The host response to poly(lactide-co-glycolide) scaffolds protects mice from diet induced obesity and glucose intolerance
The host response to poly(lactide-co-glycolide) scaffolds protects mice from diet induced obesity and glucose intolerance
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DOI：
10.1016/j.biomaterials.2019.119281
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发表时间：
2019-10-01
期刊：
影响因子：
14
通讯作者：
Gower, R. Michael
中科院分区：
文献类型：
--
作者：
Hendley, Michael A.;Murphy, Kendall P.;Gower, R. Michael
潜在的代谢疾病是脂肪组织功能低下，其特征是糖耐量受损和促进健康的脂肪因子表达低。目前，还没有专门针对脂肪组织的治疗方法，我们正在研究聚合物支架作为局部药物递送的治疗平台。本研究将多孔聚乳酸-羟基乙酸酯支架植入小鼠附睾脂肪中。令人惊讶的是，“空”支架降低了健康小鼠的血糖水平以及附睾脂肪垫的大小。通过向小鼠注射荧光葡萄糖示踪剂，我们确定附睾脂肪垫与支架的葡萄糖摄取增加了60%；相比之下，其他主要代谢器官的葡萄糖摄取并未升高，这表明支架植入部位葡萄糖摄取的增强是导致血糖水平降低的原因。组织学显示支架周围的细胞和组织重构增加，我们发现葡萄糖转运蛋白1和胰岛素样生长因子1的表达增加，这两种蛋白质参与伤口愈合，也可以通过促进葡萄糖摄取来调节血糖水平。在临床转化方面，“空”支架减少了高脂肪饮食小鼠的肥胖并改善了葡萄糖耐量。这些发现表明，脂肪组织中细胞活动的增加，比如与宿主对生物材料植入的反应有关的细胞活动，对患有营养过剩代谢并发症的小鼠是有益的，可能是因为它减轻了导致肥胖和糖尿病状态的正能量平衡。更广泛地说，这项工作重申，除了通常研究的局部宿主反应外，生物材料植入物还具有全身生理效应，并表明可能对治疗有影响。
Underlying metabolic disease is poor adipose tissue function characterized by impaired glucose tolerance and low expression of health promoting adipokines. Currently, no treatments specifically target the adipose tissue and we are investigating polymer scaffolds for localized drug delivery as a therapeutic platform. In this work we implanted porous poly(lactide-co-glycolide) scaffolds into the epididymal fat of mice. Surprisingly, "empty" scaffolds decreased blood glucose levels in healthy mice as well as epididymal fat pad size. By injecting a fluorescent glucose tracer into mice, we determined that glucose uptake increases by 60% in epididymal fat pads with scaffolds; in contrast, glucose uptake was not elevated in other major metabolic organs, suggesting the enhanced glucose uptake at the scaffold implant site was responsible for decreased blood glucose levels. Histology indicated increased cellularity and tissue remodeling around the scaffold and we found increased expression of glucose transporter 1 and insulin-like growth factor 1, which are proteins involved in wound healing that can also modulate blood glucose levels through their promotion of glucose uptake. Regarding clinical translation, "empty" scaffolds decreased obesity and improved glucose tolerance in mice fed a high fat diet. These findings demonstrate increased cellular activity in the adipose tissue, such as that associated with the host response to biomaterial implant, is beneficial in mice suffering from metabolic complications of over nutrition, possibly because it mitigates the positive energy balance that leads to the obese, diabetic state. More broadly, this work reaffirms that in addition to the local host response typically investigated, biomaterial implant has systemic physiological effects and suggests that there may be implications for therapy.