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

Dinger K, Kasper P, Hucklenbruch-Rother E, Vohlen C, Jobst E, Janoschek R, Bae-Gartz I, van Koningsbruggen-Rietschel S, Plank C, Dötsch J, Alejandre Alcázar MA - Sci Rep (2016)

Bottom Line: Childhood obesity is a risk factor for asthma, but the molecular mechanisms linking both remain elusive.Peribronchial elastic fiber content, bronchial smooth muscle layer, and deposition of connective tissue were not different after pHA.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.

View Article: PubMed Central - PubMed

Affiliation: Experimental Pulmonology, University Hospital for Pediatrics and Adolescent Medicine, Faculty of Medicine, University of Cologne, Cologne, Germany.

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-1β, IL-23, and Tnf-α, greater serum leptin and reduced glucose tolerance than Control (Ctrl); (2) less STAT3/AMPKα-activation, greater SOCS3 expression and reduced AKT/GSK3β-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-α. 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.

No MeSH data available.


Related in: MedlinePlus

Early postnatal hyperalimentation (pHA) and early-onset obesity lead to transient increased mRNA expression of adipocytokines and persistent greater circulating concentrations of serum leptin and IL-6 in murine offspring.(A,B) Total white adipose tissue (WAT) mRNA expression of genes encoding Il-1β, Il-6, Il-23, Tnf-α, and leptin was assessed by quantitative real-time PCR at postnatal day 21 P21 (A) (Ctrl: n = 9 from 5 litters; pHAmouse: n = 11 from 6 litters) and P70 (B) (Ctrl: n = 9 from 6 litters; pHAmouse: n = 9 from 6 litters). The Ctrl was normalized to 1; early postnatal hyperalimentation (white bar; pHAmouse group). (C) Serum level of leptin (ng/ml) at P21 (Ctrl: n = 8 from 5 litters; pHAmouse: n = 8 from 6 litters) and at P70 (Ctrl: n = 7 from 6 litters; pHAmouse: n = 7 from 4 litters). (D) Serum level of IL-6 (pg/ml) at P21 (Ctrl: n = 7 from 5 litters; pHAmouse: n = 5 from 5 litters) and at P70 (Ctrl: n = 4 from 3 litters; pHAmouse: n = 5 from 2 litters). pHAmouse group: white bar, Ctrl: black bar. Mean ± SEM; Mann Whitney test (*), two way ANOVA test and Bonferroni posttest (#); *,#p < 0.05, **p < 0.01, ***p < 0.001; n.s. = not significant.
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f2: Early postnatal hyperalimentation (pHA) and early-onset obesity lead to transient increased mRNA expression of adipocytokines and persistent greater circulating concentrations of serum leptin and IL-6 in murine offspring.(A,B) Total white adipose tissue (WAT) mRNA expression of genes encoding Il-1β, Il-6, Il-23, Tnf-α, and leptin was assessed by quantitative real-time PCR at postnatal day 21 P21 (A) (Ctrl: n = 9 from 5 litters; pHAmouse: n = 11 from 6 litters) and P70 (B) (Ctrl: n = 9 from 6 litters; pHAmouse: n = 9 from 6 litters). The Ctrl was normalized to 1; early postnatal hyperalimentation (white bar; pHAmouse group). (C) Serum level of leptin (ng/ml) at P21 (Ctrl: n = 8 from 5 litters; pHAmouse: n = 8 from 6 litters) and at P70 (Ctrl: n = 7 from 6 litters; pHAmouse: n = 7 from 4 litters). (D) Serum level of IL-6 (pg/ml) at P21 (Ctrl: n = 7 from 5 litters; pHAmouse: n = 5 from 5 litters) and at P70 (Ctrl: n = 4 from 3 litters; pHAmouse: n = 5 from 2 litters). pHAmouse group: white bar, Ctrl: black bar. Mean ± SEM; Mann Whitney test (*), two way ANOVA test and Bonferroni posttest (#); *,#p < 0.05, **p < 0.01, ***p < 0.001; n.s. = not significant.

Mentions: To investigate the effect of the increase of WAT on the level of adipose tissue-originated cytokines, we assessed expression of genes encoding interleukin-1β (Il-1β), Il-6, Il-23, tumor necrosis factor-α (Tnf-α), and leptin in WAT at P21 and P70. The mRNA expression of Il-1β (p < 0.05), Il-23 (p < 0.05), Tnf-α (p < 0.05), and leptin (p < 0.05) was increased at P21 (Fig. 2A), whereas at P70 no significant changes were found in the pHA-group, when compared to Ctrl (Fig. 2B).


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

Dinger K, Kasper P, Hucklenbruch-Rother E, Vohlen C, Jobst E, Janoschek R, Bae-Gartz I, van Koningsbruggen-Rietschel S, Plank C, Dötsch J, Alejandre Alcázar MA - Sci Rep (2016)

Early postnatal hyperalimentation (pHA) and early-onset obesity lead to transient increased mRNA expression of adipocytokines and persistent greater circulating concentrations of serum leptin and IL-6 in murine offspring.(A,B) Total white adipose tissue (WAT) mRNA expression of genes encoding Il-1β, Il-6, Il-23, Tnf-α, and leptin was assessed by quantitative real-time PCR at postnatal day 21 P21 (A) (Ctrl: n = 9 from 5 litters; pHAmouse: n = 11 from 6 litters) and P70 (B) (Ctrl: n = 9 from 6 litters; pHAmouse: n = 9 from 6 litters). The Ctrl was normalized to 1; early postnatal hyperalimentation (white bar; pHAmouse group). (C) Serum level of leptin (ng/ml) at P21 (Ctrl: n = 8 from 5 litters; pHAmouse: n = 8 from 6 litters) and at P70 (Ctrl: n = 7 from 6 litters; pHAmouse: n = 7 from 4 litters). (D) Serum level of IL-6 (pg/ml) at P21 (Ctrl: n = 7 from 5 litters; pHAmouse: n = 5 from 5 litters) and at P70 (Ctrl: n = 4 from 3 litters; pHAmouse: n = 5 from 2 litters). pHAmouse group: white bar, Ctrl: black bar. Mean ± SEM; Mann Whitney test (*), two way ANOVA test and Bonferroni posttest (#); *,#p < 0.05, **p < 0.01, ***p < 0.001; n.s. = not significant.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4834579&req=5

f2: Early postnatal hyperalimentation (pHA) and early-onset obesity lead to transient increased mRNA expression of adipocytokines and persistent greater circulating concentrations of serum leptin and IL-6 in murine offspring.(A,B) Total white adipose tissue (WAT) mRNA expression of genes encoding Il-1β, Il-6, Il-23, Tnf-α, and leptin was assessed by quantitative real-time PCR at postnatal day 21 P21 (A) (Ctrl: n = 9 from 5 litters; pHAmouse: n = 11 from 6 litters) and P70 (B) (Ctrl: n = 9 from 6 litters; pHAmouse: n = 9 from 6 litters). The Ctrl was normalized to 1; early postnatal hyperalimentation (white bar; pHAmouse group). (C) Serum level of leptin (ng/ml) at P21 (Ctrl: n = 8 from 5 litters; pHAmouse: n = 8 from 6 litters) and at P70 (Ctrl: n = 7 from 6 litters; pHAmouse: n = 7 from 4 litters). (D) Serum level of IL-6 (pg/ml) at P21 (Ctrl: n = 7 from 5 litters; pHAmouse: n = 5 from 5 litters) and at P70 (Ctrl: n = 4 from 3 litters; pHAmouse: n = 5 from 2 litters). pHAmouse group: white bar, Ctrl: black bar. Mean ± SEM; Mann Whitney test (*), two way ANOVA test and Bonferroni posttest (#); *,#p < 0.05, **p < 0.01, ***p < 0.001; n.s. = not significant.
Mentions: To investigate the effect of the increase of WAT on the level of adipose tissue-originated cytokines, we assessed expression of genes encoding interleukin-1β (Il-1β), Il-6, Il-23, tumor necrosis factor-α (Tnf-α), and leptin in WAT at P21 and P70. The mRNA expression of Il-1β (p < 0.05), Il-23 (p < 0.05), Tnf-α (p < 0.05), and leptin (p < 0.05) was increased at P21 (Fig. 2A), whereas at P70 no significant changes were found in the pHA-group, when compared to Ctrl (Fig. 2B).

Bottom Line: Childhood obesity is a risk factor for asthma, but the molecular mechanisms linking both remain elusive.Peribronchial elastic fiber content, bronchial smooth muscle layer, and deposition of connective tissue were not different after pHA.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.

View Article: PubMed Central - PubMed

Affiliation: Experimental Pulmonology, University Hospital for Pediatrics and Adolescent Medicine, Faculty of Medicine, University of Cologne, Cologne, Germany.

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-1β, IL-23, and Tnf-α, greater serum leptin and reduced glucose tolerance than Control (Ctrl); (2) less STAT3/AMPKα-activation, greater SOCS3 expression and reduced AKT/GSK3β-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-α. 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.

No MeSH data available.


Related in: MedlinePlus