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.
We propose to study the roles of cathelicidin in obesity and diabetes. The blood level of cathelicidin may serve as a future biomarker to indicate the severity and complications of obesity and diabetes as cathelicidin administration reduces obesity and steatosis in mice. Positive results can result in cathelicidin becoming a diagnostic or therapeutic approach against obesity and diabetes in the future.
