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Early-onset obesity dysregulates pulmonary adipocytokine/insulin signaling and induces asthma-like disease in mice.

ABSTRACT: Childhood obesity is a risk factor for asthma, but the molecular mechanisms linking both remain elusive. Since obesity leads to chronic low-grade inflammation and affects metabolic signaling we hypothesized that postnatal hyperalimentation (pHA) induced by maternal high-fat-diet during lactation leads to early-onset obesity and dysregulates pulmonary adipocytokine/insulin signaling, resulting in metabolic programming of asthma-like disease in adult mice. Offspring with pHA showed at postnatal day 21 (P21): (1) early-onset obesity, greater fat-mass, increased expression of IL-1?, IL-23, and Tnf-?, greater serum leptin and reduced glucose tolerance than Control (Ctrl); (2) less STAT3/AMPK?-activation, greater SOCS3 expression and reduced AKT/GSK3?-activation in the lung, indicative of leptin resistance and insulin signaling, respectively; (3) increased lung mRNA of IL-6, IL-13, IL-17A and Tnf-?. At P70 body weight, fat-mass, and cytokine mRNA expression were similar in the pHA and Ctrl, but serum leptin and IL-6 were greater, and insulin signaling and glucose tolerance impaired. Peribronchial elastic fiber content, bronchial smooth muscle layer, and deposition of connective tissue were not different after pHA. Despite unaltered bronchial structure mice after pHA exhibited significantly increased airway reactivity. Our study does not only demonstrate that early-onset obesity transiently activates pulmonary adipocytokine/insulin signaling and induces airway hyperreactivity in mice, but also provides new insights into metabolic programming of childhood obesity-related asthma.

SUBMITTER: Dinger K

PROVIDER: S-EPMC4834579 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Early-onset obesity dysregulates pulmonary adipocytokine/insulin signaling and induces asthma-like disease in mice.

Dinger Katharina K Kasper Philipp P Hucklenbruch-Rother Eva E Vohlen Christina C Jobst Eva E Janoschek Ruth R Bae-Gartz Inga I van Koningsbruggen-Rietschel Silke S Plank Christian C Dötsch Jörg J Alejandre Alcázar Miguel Angel MA

Scientific reports 20160418

Childhood obesity is a risk factor for asthma, but the molecular mechanisms linking both remain elusive. Since obesity leads to chronic low-grade inflammation and affects metabolic signaling we hypothesized that postnatal hyperalimentation (pHA) induced by maternal high-fat-diet during lactation leads to early-onset obesity and dysregulates pulmonary adipocytokine/insulin signaling, resulting in metabolic programming of asthma-like disease in adult mice. Offspring with pHA showed at postnatal da ...[more]

PMID: 27087690

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Project description:Studies of asthma phenotypes have identified obesity as a component of a group characterized by a high proportion of subjects with adult-onset asthma. However, whether age of asthma onset modifies the association between obesity and asthma is unknown.We sought to compare the associations between body mass index (BMI) categories with physiological, inflammatory, and clinical parameters across age of asthma onset phenotypes; and to compare the rate of BMI change in relation to asthma duration, by age of onset asthma phenotypes.From the Severe Asthma Research Program, we defined age of asthma onset as early (<12 years of age) and late (?12 years of age). Comparisons of BMI categories were done within age-of-onset groups, and obesity was also compared across these groups. Multivariable logistic regression analysis was done to evaluate the association between BMI categories with health care use and respiratory symptoms and multivariable linear regression for the association between duration of asthma and weight gain (BMI change per year). An interaction between obesity and age of asthma onset was included in the multivariable analyses.The study population consisted of 1049 subjects, and the median age for asthma onset was 10 years (interquartile range, 4-25 years); 48% had late-onset asthma (?12 years of age), and 52% had early-onset asthma (<12 years of age). Compared with obese subjects with late-onset asthma, obese subjects with early-onset asthma had more airway obstruction, bronchial hyperresponsiveness, and higher odds ratios of ever having 3 or more previous oral steroid tapers per year or intensive care unit admissions for asthma per preceding year (interactions between obesity and age of asthma onset were P = .055 and P = .02, respectively). In subjects with early-onset asthma but not in subjects with late-onset asthma, there was a significant association between increasing BMI and duration of asthma after adjusting for confounders. The interaction between asthma duration and age of asthma onset was a P value of less than .01.Asthmatic subjects are differentially affected by obesity based on whether they had asthma early (<12 years of age) or later in life. These results highlight the need to understand obesity as a comorbidity that affects specific clinical phenotypes and not all asthma subjects alike.

Project description:Prevention strategies that delay the onset of asthma may improve clinical outcomes. To identify early life environmental exposures associated with asthma age-of-onset and potential genetic modifiers of these exposures, we studied 1085 subjects with physician-diagnosed asthma and disease onset at or after age two. Subjects reported retrospectively on their exposure to 17 environmental factors before the age of two. The presence of individual or combinations of these early life exposures was then tested for association with variation in asthma age-of-onset. For exposures significantly associated with age-of-onset, we tested if 26 single nucleotide polymorphisms (SNP) with an established association with allergic disease significantly modified the effect of the exposure. Five environmental exposures were significantly associated with variation in asthma age-of-onset after correction for multiple testing: carpet at home (P = 6 × 10(-5)), a serious chest illness (P = 10(-4)), father a cigarette smoker (P = 6 × 10(-4)) and direct exposure to father's smoking (P = 3 × 10(-4)). Individuals with early childhood asthma onset, between the ages of two and six, were 1.4-fold (CI 1.1-1.9) more likely to report having lived in a house with carpet and 2.1-fold (CI 1.3-3.5) more likely to report suffering a serious chest illness before the age of two, than asthmatics with later disease onset. We further found these individual risks to increase to 3.2-fold (CI 1.7-6.0) if carpet exposure and suffering a serious chest illness co-occurred before age two. Paternal smoking exposures were less likely to be reported by asthmatics with early when compared to later disease onset (OR 0.5, CI 0.3-0.7). There were no significant SNP interactions with these environmental exposures after correction for multiple testing. Our results suggest that disease onset in individuals at a high-risk of developing asthma can potentially be delayed by avoiding exposure to carpet at home and preventing serious chest illnesses during the first 2 years of life.

Dataset Information

Early-onset obesity dysregulates pulmonary adipocytokine/insulin signaling and induces asthma-like disease in mice.

Publications

Early-onset obesity dysregulates pulmonary adipocytokine/insulin signaling and induces asthma-like disease in mice.

Similar Datasets

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