All Title Author
Keywords Abstract

PLOS ONE  2012 

Obesity Induced by Neonatal Overfeeding Worsens Airway Hyperresponsiveness and Inflammation

DOI: 10.1371/journal.pone.0047013

Full-Text   Cite this paper   Add to My Lib


Background Obesity is a risk factor for the development of certain respiratory diseases, and neonatal overfeeding results in an early onset of obesity in adulthood. However, the influence of neonatal overfeeding on respiratory diseases has rarely been studied. Therefore, this paper is aimed at investigating the effect of neonatal overfeeding on airway responsiveness and inflammation. Methodology/Principal Findings The neonatal overfeeding was induced by reducing litter size to three pups per litter (small litter, SL) in contrast to the normal litter size with ten pups per litter (NL) on postnatal day 3 (P3) in male ICR mice. On P21, mice were weaned to standard chow diet. Airway responsiveness to methacholine was measured either on P21 or P150. Total and classified inflammatory cells in bronchoalveolar lavage fluid (BALF) were counted, lung inflammatory cells were evaluated through staining with hematoxylin & eosin and F4/80 immunohistochemistry; lung fibrosis was evaluated through staining with Masson and α-SAM immunohistochemistry. Leptin levels in serum were measured by RIA; TNF-α levels in serum and BALF were quantified by ELISA; mRNA levels of TNF-α, CTGF and TGF-β1 in lung tissues were measured using real-time PCR. Mice from SL exhibited accelerated body weight gain, impaired glucose tolerance and hyperleptinemia. Enhanced airway responsiveness to methacholine was observed in SL mice on P150, but not on P21. Pulmonary inflammation was evident in SL mice on P150, as reflected by inflammatory cells especially macrophages around bronchi and interstitium. BALF and serum TNF-α levels and lung TNF-α mRNA expression were significantly increased in SL mice on P150. More collagen accumulated surrounding the bronchi on P150; lung mRNA levels of TGF-β1 and CTGF were also increased on P150. Conclusion In addition to inducing a variety of metabolic defects, neonatal overfeeding enhanced lung inflammation, which may lead to airway remodeling and airway hyperresponsiveness in adulthood.


[1]  Camargo CA Jr, Weiss ST, Zhang S, Willett WC, Speizer FE (1999) Prospective study of body mass index, weight change, and risk of adult-onset asthma in women. Arch Intern Med 159: 2582–2588.
[2]  McClean KM, Kee F, Young IS, Elborn JS (2008) Obesity and the lung: 1. Epidemiology. Thorax 63: 649–654.
[3]  Zammit C, Liddicoat H, Moonsie I, Makker H (2010) Obesity and respiratory diseases. Int J Gen Med 3: 335–343.
[4]  O’Donnell CP, Holguin F, Dixon AE (2010) Pulmonary physiology and pathophysiology in obesity. J Appl Physiol 108: 197–198.
[5]  Agrawal A, Mabalirajan U, Ahmad T, Ghosh B (2011) Emerging interface between metabolic syndrome and asthma. Am J Respir Cell Mol Biol 44: 270–275.
[6]  Litonjua AA, Sparrow D, Celedon JC, DeMolles D, Weiss ST (2002) Association of body mass index with the development of methacholine airway hyperresponsiveness in men: the Normative Aging Study. Thorax 57: 581–585.
[7]  Beuther DA, Sutherland ER (2007) Overweight, obesity, and incident asthma: a meta-analysis of prospective epidemiologic studies. Am J Respir Crit Care Med 175: 661–666.
[8]  Canoy D, Luben R, Welch A, Bingham S, Wareham N, et al. (2004) Abdominal obesity and respiratory function in men and women in the EPIC-Norfolk Study, United Kingdom. Am J Epidemiol 159: 1140–1149.
[9]  Shore SA (2007) Obesity and asthma: implications for treatment. Curr Opin Pulm Med 13: 56–62.
[10]  Salome CM, King GG, Berend N (2010) Physiology of obesity and effects on lung function. Eur J Appl Physiol 108: 206–211.
[11]  Gould HJ, Sutton BJ (2008) IgE in allergy and asthma today. Nat Rev Immunol 8: 205–217.
[12]  Lemanske RF Jr, Busse WW (2010) Asthma: clinical expression and molecular mechanisms. J Allergy Clin Immun 125: S95–102.
[13]  Fresno M, Alvarez R, Cuesta N (2011) Toll-like receptors, inflammation, metabolism and obesity. Arch Physiol Biochem 117: 151–164.
[14]  Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259: 87–91.
[15]  Mauad T, Bel EH, Sterk PJ (2007) Asthma therapy and airway remodeling. J Allergy Clin Immunol 120: 997–1009.
[16]  Ask K, Bonniaud P, Maass K, Eickelberg O, Margetts PJ, et al. (2008) Progressive pulmonary fibrosis is mediated by TGF-beta isoform 1 but not TGF-beta3. Int J Biochem Cell Biol 40: 484–495.
[17]  Robinson PM, Blalock TD, Yuan R, Lewin AS, Schultz GS (2012) Hammerhead ribozyme-mediated knockdown of mRNA for fibrotic growth factors: transforming growth factor-beta 1 and connective tissue growth factor. Methods Mol Biol 820: 117–132.
[18]  Ponticos M, Holmes AM, Shi-wen X, Leoni P, Khan K, et al. (2009) Pivotal role of connective tissue growth factor in lung fibrosis: MAPK-dependent transcriptional activation of type I collagen. Arthritis Rheum-Us 60: 2142–2155.
[19]  Shore SA Obesity, asthma: lessons from animal models (2007) J Appl Physiol. 102: 516–528.
[20]  Johnston RA, Zhu M, Rivera-Sanchez YM, Lu FL, Theman TA, et al. (2007) Allergic airway responses in obese mice. Am J Respir Crit Care Med 176: 650–658.
[21]  Johnston RA, Theman TA, Lu FL, Terry RD, Williams ES, et al. (2008) Diet-induced obesity causes innate airway hyperresponsiveness to methacholine and enhances ozone-induced pulmonary inflammation. J Appl Physiol 104: 1727–1735.
[22]  Zhu M, Hug C, Kasahara DI, Johnston RA, Williams AS, et al. (2010) Impact of adiponectin deficiency on pulmonary responses to acute ozone exposure in mice. Am J Respir Cell Mol Biol 43: 487–497.
[23]  Johnston RA, Zhu M, Hernandez CB, Williams ES, Shore SA (2010) Onset of obesity in carboxypeptidase E-deficient mice and effect on airway responsiveness and pulmonary responses to ozone. J Appl Physiol 108: 1812–1819.
[24]  Mito N, Kitada C, Hosoda T, Sato K (2002) Effect of diet-induced obesity on ovalbumin-specific immune response in a murine asthma model. Metabolism 51: 1241–1246.
[25]  Plagemann A, Harder T, Rake A, Voits M, Fink H, et al. (1999) Perinatal elevation of hypothalamic insulin, acquired malformation of hypothalamic galaninergic neurons, and syndrome x-like alterations in adulthood of neonatally overfed rats. Brain Res 836: 146–155.
[26]  Boullu-Ciocca S, Achard V, Tassistro V, Dutour A, Grino M (2008) Postnatal programming of glucocorticoid metabolism in rats modulates high-fat diet-induced regulation of visceral adipose tissue glucocorticoid exposure and sensitivity and adiponectin and proinflammatory adipokines gene expression in adulthood. Diabetes 57: 669–677.
[27]  Xiao XQ, Williams SM, Grayson BE, Glavas MM, Cowley MA, et al. (2007) Excess weight gain during the early postnatal period is associated with permanent reprogramming of brown adipose tissue adaptive thermogenesis. Endocrinology 148: 4150–4159.
[28]  Glavas MM, Kirigiti MA, Xiao XQ, Enriori PJ, Fisher SK, et al. (2010) Early overnutrition results in early-onset arcuate leptin resistance and increased sensitivity to high-fat diet. Endocrinology 151: 1598–1610.
[29]  Song Y, Li J, Zhao Y, Zhang Q, Liu Z, et al. (2012) Severe maternal hyperglycemia exacerbates the development of insulin resistance and fatty liver in the offspring on high fat diet. Exp Diabetes Res 2012: 254976.
[30]  Calixto MC, Lintomen L, Schenka A, Saad MJ, Zanesco A, et al. (2010) Obesity enhances eosinophilic inflammation in a murine model of allergic asthma. Br J Pharmacol 159(3): 617–25.
[31]  Davidowa H, Plagemann A (2007) Insulin resistance of hypothalamic arcuate neurons in neonatally overfed rats. Neuroreport 18: 521–524.
[32]  Rodrigues AL, De Souza EP, Da Silva SV, Rodrigues DS, Nascimento AB, et al. (2007) Low expression of insulin signaling molecules impairs glucose uptake in adipocytes after early overnutrition. J Endocrinol 195: 485–494.
[33]  Santamaria F, Montella S, Greco L, Valerio G, Franzese A, et al. (2011) Obesity duration is associated to pulmonary function impairment in obese subjects. Obesity (Silver Spring) 19: 1623–1628.
[34]  Boulet LP (2003) Physiophology of airway hyperresponsiveness. Curr Allergy Asthma Rep 3: 166–171.
[35]  Sharma S, Malur A, Marshall I, Huizar I, Barna BP, et al. (2012) Alveolar macrophage activation in obese patients with obstructive sleep apnea. Surgery 151: 107–112.
[36]  Sbarbati A, Osculati F, Silvagni D, Benati D, Galie M, et al. (2006) Obesity and inflammation: evidence for an elementary lesion. Pediatrics 117: 220–223.
[37]  Lu FL, Johnston RA, Flynt L, Theman TA, Terry RD, et al. (2006) Increased pulmonary responses to acute ozone exposure in obese db/db mice. Am J Physiol Lung Cell Mol Physiol 290: 856–865.
[38]  Lintomen L, Calixto MC, Schenka A, Antunes E (2012) Allergen-induced bone marrow eosinophilopoiesis and airways eosinophilic inflammation in leptin-deficient ob/ob mice. Obesity (Silver Spring) doi: 10.1038/oby.2012.93.
[39]  Di Marzo V, Goparaju SK, Wang L, Liu J, Bátkai S, et al. (2001) Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410: 822–825.
[40]  Panchal SK, Poudyal H, Iyer A, Nazer R, Alam MA, et al. (2011) High-carbohydrate, high-fat diet-induced metabolic syndrome and cardiovascular remodeling in rats. J Cardiovasc Pharmacol 57: 611–24.
[41]  Hou M, Liu Y, Zhu L, Sun B, Guo M, et al. (2011) Neonatal overfeeding induced by small litter rearing causes altered glucocorticoid metabolism in rats. PLoS One 6: e25726.
[42]  Summer R, Little FF, Ouchi N, Takemura Y, Aprahamian T, et al. (2008) Alveolar macrophage activation and an emphysema-like phenotype in adiponectin-deficient mice. Am J Physiol Lung Cell Mol Physiol 294: L1035–L1042.
[43]  Barranco P, Delgado J, Gallego LT, Bobolea I, Pedrosa M, et al. (2012) Asthma, obesity and diet. Nutr Hosp 27: 138–45.
[44]  Thomas PS, Yates DH, Barnes PJ (1995) Tumor necrosis factor-alpha increases airway responsiveness and sputum neutrophilia in normal human subjects. Am J Respir Crit Care Med 152: 76–80.
[45]  Williams AS, Chen L, Kasahara DI, Si H, Wurmbrand AP, et al. (2012) Obesity and airway responsiveness: Role of TNFR2. Pulm Pharmacol Ther. doi: 10.1016/j.pupt.2012.5.001.
[46]  Thomson EM, Williams A, Yauk CL, Vincent R (2012) Overexpression of tumor necrosis factor-α in the lungs alters immune response, matrix remodeling, and repair and maintenance pathways. Am J Pathol 180: 1413–1430.
[47]  Rydell-Tormanen K, Andreasson K, Hesselstrand R, Risteli J, Heinegard D, et al. (2012) Extracellular matrix alterations and acute inflammation; developing in parallel during early induction of pulmonary fibrosis. Lab Invest 92: 917–925.


comments powered by Disqus