Role of Cathelicidin in Obesity and Diabetes

 描述(申请人提供)：放线菌素(人类的IL-37和小鼠的mCRAMP)是一类内源性多肽，具有抗菌功能，参与先天性免疫反应，保护宿主免受感染。长春花碱还具有抗炎和抗肿瘤作用，并促进糖尿病小鼠皮肤伤口的愈合。尽管长春花碱的所有这些确定的积极益处，没有报告显示长春花素的代谢功能。初步结果表明，非糖尿病患者血液中的淫羊藿苷水平随着体重指数的增加而增加。在链脲佐菌素治疗的糖尿病小鼠中，注射表达慢病毒的放线菌素可减少高脂诱导的肥胖和肝脏脂肪变性。长春花碱抑制脂肪受体CD36表达减少的小鼠和人分化脂肪细胞的脂肪蓄积。放线菌素似乎是一种调节脂肪代谢的代谢荷尔蒙。该项目的假设是放线菌素能抑制 脂肪细胞或肝细胞通过减少PPARα/γ和CD36脂肪受体的表达而积聚脂肪。慢病毒长春花碱的表达有望减少肥胖糖尿病db/db小鼠的脂肪量和肝脏相关并发症(脂肪性肝炎和肝纤维化)。长春花碱通过抑制PPAR家族和通过PPARpha、PPARGamma和CD36的过度表达抑制CD36的表达来抑制动物的脂肪量的作用将被确定。长春花碱通过抑制PPAR家族在人分化的脂肪细胞和肝细胞中的作用将被确定。血液中的放线菌素也可能预示着肥胖和糖尿病的严重程度和并发症。将测定肥胖和糖尿病患者的IL-37水平与体重指数、血糖水平、血脂水平和糖尿病并发症等的相关性。这项建议将为长春花碱作为一种潜在的肥胖和糖尿病诊断或治疗方法的作用和机制提供有价值的见解。

 DESCRIPTION (provided by applicant): Cathelicidin (LL-37 in humans and mCRAMP in mice) is a family of endogenous peptides with antimicrobial functions that is involved with innate immune response to protect the host against infection. Cathelicidin also exhibits anti-inflammatory and anti-tumoral effects, and promotes skin wound healing in diabetic mice. Despite all of these determined positive benefits of cathelicidin, there is no report showing the metabolic functions of cathelicidin. Preliminary results have shown that cathelicidin level in the blood increases with body mass index of non-diabetic patients. Administration of cathelicidin expressing lentivirus reduces high fat induced obesity and hepatic steatosis in streptozotocin treated diabetic mice. Cathelicidin inhibits fat accumulation in mouse and human differentiated adipocytes with reduced fat receptor CD36 expression. Cathelicidin appears to be a metabolic hormone that regulates fat metabolism. The hypothesis of this project is that cathelicidin inhibits adipocyte or hepatocyte fat accumulation by reducing PPARalpha/gamma and CD36 fat receptor expression. Lentiviral cathelicidin expression is expected to reduce fat mass and liver related complications (steatohepatitis and liver fibrosis) of obese diabetic db/db mice. The role of cathelicidin in inhibiting fat mass of the animal via inhibiting PPAR family and CD36 expression using PPARalpha, PPARgamma, and CD36 overexpression will be determined. The effect of cathelicidin in inhibiting fat accumulation and/or CD36 expression via PPAR family inhibition using various pharmacological and molecular approaches in human differentiated adipocytes and hepatocytes will be determined. Cathelicidin in the blood may also indicate severity and complications of obesity and diabetes. The correlation of LL-37 levels in obese and diabetic patients with body mass index, blood glucose level, lipid levels and diabetic complications, etc will be determined. This proposal will provide valuable insight to the role and mechanism of cathelicidin as a potential diagnostic or therapeutic approach against obesity and diabetes.