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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 induces transient activation of intrinsic pulmonary insulin signaling at postnatal day 21 (P21), and inhibition at P70.(A–E) Immunoblots showing indicators of insulin signaling at P21. (A) Protein expression of insulin receptor (INS-R) in lungs at P21; Ctrl: n = 5 from 4 litters; pHAmouse: n = 5 from 4 litters. (B) Protein abundance of insulin receptor substrate 1 (IRS1) in lungs at P21; Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters. (C) Assessment of phosphorylated AKT (pAKT) and total AKT in the lungs at P21; Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters. (D) Immunoblots showing phosphorylated and total GSK-3β in lungs at P21; Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters. (E) Protein abundance of proliferating cell nuclear antigen (PCNA) as an index of proliferation at P21; Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters. (F–J) Assessement of indicators of insulin signaling at P70 using immunoblots. (F) Protein expression of INS-R in the lungs at P70; Ctrl: n = 5 from 4 litters; pHAmouse: n = 5 from 4 litters. (G) Protein abundance of IRS1 in lungs at P70; Ctrl: n = 5 from 4 litters; pHAmouse: n = 5 from 4 litters. (H) Immunoblots for pAKT and total AKT in lungs at P70; Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters. (I) Phosphorylated and total GSK-3β in lungs at P21; Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters. (J) Immunoblots showing PCNA at P70; Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters. Densitometric analyses were performed and are shown below the corresponding immunoblot; β-ACTIN served as loading Control (Ctrl). Mann Whitney or unpaired t-test. pHAmousegroup: white bar; Ctrl: black bar. Mean ± SEM; *p < 0.05, **p < 0.01, ***p < 0.001; n.s. = not significant.
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f6: Early postnatal hyperalimentation (pHA) with early-onset obesity induces transient activation of intrinsic pulmonary insulin signaling at postnatal day 21 (P21), and inhibition at P70.(A–E) Immunoblots showing indicators of insulin signaling at P21. (A) Protein expression of insulin receptor (INS-R) in lungs at P21; Ctrl: n = 5 from 4 litters; pHAmouse: n = 5 from 4 litters. (B) Protein abundance of insulin receptor substrate 1 (IRS1) in lungs at P21; Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters. (C) Assessment of phosphorylated AKT (pAKT) and total AKT in the lungs at P21; Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters. (D) Immunoblots showing phosphorylated and total GSK-3β in lungs at P21; Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters. (E) Protein abundance of proliferating cell nuclear antigen (PCNA) as an index of proliferation at P21; Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters. (F–J) Assessement of indicators of insulin signaling at P70 using immunoblots. (F) Protein expression of INS-R in the lungs at P70; Ctrl: n = 5 from 4 litters; pHAmouse: n = 5 from 4 litters. (G) Protein abundance of IRS1 in lungs at P70; Ctrl: n = 5 from 4 litters; pHAmouse: n = 5 from 4 litters. (H) Immunoblots for pAKT and total AKT in lungs at P70; Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters. (I) Phosphorylated and total GSK-3β in lungs at P21; Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters. (J) Immunoblots showing PCNA at P70; Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters. Densitometric analyses were performed and are shown below the corresponding immunoblot; β-ACTIN served as loading Control (Ctrl). Mann Whitney or unpaired t-test. pHAmousegroup: white bar; Ctrl: black bar. Mean ± SEM; *p < 0.05, **p < 0.01, ***p < 0.001; n.s. = not significant.

Mentions: Measurement of total insulin receptor (INS-R) and insulin receptor substrate 1 (IRS1) using immunoblot did not show any significant differences between pHAmouse and Ctrl at P21 (Fig. 6A,B). We next analyzed the intrinsic pulmonary insulin pathway by assessing AKT and glycogen synthase kinase 3β (GSK-3β) signaling as indicators of intracellular insulin signaling. GSK-3β is phosphorylated at Ser-9 and thereby inactivated by phosphorylated Akt. We found that total protein abundance of AKT (p < 0.05) and GSK3β (p < 0.001) and also the phosphoryalation of both (p < 0.001 and p < 0.05, respectively) were markedly increased after pHA at P21 when compared to the Ctrl (Fig. 6C,D). Since insulin is known as a proliferative signaling pathway we assessed proliferating cell nuclear antigen (PCNA) as an indicator of proliferation and found a significant increase in lungs of the pHAmouse-group at P21 (Fig. 6E). At P70, however, we detected a slightly higher protein abundance of INS-R (p = 0.1; Fig. 6F), reduced expression of IRS1 (p < 0.01) (Fig. 6G), lower phosphorylated AKT (p < 0.05) (Fig. 6H), and reduced phosphorylated GSK-3β related to total GSK-3β. Assessment of PCNA did not show any differences between pHAmouse-group and Ctrl at P70 (Fig. 6J).


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 induces transient activation of intrinsic pulmonary insulin signaling at postnatal day 21 (P21), and inhibition at P70.(A–E) Immunoblots showing indicators of insulin signaling at P21. (A) Protein expression of insulin receptor (INS-R) in lungs at P21; Ctrl: n = 5 from 4 litters; pHAmouse: n = 5 from 4 litters. (B) Protein abundance of insulin receptor substrate 1 (IRS1) in lungs at P21; Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters. (C) Assessment of phosphorylated AKT (pAKT) and total AKT in the lungs at P21; Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters. (D) Immunoblots showing phosphorylated and total GSK-3β in lungs at P21; Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters. (E) Protein abundance of proliferating cell nuclear antigen (PCNA) as an index of proliferation at P21; Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters. (F–J) Assessement of indicators of insulin signaling at P70 using immunoblots. (F) Protein expression of INS-R in the lungs at P70; Ctrl: n = 5 from 4 litters; pHAmouse: n = 5 from 4 litters. (G) Protein abundance of IRS1 in lungs at P70; Ctrl: n = 5 from 4 litters; pHAmouse: n = 5 from 4 litters. (H) Immunoblots for pAKT and total AKT in lungs at P70; Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters. (I) Phosphorylated and total GSK-3β in lungs at P21; Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters. (J) Immunoblots showing PCNA at P70; Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters. Densitometric analyses were performed and are shown below the corresponding immunoblot; β-ACTIN served as loading Control (Ctrl). Mann Whitney or unpaired t-test. pHAmousegroup: white bar; Ctrl: black bar. Mean ± SEM; *p < 0.05, **p < 0.01, ***p < 0.001; n.s. = not significant.
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f6: Early postnatal hyperalimentation (pHA) with early-onset obesity induces transient activation of intrinsic pulmonary insulin signaling at postnatal day 21 (P21), and inhibition at P70.(A–E) Immunoblots showing indicators of insulin signaling at P21. (A) Protein expression of insulin receptor (INS-R) in lungs at P21; Ctrl: n = 5 from 4 litters; pHAmouse: n = 5 from 4 litters. (B) Protein abundance of insulin receptor substrate 1 (IRS1) in lungs at P21; Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters. (C) Assessment of phosphorylated AKT (pAKT) and total AKT in the lungs at P21; Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters. (D) Immunoblots showing phosphorylated and total GSK-3β in lungs at P21; Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters. (E) Protein abundance of proliferating cell nuclear antigen (PCNA) as an index of proliferation at P21; Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters. (F–J) Assessement of indicators of insulin signaling at P70 using immunoblots. (F) Protein expression of INS-R in the lungs at P70; Ctrl: n = 5 from 4 litters; pHAmouse: n = 5 from 4 litters. (G) Protein abundance of IRS1 in lungs at P70; Ctrl: n = 5 from 4 litters; pHAmouse: n = 5 from 4 litters. (H) Immunoblots for pAKT and total AKT in lungs at P70; Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters. (I) Phosphorylated and total GSK-3β in lungs at P21; Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters. (J) Immunoblots showing PCNA at P70; Ctrl: n = 6 from 4 litters; pHAmouse: n = 8 from 4 litters. Densitometric analyses were performed and are shown below the corresponding immunoblot; β-ACTIN served as loading Control (Ctrl). Mann Whitney or unpaired t-test. pHAmousegroup: white bar; Ctrl: black bar. Mean ± SEM; *p < 0.05, **p < 0.01, ***p < 0.001; n.s. = not significant.
Mentions: Measurement of total insulin receptor (INS-R) and insulin receptor substrate 1 (IRS1) using immunoblot did not show any significant differences between pHAmouse and Ctrl at P21 (Fig. 6A,B). We next analyzed the intrinsic pulmonary insulin pathway by assessing AKT and glycogen synthase kinase 3β (GSK-3β) signaling as indicators of intracellular insulin signaling. GSK-3β is phosphorylated at Ser-9 and thereby inactivated by phosphorylated Akt. We found that total protein abundance of AKT (p < 0.05) and GSK3β (p < 0.001) and also the phosphoryalation of both (p < 0.001 and p < 0.05, respectively) were markedly increased after pHA at P21 when compared to the Ctrl (Fig. 6C,D). Since insulin is known as a proliferative signaling pathway we assessed proliferating cell nuclear antigen (PCNA) as an indicator of proliferation and found a significant increase in lungs of the pHAmouse-group at P21 (Fig. 6E). At P70, however, we detected a slightly higher protein abundance of INS-R (p = 0.1; Fig. 6F), reduced expression of IRS1 (p < 0.01) (Fig. 6G), lower phosphorylated AKT (p < 0.05) (Fig. 6H), and reduced phosphorylated GSK-3β related to total GSK-3β. Assessment of PCNA did not show any differences between pHAmouse-group and Ctrl at P70 (Fig. 6J).

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