Obesity-related Asthma Research Articles

Metformin prevents airway hyperreactivity in rats with dietary obesity.

Increased insulin is associated with obesity-related airway hyperreactivity and asthma. We tested whether the use of metformin, an antidiabetic drug used to reduce insulin resistance, can reduce circulating insulin, thereby preventing airway hyperreactivity in rats with dietary obesity. Male and female rats were fed a high- or low-fat diet for 5 wk. Some male rats were simultaneously treated with metformin (100 mg/kg orally). In separate experiments, after 5 wk of a high-fat diet, some rats were switched to a low-fat diet, whereas others continued a high-fat diet for an additional 5 wk. Bronchoconstriction and bradycardia in response to bilateral electrical vagus nerve stimulation or to inhaled methacholine were measured in anesthetized and vagotomized rats. Body weight, body fat, caloric intake, fasting glucose, and insulin were measured. Vagally induced bronchoconstriction was potentiated only in male rats on a high-fat diet. Males gained more body weight, body fat, and had increased levels of fasting insulin compared with females. Metformin prevented development of vagally induced airway hyperreactivity in male rats on high-fat diet, in addition to inhibiting weight gain, fat gain, and increased insulin. In contrast, switching rats to a low-fat diet for 5 wk reduced body weight and body fat, but it did not reverse fasting glucose, fasting insulin, or potentiation of vagally induced airway hyperreactivity. These data suggest that medications that target insulin may be effective treatment for obesity-related asthma.

Different Phenotypes in Asthma: Clinical Findings and Experimental Animal Models.

Asthma is a respiratory allergic disease presenting a high prevalence worldwide, and it is responsible for several complications throughout life, including death. Fortunately, asthma is no longer recognized as a unique manifestation but as a very heterogenic manifestation. Its phenotypes and endotypes are known, respectively, as pathologic and molecular features that might not be directly associated with each other. The increasing number of studies covering this issue has brought significant insights and knowledge that are constantly expanding. In this review, we intended to summarize this new information obtained from clinical studies, which not only allowed for the creation of patient clusters by means of personalized medicine and a deeper molecular evaluation, but also created a connection with data obtained from experimental models, especially murine models. We gathered information regarding sensitization and trigger and emphasizing the most relevant phenotypes and endotypes, such as Th2-high asthma and Th2-low asthma, which included smoking and obesity-related asthma and mixed and paucigranulocytic asthma, not only in physiopathology and the clinic but also in how these phenotypes can be determined with relative similarity using murine models. We also further investigated how clinical studies have been treating patients using newly developed drugs focusing on specific biomarkers that are more relevant according to the patient's clinical manifestation of the disease.

Pioglitazone prevents obesity-related airway hyperreactivity and neuronal M2 receptor dysfunction.

Obesity-related asthma often presents with more severe symptoms than non-obesity-related asthma and responds poorly to current treatments. Both insulin resistance and hyperinsulinemia are common in obesity. We have shown that increased insulin mediates airway hyperreactivity in diet-induced obese rats by causing neuronal M2 muscarinic receptor dysfunction, which normally inhibits acetylcholine release from parasympathetic nerves. Decreasing insulin with streptozotocin prevented airway hyperreactivity and M2 receptor dysfunction. The objective of the present study was to investigate whether pioglitazone, a hypoglycemic drug, prevents airway hyperreactivity and M2 receptor dysfunction in obese rats. Male rats fed a low- or high-fat diet were treated with pioglitazone or PBS by daily gavage. Body weight, body fat, fasting insulin, and bronchoconstriction and bradycardia in response to electrical stimulation of vagus nerves and to aerosolized methacholine were recorded. Pilocarpine, a muscarinic receptor agonist, was used to measure M2 receptor function. Rats on a high-fat diet had potentiated airway responsiveness to vagal stimulation and dysfunctional neuronal M2 receptors, whereas airway responsiveness to methacholine was unaffected. Pioglitazone reduced fasting insulin and prevented airway hyperresponsiveness and M2 receptor dysfunction but did not change inflammatory cytokine mRNA expression in alveolar macrophages. High-fat diet, with and without pioglitazone, had tissue-specific effects on insulin receptor mRNA expression. In conclusion, pioglitazone prevents vagally mediated airway hyperreactivity and protects neuronal M2 muscarinic receptor function in obese rats.

Associations of TNFA, IL17A, and RORC mRNA expression levels in peripheral blood leukocytes with obesity-related asthma in adolescents

Obesity is associated with a unique non-T2 asthma phenotype, characterised by a Th17 immune response. Retinoid-related orphan receptor C (RORC) is the master transcription factor for Th17 polarisation. We investigated the association of TNFA, IL17A, and RORC mRNA expression levels with the non-T2 phenotype. We conducted a cross-sectional study in adolescents, subdivided as follows: healthy (HA), allergic asthma without obesity (AA), obesity without asthma (OB), and non-allergic asthma with obesity (NAO). TNFA, IL17A, and RORC mRNA expression in peripheral blood leukocytes were assessed by RT-PCR. NAO exhibited higher TNFA mRNA expression levels than HA or OB, as well as the highest IL17A and RORC mRNA expression levels among the four groups. The best biomarker for discriminating non-allergic asthma among obese adolescents was RORC mRNA expression levels (area under the curve: 0.95). RORC mRNA expression levels were associated with the non-T2 asthma phenotype, hinting at a therapeutic target in obesity-related asthma.

Obesity-related asthma in children: A role for vitamin D.

Excess adipose tissue predisposes to an enhanced inflammatory state and can contribute to the pathogenesis and severity of asthma. Vitamin D has anti-inflammatory properties and low-serum levels are seen in children with asthma and in children with obesity. Here we review the intersection of asthma, obesity, and hypovitaminosis D in children. Supplementation with vitamin D has been proposed as a simple, safe, and inexpensive adjunctive therapy in a number of disease states. However, little research has examined the pharmacokinetics of vitamin D and its therapeutic potential in children who suffer from obesity-related asthma.

Effects of Age, Sex, Race/Ethnicity, and Allergy Status in Obesity-Related Pediatric Asthma

JE Lang, HT Bunnell, JJ Lima. Pediatr Pulmonol. 2019;54(11):1684–1693 To determine the relationship between obesity and asthma incidence and assess the impact of age, gender, race/ethnicity and allergic status. The study included 507 496 children ages 2–17 years. Children without a history of asthma prior to the pre-defined study start date were included and overweight or obese children were 1:1 matched with healthy weight children. This was a large retrospective cohort study from 8 Pediatric institutions in the United States that were a part of PEDSNet (National Pediatric Clinical Network for Research), utilizing data through the Observational Health Data Sciences and Informatics (OHDSI) common data model from …

Atopy and pulmonary function among healthy-weight and overweight/obese children with asthma.

Epidemiologic studies have found low/absence of atopy in obese asthmatic children, but the association or lack thereof of atopy with disease morbidity, including pulmonary function, in obese asthma is not well understood. We sought to define the association of atopy with pulmonary function in overweight/obese minority children with asthma. In a retrospective chart review of 200 predominantly minority children evaluated at an academic Pediatric Asthma Center over 5 years, we compared the prevalence of atopy, defined as 1 positive skin prick test or serum-specific immunoglobulin E quantification to environmental allergens, and its association with pulmonary function in overweight/obese (body mass index [BMI] > 85th percentile) (n = 99) to healthy-weight children (BMI, 5th-85thpercentile for age) (n = 101). In a cohort comprised of 47.5% Hispanics and 39.5% African Americans, 81% of overweight/obese and 74% of healthy-weight children were atopic. While atopic healthy-weight children had lower percent-predicted forced expiratory volume in the first second (FEV1 ) (93 ± 13.6 vs 107% ± 33.2%, P = .03) and lower percent-predicted forced vital capacity (FVC) (93% ± 12.2% vs 104% ± 16.1%, P = .01) as compared to nonatopic children, atopy was not associated with FEV1 (P = .7) or FVC (P = .17) in overweight/obese children. Adjusting for demographic and clinical variables, atopy was found to be an independent predictor of FEV1 and FVC in healthy-weight (β = -2.4, P = .07 and β = -1.7, P = .04, respectively) but not in overweight/obese children (β = .6, P = .5 and β = .8, P = .3). Atopy is associated with lower lung function in healthy-weight asthmatics but not in overweight/obese asthmatics, supporting the role of nonallergic mechanisms in disease burden in pediatric obesity-related asthma.

Metabolic Dysfunction and Asthma: Current Perspectives.

The increasing knowledge of the mechanisms involved in metabolism is shifting the paradigms by which the pathophysiology of many pulmonary diseases is understood. Metabolic dysfunction is recognized in obesity-associated asthma, but other metabolic conditions have been shown to be independently related to asthma. Novel insights have also recently been brought by metabolomics in this filed. The purpose of this review is to discuss current perspectives regarding metabolic dysfunction in asthma, from obesity-related asthma to other metabolic conditions and the role of current pharmacological therapeutic strategies and lifestyle interventions. Obesity is a well-recognized risk factor for asthma across the lifespan, which is generally associated with poorer response to current available treatments, rendering a more severe, refractory disease status. Besides the epidemiological and clinical link, untargeted metabolomics studies have recently supported the obesity-associated asthma phenotype at the molecular level. Not only obesity-related, but also other aspects of metabolic dysregulation can be independently linked to asthma. These include hyperinsulinemia, dyslipidemia and hypertension, which need to be taken into account, even in the non-obese patient. Untargeted metabolomics studies have further highlighted several other metabolic pathways that can be altered in asthma, namely regarding oxidative stress and systemic inflammation, and also suggesting the importance of microbiota in asthma pathogenesis. Considering the reduced response to corticosteroids, other pharmacologic treatments have been shown to be effective regardless of body mass index. Non-pharmacologic treatments (namely weight reduction and dietary changes) may bring substantial benefit to the asthmatic patient. Taken together, this evidence points towards the need to improve our knowledge in this filed and, in particular, to address the influence of environmental factors in metabolic dysfunction and asthma development. Personalized medicine is definitely needed to optimize treatment, including a holistic view of the asthmatic patient in order to set accurate pharmacologic therapy together with dietary, physical exercise and lifestyle interventions.

Obesity-related asthma in children is characterized by T-helper 1 rather than T-helper 2 immune response: A meta-analysis

BackgroundAsthma is a chronic inflammatory condition characterized by T-helper (TH) 2 polarization. In children, the prevalence of obesity is associated with an increased incidence of asthma. Notably, obesity is linked with TH1-mediated inflammation and has been identified as a major risk factor for asthma. ObjectiveTo investigate the impact of obesity on TH1 (tumor necrosis factor α, interferon gamma, interleukin (IL)-6, IL-8) and TH2 (IL-4, IL-5, IL-10, IL-13) immune responses in children with asthma. MethodsWe searched the MEDLINE and gray literature electronic databases for eligible studies from inception up until April 2020. The quality of included studies and evidence was independently assessed by 2 reviewers. The random-effects model was used in this meta-analysis, and outcomes were reported as standardized mean difference (SMD) and 95% confidence interval (CI). ResultsOverall, 5 studies comprising 482 participants met the inclusion criteria. The meta-analysis revealed an increased TH2-mediated immune response in lean people with asthma compared with controls without asthma (SMD: −1.15 [95% CI: −1.93, 0.36]; I2 = 93%; pH < .001). However, in obese people with asthma, there was polarization toward TH1 immune response compared with lean people with asthma (SMD: −0.43 [95% CI: −0.79, −0.08]; I2 = 88%, pH < .001). ConclusionThis meta-analysis reveals that there are differences in immune responses mediated by T-helper cells in lean and obese children with asthma. Moreover, and not unique to asthma, obesity polarizes the immune response toward TH1 rather than the classical TH2. This could be an important aspect to understand to establish effective therapeutic targets for obese children with asthma.

Association of asthma and its genetic predisposition with the risk of severe COVID-19

Summary In a large population-based cohort data, adults with asthma had a higher risk of severe COVID-19, which was driven by the increased risk among patients with non-allergic asthma.

Cross talk between Hsp72, HMGB1 and RAGE/ERK1/2 signaling in the pathogenesis of bronchial asthma in obese patients.

The incidence of obesity-related asthma has shown a remarkable increase. We aimed to explore the role of heat shock protein 72 (Hsp72) and receptor for advanced glycation end products (RAGE) axis with its downstream signaling in the pathogenesis of obesity-related asthma. We enrolled a total of 55 subjects and divided them into three groups. Groups I and II included healthy, normal weight (n = 15) and obese (n = 15) subjects, respectively. Twenty-five obese asthmatics (group III) were subdivided into group IIIa (10 patients with mild to moderate asthma) and group IIIb (15 patients with severe asthma). High mobility group box 1 (HMGB1), interleukin 8 (IL-8), monocyte chemoattractant protein 1 (MCP-1), extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), and urinary Hsp72 were immunoassayed. Hydrogen peroxide (H2O2) and free fatty acids (FFAs) levels were photometrically measured. RAGE mRNA expression was relatively quantified by real-time PCR. We found significant elevations of serum HMGB1, IL-8, MCP1, ERK1/2, FFAs, and H2O2 levels as well as urinary Hsp72 levels in obese subjects compared to healthy control. These were more evident in patients with severe asthma (group IIIb). Multivariate regression analysis identified Hsp72 and ERK1/2 as independent predictors of bronchial asthma severity. Receiver operating characteristic (ROC) curve analysis revealed that areas under the curve (AUC) for Hsp72 and ERK1/2 were 0.991 and 0.981, respectively, which denotes a strong predictive value for identifying the severity of bronchial asthma in obese patients. The current study highlights the role of Hsp72 and HMGB1/RAGE/ERK1/2 signaling cascade in the pathogenesis of bronchial asthma and its link to obesity, which could be reflected on monitoring, severity grading, and management of this disease.

Pediatric obesity-related asthma: A prototype of pediatric severe non-T2 asthma.

Childhood obesity contributes to many diseases, including asthma. There is literature to suggest that asthma developing as a consequence of obesity has a nonallergic or non-T2 phenotype. In this review, obesity-related asthma is utilized as a prototype of non-T2 asthma in children to discuss several nonallergic mechanisms that underlie childhood asthma. Obesity-related asthma is associated with systemic T helper (Th)1 polarization occurring with monocyte activation. These immune responses are mediated by insulin resistance and dyslipidemia, metabolic abnormalities associated with obesity, that are themselves associated with pulmonary function deficits in obese asthmatics. As in other multifactorial diseases, there is both a genetic and an environmental contribution to pediatric obesity-related asthma. In addition to genetic susceptibility, differential DNA methylation is associated with non-T2 immune responses in pediatric obesity-related asthma. Initial investigations into the biology of non-T2 immune responses have identified the upregulation of genes in the CDC42 pathway. CDC42 is a RhoGTPase that plays a key role in Th cell physiology, including preferential naïve Th cell differentiation to Th1 cells, and cytokine production and exocytosis. Although these novel pathways are promising findings to direct targeted therapy development for obesity-related asthma to address the disease burden, there is evidence to suggest that dietary interventions, including diet modification, rather than caloric restriction alone, decrease disease burden. Adoption of a diet rich in micronutrients, including carotenoids and 25-OH cholecalciferol, a vitamin D metabolite, may be beneficial since these are positively correlated with pulmonary function indices, while being protective against metabolic abnormalities associated with the obese asthma phenotype.

Shared genetic and experimental links between obesity-related traits and asthma subtypes in UK Biobank

Clinical and epidemiologic studies have shown that obesity is associated with asthma and that these associations differ by asthma subtype. Little is known about the shared genetic components between obesity and asthma. We sought to identify shared genetic associations between obesity-related traits and asthma subtypes in adults. A cross-trait genome-wide association study (GWAS) was performed using 457,822 subjects of European ancestry from the UK Biobank. Experimental evidence to support the role of genes significantly associated with both obesity-related traits and asthma through a GWAS was sought by using results from obese versus lean mouse RNA sequencing and RT-PCR experiments. We found a substantial positive genetic correlation between body mass index and later-onset asthma defined by asthma age of onset at 16 years or greater (Rg= 0.25, P= 9.56×10-22). Mendelian randomization analysis provided strong evidence in support of body mass index causally increasing asthma risk. Cross-trait meta-analysis identified 34 shared loci among 3 obesity-related traits and 2 asthma subtypes. GWAS functional analyses identified potential causal relationships between the shared loci and Genotype-Tissue Expression (GTEx) quantitative trait loci and shared immune- and cell differentiation-related pathways between obesity and asthma. Finally, RNA sequencing data from lungs of obese versus control mice found that 2 genes (acyl-coenzyme Aoxidase-like [ACOXL] and myosin light chain 6 [MYL6]) from the cross-trait meta-analysis were differentially expressed, and these findings were validated by using RT-PCR in an independent set of mice. Our work identified shared genetic components between obesity-related traits and specific asthma subtypes, reinforcing the hypothesis that obesity causally increases the risk of asthma and identifying molecular pathways that might underlie both obesity and asthma.

Pravastatin alleviates allergic airway inflammation in obesity-related asthma mouse model

Background: Obesity is one of the factors associated with severe, uncontrolled asthma. The effect of pravastatin on asthmatic airway inflammation in obesity has not been evaluated. Methods: C57BL/6 mice were fed a high-fat diet (HFD) to induce obesity with or without ovalbumin (OVA) sensitization and challenge. Pravastatin was administered intraperitoneally during the OVA treatment. Airway inflammation and airway hyper-responsiveness (AHR) were analyzed and lung tissues were examined. The changes in mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways were measured in the lung tissues. Results: HFD with OVA sensitization and challenge exacerbated eosinophilic and neutrophilic airway inflammation and increased AHR compared to lean asthma mice. The levels of cytokines examined in bronchoalveolar lavage fluid (BALF) revealed that the expressions of IL-4, 5, and 17 were elevated in the obese asthmatic group and decreased after pravastatin treatment, indicating that both the Th2 and Th17 pathways were stimulated by HFD-induced obesity and OVA challenge and suppressed by pravastatin treatment. Moreover, the serum leptin and adiponectin ratio was elevated only in obese asthmatic mice and decreased with pravastatin administration. Pravastatin successfully alleviated the airway inflammation of lung tissues and AHR in both obese and lean asthmatic mice, however, treatment with pravastatin had no effects on BALF cell counts and cytokines in lean asthma mice. In lung tissues, the phosphorylation of p38 MAPK was significantly decreased in lean as well as obese asthmatic mice. Conclusions: Pravastatin treatment in obese asthmatic mice suppressed allergic airway infiltration and AHR by inhibition of Th2 and Th17-associated signaling pathways, decreasing the leptin expression and downstream p38 MAPK signaling pathways. The effect on lean asthmatic mice was different, independent of airway cell counts and cytokines.

Effects of age, sex, race/ethnicity, and allergy status in obesity-related pediatric asthma.

Obesity in children increases the risk for new asthma. How age, sex, race/ethnicity, and allergy status affect the relationship between obesity and asthma is unclear. This study describes the relationship between high body mass index (BMI) and incident asthma. We conducted a retrospective cohort study to compare asthma incidence among normal weight, overweight, and obese 2 to 6, 7 to 11, and 12 to 17 year olds to define the effects of sex, race/ethnicity, and allergy status. Weight status was determined at baseline and asthma incidence was defined as ≥2 asthma encounters and ≥1 asthma prescriptions. We used multivariable Poisson regression to estimate adjusted incident asthma rates and risk ratios. Data from 192 843 2 to 6 year olds, 157 284 7 to 11 year olds, and 157 369 12 to 17 year olds were included. The relative risks (95% confidence interval [CI]) of new asthma among obese children in 2 to 6 year olds, 7 to 11 year olds, and 12 to 17 year olds were 1.25 (1.15, 1.37), 1.49 (1.32, 1.69) and 1.40 (1.21, 1.63), respectively. Among children with underlying allergic rhinitis, obesity did not increase the risk of new asthma. In children without allergic rhinitis, the risk for obesity-related asthma was highest in 7 to 11 year olds (risk ratio = 1.50 95% CI, 1.33, 1.60). Before age 12, females had a higher risk for obesity-related asthma; but after age 12, obese males had a higher asthma risk (interaction P-value < .05). Obesity is a major preventable risk factor for pediatric asthma that appears to vary along the pediatric age continuum and depends on sex, race/ethnicity and atopy status.

Pulmonary Function should be the Surveillance Tool in Obese Children to Prevent Asthma

ObjectiveTo investigate the important mediator linking from obesity to childhood asthmaIntroductionThe mediating pathways in the obesity-asthma link are largely unknown. We aimed to investigate the mediating pathways and to search for the most prominent pathological mechanism between central obesity and childhood asthma.MethodsIn Taiwan Children Health Study, we collected data on an open cohort of children ranged from 9 to 13 years old. Children's respiratory outcomes, atopic conditions, obesity measures, and pulmonary function were surveyed annually between 2010 and 2012. Fractional exhaled nitric oxide concentrations were recorded in 2012. Generalized estimating equations and general linear models were used to examine the associations among central obesity, possible mediators, and asthma. Structural equation models were applied to investigate the pathways that mediate the link between central obesity and asthma.ResultsCentral obesity (waist-to-hip ratio) most accurately predicted childhood asthma. In the model of active asthma, the percentage of mediation was 28.6% for pulmonary function, 18.1% for atopy, and 5.7% for airway inflammation. The percentage of mediation for pulmonary function was 40.2% in the model of lifetime wheeze. Pulmonary function was responsible for the greatest percentage of mediation among the three mediators in both models.ConclusionsDecline in pulmonary function is the most important pathway in central obesity–related asthma. Pulmonary function surveillance should be applied to obese children for asthma risk prediction.

Actualités physiopathologiques et thérapeutiques dans l’asthme sévère

Asthma is an inflammatory airway disease which presentation is highly heterogeneous. Last two decades provided new clinical and basic data concerning asthma physiopathology that make global understanding much complex. Phenotypes based on clinical settings and paraclinical investigations from large cohorts confirm old paradigm (eosinophilic vs. non-eosinophilic asthma) but also introduce new concepts (obesity-related asthma, late onset asthma, etc.). Conversely, improvement of big data analytics allows to initiate new cohorts aiming at better understanding the pathophysiology underlying those phenotypes and unraveling new ones. However, clinical and therapeutic impacts of those big data need to be further detailed. In parallel, biotherapies and innovative techniques as bronchial thermoplasty become available for severe asthmatic patients who did not respond to specific treatment in the past. Development of a personalized medicine in severe asthma becomes an important challenge for tomorrow. This review will focus on new pathophysiological concepts arisen from large cohorts and new therapeutic strategies available and in progress for severe asthma.

Carotenoids, fatty acids and disease burden in obese minority adolescents with asthma

Paediatric obesity-related asthma causes high disease burden, is associated with metabolic abnormalities, has few therapeutic options, and disproportionately affects urban minority children. Although poor diet quality is linked to asthma, the association of nutritional status with disease burden among children with obesity-related asthma is not well understood. To quantify nutritional status, defined as concentrations of serum carotenoids and n-3 fatty acids, and its association with pulmonary function and metabolic markers among obese asthmatic children. We quantified serum carotenoids and fatty acids in a study cohort of 158 urban minority adolescents including 39 obese asthmatics, 39 healthy weight asthmatics, 38 obese controls and 42 healthy weight controls and compared between the groups. We correlated carotenoid and fatty acid levels with pulmonary function indices and with insulin resistance and dyslipidemia. Mean total carotenoids were lowest in obese asthmatic children (0.41μg/mL), lower than healthy weight asthmatics (0.52μg/mL, P<0.05) and healthy weight controls (0.60μg/mL, P<0.001). n-6/n-3 polyunsaturated fatty acid (PUFA) ratio also differed between the groups (P<0.05). Total carotenoids positively correlated with per cent-predicted FEV1 and inversely correlated with insulin resistance among obese asthmatics only. n-6/n-3 PUFA ratio inversely correlated with per cent-predicted FEV1 in obese asthmatics. Our findings suggest that carotenoids, which are lowest in obese asthmatic children, may have protective effects on metabolic health and pulmonary function among obese asthmatic children. Similarly, n-3 PUFA appear to be protective for pulmonary function.

OR01-1 Leveraging Immunometabolic Control to Prevent and Treat Obesity Related Asthma

Asthma is a chronic inflammatory disease of the airways with an increasing prevalence but limited treatment options. Although the pathogenesis is not fully understood, it has a major immunometabolic component including contribution of lipid mediators to airway inflammation. Interestingly, accumulating evidence implicates obesity as a critical risk factor for asthma where these lipid mediators are upregulated. However, how obesity leads to asthma remains a critical but poorly understood area. There is a great need for novel treatments for obesity-related asthma as this group of patients are less-responsive to conventional therapies. The fatty acid binding protein aP2 is a fundamental immunometabolic regulator, which is increased in obese mice and humans. aP2 deficiency in mice improves the dysregulated metabolic outcomes of obesity and related diseases such as diabetes and atherosclerosis, which share similar lipid derangements and immunometabolic underpinnings. Moreover, we reported that aP2 secreted from adipose tissue acts as a hormone, supporting inter-organ communication. We and others have shown that increased serum aP2 levels strongly correlate with poor metabolic, inflammatory and cardiovascular outcomes in multiple independent human studies. Lastly, humans who carry a haploinsufficiency allele of aP2 have reduced risk for developing dyslipidemia, diabetes, and cardiovascular disease. Together, these findings indicate that the biological functions of aP2 are conserved and highly relevant to human pathophysiology. Interestingly, in recent studies we detected increased expression of aP2 in lung and bronchoalveolar lavage fluid (BALF) in obese mice. Strikingly, severely obese (ob/ob) aP2 deficient mice were markedly protected against obesity-related airway hyperresponsiveness. These data strongly support that aP2 is a mediator of this unique form of airway disease associated with obesity in experimental models. To evaluate the translational implications of these observations, we measured serum aP2 in humans and found 25.4% higher aP2 concentrations (54.5 ± 19.2 vs 43.4 ± 20.1 ng/ml *p<0.05) in overweight and obese asthmatics compared to obese non-asthmatics. Importantly, higher levels of serum aP2 was positively correlated with asthma status only in overweight and obese individuals, whereas there was no significant difference between lean asthmatics vs non-asthmatics. (Groups; non-asthmatics and asthmatics BMI<25 vs BMI>25, n= 510, 15, 370, 15, respectively, analyzed by two-way ANOVA *p<0.05). The frequency of asthma was also 8% higher (50% vs 42%) in overweight and obese group as compared to lean subjects. With this line of investigation, we generated critical insights into obesity related asthma pathogenesis and showing that secreted aP2 might represent a well-validated and promising target for the development of a novel therapeutic strategy in humans.

Obesity and childhood asthma.

Asthma is a common chronic disease of the airways characterized by recurrent respiratory symptoms, bronchoreactivity, and airway inflammation. The high toll on quality of life has led to sustained efforts to understand the factors leading to asthma inception and poor disease control. Obesity is another increasingly common pediatric disease, which appears to increase the risk for incident asthma and worsened disease severity. Currently, our understanding of how obesity affects asthma risk and affects its phenotypic characteristics remains incomplete. The current review describes our current understanding of the epidemiology, clinical characteristics, and management considerations of obesity-related asthma in children. The epidemiologic relationship between obesity in children and incident asthma remains confusing despite numerous longitudinal cohort studies, and appears to be influenced by early life exposures, patterns of somatic growth and underlying familial risks of allergic disease. Children with comorbid obesity and asthma demonstrate diverse phenotypic characteristics which are still becoming clear. Like any child with asthma, a child with comorbid obesity requires an individualized approach adhering to current best-practice guidelines and an understanding of how obesity and asthma may interact.