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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 temporo dynamically regulates murine pulmonary elastin synthesis and induces greater collagen Iα1 protein abundance.(A,B) Assessment of tropoelastin mRNA in total lung homogenate by quantitative qRT-PCR at postnatal day 21 (P21) (A) (Ctrl: n = 10 from 5 litters; pHAmouse: n = 10 from 6 litters) and at P70 (B) (Ctrl: n = 9–10 from 6 litters; pHAmouse: n = 10 from 6 litters). (C,D) Lung protein abundance of TROPOELASTIN at P21 (C) (Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters) and at P70 (D) (Ctrl: n = 5 from 4 litters; pHAmouse: n = 5 from 4 litters). β-ACTIN served as loading Control (Ctrl). Densitometric analyses below the corresponding immunoblot. (E) Representative images illustrating elastic fibers using Hart’s staining in paraffin-embedded and paraformaldehyde-fixed lungs of the Ctrl-group (left panel) and of the pHAmouse-group (right panel) at P70. Red arrows are depicting positive staining of elastic fibers of the conducting airways (100–200 μm diameter). (F) Summary data of the quantification of positive elastic fiber staining surrounding the bronchi (100–200 μm) at P70. Elastin surface density was related to bronchial wall surface; pHAmouse group: n = 6 from 4 litterss, Ctrl: n = 6 from 5 litterss. (G) Representative images illustrating sirius-red staining used to visualize connective tissue of the peribronchial area (black arrows); pHAmouse group: n = 6 from 4 litterss, Ctrl: n = 6 from 5 litterss. (H) Immunoblot showing protein abundance of collagen Iα1 (COL Iα1) at P70. β-ACTIN served as loading Control (Ctrl); Ctrl: n = 5 from 4 litters; pHAmouse: n = 5 from 4 litters. Early postnatal hyperalimentation (pHAmouse group) compared to the Ctrl (Ctrl). pHAmouse group: white bar; Ctrl: black bar. Mean ± SEM; Mann Whitney test. *p < 0.05, **p < 0.01; n.s. = not significant.
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f7: Early postnatal hyperalimentation (pHA) with early-onset obesity temporo dynamically regulates murine pulmonary elastin synthesis and induces greater collagen Iα1 protein abundance.(A,B) Assessment of tropoelastin mRNA in total lung homogenate by quantitative qRT-PCR at postnatal day 21 (P21) (A) (Ctrl: n = 10 from 5 litters; pHAmouse: n = 10 from 6 litters) and at P70 (B) (Ctrl: n = 9–10 from 6 litters; pHAmouse: n = 10 from 6 litters). (C,D) Lung protein abundance of TROPOELASTIN at P21 (C) (Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters) and at P70 (D) (Ctrl: n = 5 from 4 litters; pHAmouse: n = 5 from 4 litters). β-ACTIN served as loading Control (Ctrl). Densitometric analyses below the corresponding immunoblot. (E) Representative images illustrating elastic fibers using Hart’s staining in paraffin-embedded and paraformaldehyde-fixed lungs of the Ctrl-group (left panel) and of the pHAmouse-group (right panel) at P70. Red arrows are depicting positive staining of elastic fibers of the conducting airways (100–200 μm diameter). (F) Summary data of the quantification of positive elastic fiber staining surrounding the bronchi (100–200 μm) at P70. Elastin surface density was related to bronchial wall surface; pHAmouse group: n = 6 from 4 litterss, Ctrl: n = 6 from 5 litterss. (G) Representative images illustrating sirius-red staining used to visualize connective tissue of the peribronchial area (black arrows); pHAmouse group: n = 6 from 4 litterss, Ctrl: n = 6 from 5 litterss. (H) Immunoblot showing protein abundance of collagen Iα1 (COL Iα1) at P70. β-ACTIN served as loading Control (Ctrl); Ctrl: n = 5 from 4 litters; pHAmouse: n = 5 from 4 litters. Early postnatal hyperalimentation (pHAmouse group) compared to the Ctrl (Ctrl). pHAmouse group: white bar; Ctrl: black bar. Mean ± SEM; Mann Whitney test. *p < 0.05, **p < 0.01; n.s. = not significant.

Mentions: To analyze whether transient early-onset overweight along with a transient activation of adipocytokine and insulin signaling is related to long-term changes of the expression of key ECM molecules, we assessed expression of tropoelastin at P21 and P70. Even though gene expression was not significantly changed at P21 (Fig. 7A) or P70 (Fig. 7B), protein abundance of tropoelastin in total lung homogenate was markedly increased at P21 (p < 0.01), but decreased at P70 (p < 0.05) (Fig. 7C,D). The process of elastic fiber formation and assembly occurs during development and the fibers are present throughout life. Some studies indicate that there is a reduction of elastic fibers in the ageing lung3435. Since elastin is an important component of elastic fibers, main regulator of elasticity of the lung, we performed Hart’s stain using tartrazine as counterstain. Neither representative images depicting peribronchial elastic fibers as indicated by red arrows in lungs at P70 (Fig. 7E) nor the corresponding quantification (Fig. 7F) showed significant differences between pHAmouse and Ctrl-group.


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 temporo dynamically regulates murine pulmonary elastin synthesis and induces greater collagen Iα1 protein abundance.(A,B) Assessment of tropoelastin mRNA in total lung homogenate by quantitative qRT-PCR at postnatal day 21 (P21) (A) (Ctrl: n = 10 from 5 litters; pHAmouse: n = 10 from 6 litters) and at P70 (B) (Ctrl: n = 9–10 from 6 litters; pHAmouse: n = 10 from 6 litters). (C,D) Lung protein abundance of TROPOELASTIN at P21 (C) (Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters) and at P70 (D) (Ctrl: n = 5 from 4 litters; pHAmouse: n = 5 from 4 litters). β-ACTIN served as loading Control (Ctrl). Densitometric analyses below the corresponding immunoblot. (E) Representative images illustrating elastic fibers using Hart’s staining in paraffin-embedded and paraformaldehyde-fixed lungs of the Ctrl-group (left panel) and of the pHAmouse-group (right panel) at P70. Red arrows are depicting positive staining of elastic fibers of the conducting airways (100–200 μm diameter). (F) Summary data of the quantification of positive elastic fiber staining surrounding the bronchi (100–200 μm) at P70. Elastin surface density was related to bronchial wall surface; pHAmouse group: n = 6 from 4 litterss, Ctrl: n = 6 from 5 litterss. (G) Representative images illustrating sirius-red staining used to visualize connective tissue of the peribronchial area (black arrows); pHAmouse group: n = 6 from 4 litterss, Ctrl: n = 6 from 5 litterss. (H) Immunoblot showing protein abundance of collagen Iα1 (COL Iα1) at P70. β-ACTIN served as loading Control (Ctrl); Ctrl: n = 5 from 4 litters; pHAmouse: n = 5 from 4 litters. Early postnatal hyperalimentation (pHAmouse group) compared to the Ctrl (Ctrl). pHAmouse group: white bar; Ctrl: black bar. Mean ± SEM; Mann Whitney test. *p < 0.05, **p < 0.01; n.s. = not significant.
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Related In: Results  -  Collection

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f7: Early postnatal hyperalimentation (pHA) with early-onset obesity temporo dynamically regulates murine pulmonary elastin synthesis and induces greater collagen Iα1 protein abundance.(A,B) Assessment of tropoelastin mRNA in total lung homogenate by quantitative qRT-PCR at postnatal day 21 (P21) (A) (Ctrl: n = 10 from 5 litters; pHAmouse: n = 10 from 6 litters) and at P70 (B) (Ctrl: n = 9–10 from 6 litters; pHAmouse: n = 10 from 6 litters). (C,D) Lung protein abundance of TROPOELASTIN at P21 (C) (Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters) and at P70 (D) (Ctrl: n = 5 from 4 litters; pHAmouse: n = 5 from 4 litters). β-ACTIN served as loading Control (Ctrl). Densitometric analyses below the corresponding immunoblot. (E) Representative images illustrating elastic fibers using Hart’s staining in paraffin-embedded and paraformaldehyde-fixed lungs of the Ctrl-group (left panel) and of the pHAmouse-group (right panel) at P70. Red arrows are depicting positive staining of elastic fibers of the conducting airways (100–200 μm diameter). (F) Summary data of the quantification of positive elastic fiber staining surrounding the bronchi (100–200 μm) at P70. Elastin surface density was related to bronchial wall surface; pHAmouse group: n = 6 from 4 litterss, Ctrl: n = 6 from 5 litterss. (G) Representative images illustrating sirius-red staining used to visualize connective tissue of the peribronchial area (black arrows); pHAmouse group: n = 6 from 4 litterss, Ctrl: n = 6 from 5 litterss. (H) Immunoblot showing protein abundance of collagen Iα1 (COL Iα1) at P70. β-ACTIN served as loading Control (Ctrl); Ctrl: n = 5 from 4 litters; pHAmouse: n = 5 from 4 litters. Early postnatal hyperalimentation (pHAmouse group) compared to the Ctrl (Ctrl). pHAmouse group: white bar; Ctrl: black bar. Mean ± SEM; Mann Whitney test. *p < 0.05, **p < 0.01; n.s. = not significant.
Mentions: To analyze whether transient early-onset overweight along with a transient activation of adipocytokine and insulin signaling is related to long-term changes of the expression of key ECM molecules, we assessed expression of tropoelastin at P21 and P70. Even though gene expression was not significantly changed at P21 (Fig. 7A) or P70 (Fig. 7B), protein abundance of tropoelastin in total lung homogenate was markedly increased at P21 (p < 0.01), but decreased at P70 (p < 0.05) (Fig. 7C,D). The process of elastic fiber formation and assembly occurs during development and the fibers are present throughout life. Some studies indicate that there is a reduction of elastic fibers in the ageing lung3435. Since elastin is an important component of elastic fibers, main regulator of elasticity of the lung, we performed Hart’s stain using tartrazine as counterstain. Neither representative images depicting peribronchial elastic fibers as indicated by red arrows in lungs at P70 (Fig. 7E) nor the corresponding quantification (Fig. 7F) showed significant differences between pHAmouse and Ctrl-group.

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