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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 with early-onset obesity leads to greater airway resistance in murine model at postnatal day (P70) despite unaltered bronchial structure.(A) Airway resistance (Res) after methacholine stimulation measured by direct plethysmography. Exposure of the mice at postnatal day 70 (P70) to PBS, followed by methacholine: 6.25 mg/ml and 12.5 mg/ml. Res was significantly increased after methacholine stimulation at P70 in the group with early postnatal hyperalimentation (pHAmousegroup, n = 14 from 4 litters; open square) compared to the Ctrl (Ctrl, n = 9 from 6 litters; solid square); two-way ANOVA and Bonferroni posttest. (B) Minute volume and (C) tidal volume were measured during direct plethysmography; Mann Whitney test. pHAmouse group: white bar; Ctrl: black bar; Mean ± SEM; Significance for each bar is indicated by p values. (D) Representative images of bronchi stained for α-smooth muscle actin (α-SMA) as an indicator of smooth muscle cells. Summary data for (E) measurement of the thickness of the bronchial smooth muscle layer (bSML) in the Ctrl-group and in the pHAmouse-group at P70; (F) ratio of thickness of the bSML and bronchial wall thickness; (G) diameter of the lumen of the bronchi. Only bronchi with 100–200 μm diameter were used for assessment of bSML and bronchial wall thickness. pHAmousegroup (n = 6 from 4 litterss): white bar; Ctrl (n = 6 from 5 litterss): black bar. Mean ± SEM; Mann Whitney test. *p < 0.05, **p < 0.01; n.s. = not significant.
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f8: Early postnatal hyperalimentation pHA with early-onset obesity leads to greater airway resistance in murine model at postnatal day (P70) despite unaltered bronchial structure.(A) Airway resistance (Res) after methacholine stimulation measured by direct plethysmography. Exposure of the mice at postnatal day 70 (P70) to PBS, followed by methacholine: 6.25 mg/ml and 12.5 mg/ml. Res was significantly increased after methacholine stimulation at P70 in the group with early postnatal hyperalimentation (pHAmousegroup, n = 14 from 4 litters; open square) compared to the Ctrl (Ctrl, n = 9 from 6 litters; solid square); two-way ANOVA and Bonferroni posttest. (B) Minute volume and (C) tidal volume were measured during direct plethysmography; Mann Whitney test. pHAmouse group: white bar; Ctrl: black bar; Mean ± SEM; Significance for each bar is indicated by p values. (D) Representative images of bronchi stained for α-smooth muscle actin (α-SMA) as an indicator of smooth muscle cells. Summary data for (E) measurement of the thickness of the bronchial smooth muscle layer (bSML) in the Ctrl-group and in the pHAmouse-group at P70; (F) ratio of thickness of the bSML and bronchial wall thickness; (G) diameter of the lumen of the bronchi. Only bronchi with 100–200 μm diameter were used for assessment of bSML and bronchial wall thickness. pHAmousegroup (n = 6 from 4 litterss): white bar; Ctrl (n = 6 from 5 litterss): black bar. Mean ± SEM; Mann Whitney test. *p < 0.05, **p < 0.01; n.s. = not significant.

Mentions: To determine whether a dysregulation of insulin and adipocytokine signaling as a result of early pHA affects long-term lung function we assessed airway resistance (Res) in adulthood, performing direct plethysmography at P70. The pHAmouse group exhibited a significant greater airway Res and airway hyperresponsiveness after methacholine stimulation when compared to the Ctrl-group (Fig. 8A). Minute volume (Fig. 8B) and tidal volume (Fig. 8C) were similar in the pHAmouse group and Ctrl. Moreover, assessment of respiratory dynamic compliance (Cdyn) to determine elasticity of the lung did show a slight, but not significant increase (supplemental Fig. 1C).


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 with early-onset obesity leads to greater airway resistance in murine model at postnatal day (P70) despite unaltered bronchial structure.(A) Airway resistance (Res) after methacholine stimulation measured by direct plethysmography. Exposure of the mice at postnatal day 70 (P70) to PBS, followed by methacholine: 6.25 mg/ml and 12.5 mg/ml. Res was significantly increased after methacholine stimulation at P70 in the group with early postnatal hyperalimentation (pHAmousegroup, n = 14 from 4 litters; open square) compared to the Ctrl (Ctrl, n = 9 from 6 litters; solid square); two-way ANOVA and Bonferroni posttest. (B) Minute volume and (C) tidal volume were measured during direct plethysmography; Mann Whitney test. pHAmouse group: white bar; Ctrl: black bar; Mean ± SEM; Significance for each bar is indicated by p values. (D) Representative images of bronchi stained for α-smooth muscle actin (α-SMA) as an indicator of smooth muscle cells. Summary data for (E) measurement of the thickness of the bronchial smooth muscle layer (bSML) in the Ctrl-group and in the pHAmouse-group at P70; (F) ratio of thickness of the bSML and bronchial wall thickness; (G) diameter of the lumen of the bronchi. Only bronchi with 100–200 μm diameter were used for assessment of bSML and bronchial wall thickness. pHAmousegroup (n = 6 from 4 litterss): white bar; Ctrl (n = 6 from 5 litterss): black bar. Mean ± SEM; Mann Whitney test. *p < 0.05, **p < 0.01; n.s. = not significant.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f8: Early postnatal hyperalimentation pHA with early-onset obesity leads to greater airway resistance in murine model at postnatal day (P70) despite unaltered bronchial structure.(A) Airway resistance (Res) after methacholine stimulation measured by direct plethysmography. Exposure of the mice at postnatal day 70 (P70) to PBS, followed by methacholine: 6.25 mg/ml and 12.5 mg/ml. Res was significantly increased after methacholine stimulation at P70 in the group with early postnatal hyperalimentation (pHAmousegroup, n = 14 from 4 litters; open square) compared to the Ctrl (Ctrl, n = 9 from 6 litters; solid square); two-way ANOVA and Bonferroni posttest. (B) Minute volume and (C) tidal volume were measured during direct plethysmography; Mann Whitney test. pHAmouse group: white bar; Ctrl: black bar; Mean ± SEM; Significance for each bar is indicated by p values. (D) Representative images of bronchi stained for α-smooth muscle actin (α-SMA) as an indicator of smooth muscle cells. Summary data for (E) measurement of the thickness of the bronchial smooth muscle layer (bSML) in the Ctrl-group and in the pHAmouse-group at P70; (F) ratio of thickness of the bSML and bronchial wall thickness; (G) diameter of the lumen of the bronchi. Only bronchi with 100–200 μm diameter were used for assessment of bSML and bronchial wall thickness. pHAmousegroup (n = 6 from 4 litterss): white bar; Ctrl (n = 6 from 5 litterss): black bar. Mean ± SEM; Mann Whitney test. *p < 0.05, **p < 0.01; n.s. = not significant.
Mentions: To determine whether a dysregulation of insulin and adipocytokine signaling as a result of early pHA affects long-term lung function we assessed airway resistance (Res) in adulthood, performing direct plethysmography at P70. The pHAmouse group exhibited a significant greater airway Res and airway hyperresponsiveness after methacholine stimulation when compared to the Ctrl-group (Fig. 8A). Minute volume (Fig. 8B) and tidal volume (Fig. 8C) were similar in the pHAmouse group and Ctrl. Moreover, assessment of respiratory dynamic compliance (Cdyn) to determine elasticity of the lung did show a slight, but not significant increase (supplemental Fig. 1C).

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