) 213, 561–574.Google Scholar
149. Nau, F Jr, Miller, J, Saravia, J, et al. (2015) Serotonin 5-HT2 receptor activation prevents allergic asthma in a mouse model. Am J Physiol Lung Cell Mol Physiol 308, L191–L198.Google Scholar
150. Oury, F & Karsenty, G (2011) Towards a serotonin-dependent leptin roadmap in the brain. Trends Endocrinol Metab 22, 382–387.Google Scholar
151. Jensen, ME, Collins, CE, Gibson, PG, et al. (2011) The obesity phenotype in children with asthma. Paediatr Respir Rev 12, 152–159.Google Scholar
152. Sutherland, ER, Goleva, E, King, TS, et al. (2012) Cluster analysis of obesity and asthma phenotypes. PLOS ONE 7, e36631.Google Scholar
153. Lang, JE, Hossain, J, Dixon, AE, et al. (2011) Does age impact the obese asthma phenotype? Longitudinal asthma control, airway function, and airflow perception among mild persistent asthmatics. Chest 140, 1524–1533.Google Scholar
154. Visness, CM, London, SJ, Daniels, JL, et al. (2010) Association of childhood obesity with atopic and nonatopic asthma: results from the National Health and Nutrition Examination Survey 1999–2006. J Asthma 47, 822–829.Google Scholar
155. Forno, E, Lescher, R, Strunk, R, et al. (2011) Decreased response to inhaled steroids in overweight and obese asthmatic children. J Allergy Clin Immunol 127, 741–749.Google Scholar
156. Quinto, KB, Zuraw, BL, Poon, KY, et al. (2011) The association of obesity and asthma severity and control in children. J Allergy Clin Immunol 128, 964–969.Google Scholar
157. Rastogi, D, Canfield, SM, Andrade, A, et al. (2012) Obesity-associated asthma in children: a distinct entity. Chest 141, 895–905.Google Scholar
158. Jung, KH, Perzanowski, M, Rundle, A, et al. (2014) Polycyclic aromatic hydrocarbon exposure, obesity and childhood asthma in an urban cohort. Environ Res 128, 35–41.Google Scholar