Oruqaj Learta, Forst Svenja, Schreckenberg Rolf, Inserte Javier, Poncelas Marcos, Bañeras Jordi, Garcia-Dorado David, Rohrbach Susanne, Schlüter Klaus-Dieter
Institut für Physiologie, JLU Gießen, Aulweg 129, 35392 Gießen, Germany.
Servicio de Cardiologia, Hospital Universitari Vall d'Hebron, 119-129, Barcelona 08035, Spain.
Heliyon. 2016 Oct 27;2(10):e00182. doi: 10.1016/j.heliyon.2016.e00182. eCollection 2016 Oct.
Parathyroid hormone-related protein (PTHrP) is involved in lung development and surfactant production. The latter one requires a paracrine interaction between type II alveolar cells and lipofibroblasts in which leptin triggers PTHrP-induced effects. Whether increased plasma leptin levels, as they occur in high fat diet, modify the expression of PTHrP remains unclear. Furthermore, the effect of high fat diet under conditions of forced pulmonary remodelling such as response to post myocardial infarction remains to be defined.
C57 bl/6 mice were randomized to either normal diet or high fat diet at an age of 6 weeks. Seven months later, the mice were euthanized and the lung was removed and frozen in fluid nitrogen until use. Samples were analyzed by real-time RT-PCR and western blot. Leptin deficient mice were used to investigate the effect of leptin on pulmonary expression of PTHrP more directly. A subgroup of mice with and without high fat diet underwent ischemia (45 min) and reperfusion (4 weeks). Finally, experiments were repeated with prolonged high-fat diet.
High fat diet increased plasma leptin levels by 30.4% and the pulmonary mRNA expression of PTHrP (1,447-fold), PTH-1 receptor (4.21-fold), and PTHrP-downstream targets ADRP (7.54-fold) and PPARγ (5.27-fold). Pulmonary PTHrP expression was reduced in leptin deficient mice by 88% indicating leptin dependent regulation. High fat diet further improved changes in pulmonary adaptation caused by ischemia/reperfusion (1.48-fold increased PTH-1 receptor protein expression). These effects were lost during prolonged high fat diet.
This study established that physiological regulation of leptin plasma levels by high fat diet affects the pulmonary PTHrP expression and of PTHrP downstream targets. Modification of pulmonary expression of PTH-1 receptors by high fat diet after myocardial infarction suggests that the identified interaction may participate in the obesity paradox.
甲状旁腺激素相关蛋白（PTHrP）参与肺发育和表面活性剂的产生。后者需要II型肺泡细胞与脂肪成纤维细胞之间的旁分泌相互作用，其中瘦素触发PTHrP诱导的效应。高脂肪饮食时出现的血浆瘦素水平升高是否会改变PTHrP的表达仍不清楚。此外，高脂肪饮食在诸如心肌梗死后反应等强迫性肺重塑条件下的作用仍有待确定。
6周龄的C57 bl/6小鼠被随机分为正常饮食组或高脂肪饮食组。7个月后，对小鼠实施安乐死并取出肺，在液氮中冷冻备用。通过实时逆转录聚合酶链反应（RT-PCR）和蛋白质免疫印迹法（western blot）对样本进行分析。使用瘦素缺陷小鼠更直接地研究瘦素对肺中PTHrP表达的影响。一组有或没有高脂肪饮食的小鼠经历缺血（45分钟）和再灌注（4周）。最后，对长期高脂肪饮食的情况重复进行实验。
高脂肪饮食使血浆瘦素水平升高30.4%，并使肺中PTHrP的mRNA表达（1447倍）、PTH-1受体（4.21倍）以及PTHrP下游靶点ADRP（7.54倍）和PPARγ（5.27倍）增加。瘦素缺陷小鼠肺中PTHrP表达降低了88%，表明存在瘦素依赖性调节。高脂肪饮食进一步改善了缺血/再灌注引起的肺适应性变化（PTH-1受体蛋白表达增加1.48倍）。在长期高脂肪饮食期间，这些效应消失。
本研究证实，高脂肪饮食对瘦素血浆水平的生理调节会影响肺中PTHrP的表达及其下游靶点。心肌梗死后高脂肪饮食对肺中PTH-1受体表达的改变表明，所确定的相互作用可能参与了肥胖悖论。
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