Dinger Katharina, Kasper Philipp, Hucklenbruch-Rother Eva, Vohlen Christina, Jobst Eva, Janoschek Ruth, Bae-Gartz Inga, van Koningsbruggen-Rietschel Silke, Plank Christian, Dötsch Jörg, Alejandre Alcázar Miguel Angel
Experimental Pulmonology, University Hospital for Pediatrics and Adolescent Medicine, Faculty of Medicine, University of Cologne, Cologne, Germany.
Metabolism and Perinatal Programming, University Hospital for Pediatrics and Adolescent Medicine, Faculty of Medicine, University of Cologne, Cologne, Germany.
Sci Rep. 2016 Apr 18;6:24168. doi: 10.1038/srep24168.
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.
儿童肥胖是哮喘的一个风险因素，但两者之间的分子机制仍不清楚。由于肥胖会导致慢性低度炎症并影响代谢信号，我们推测哺乳期母体高脂饮食诱导的产后过度营养（pHA）会导致早发性肥胖，并使肺部脂肪细胞因子/胰岛素信号失调，从而导致成年小鼠出现类似哮喘疾病的代谢编程。pHA后代在出生后第21天（P21）表现出：（1）早发性肥胖、更大的脂肪量、IL-1β、IL-23和Tnf-α表达增加、血清瘦素水平更高且葡萄糖耐量低于对照组（Ctrl）；（2）肺中STAT3/AMPKα激活减少、SOCS3表达增加以及AKT/GSK3β激活减少，分别表明存在瘦素抵抗和胰岛素信号；（3）肺中IL-6、IL-13、IL-17A和Tnf-α的mRNA增加。在P70时，pHA组和Ctrl组的体重、脂肪量和细胞因子mRNA表达相似，但血清瘦素和IL-6更高，胰岛素信号和葡萄糖耐量受损。pHA后支气管周围弹性纤维含量、支气管平滑肌层和结缔组织沉积没有差异。尽管pHA后小鼠的支气管结构未改变，但其气道反应性显著增加。我们的研究不仅表明早发性肥胖会短暂激活小鼠肺部脂肪细胞因子/胰岛素信号并诱导气道高反应性，还为儿童肥胖相关哮喘的代谢编程提供了新的见解。
