ABSTRACT
BACKGROUND AND OBJECTIVES: Obesity is a global epidemic which increases the risk of the metabolic syndrome. Cathelicidin (LL-37 and mCRAMP) is an antimicrobial peptide with an unknown role in obesity. We hypothesize that cathelicidin expression correlates with obesity and modulates fat mass and hepatic steatosis. MATERIALS AND METHODS: Male C57BL/6 J mice were fed a high-fat diet. Streptozotocin was injected into mice to induce diabetes. Experimental groups were injected with cathelicidin and CD36 overexpressing lentiviruses. Human mesenteric fat adipocytes, mouse 3T3-L1 differentiated adipocytes and human HepG2 hepatocytes were used in the in vitro experiments. Cathelicidin levels in non-diabetic, prediabetic and type II diabetic patients were measured by enzyme-linked immunosorbent assay. RESULTS: Lentiviral cathelicidin overexpression reduced hepatic steatosis and decreased the fat mass of high-fat diet-treated diabetic mice. Cathelicidin overexpression reduced mesenteric fat and hepatic fatty acid translocase (CD36) expression that was reversed by lentiviral CD36 overexpression. Exposure of adipocytes and hepatocytes to cathelicidin significantly inhibited CD36 expression and reduced lipid accumulation. Serum cathelicidin protein levels were significantly increased in non-diabetic and prediabetic patients with obesity, compared with non-diabetic patients with normal body mass index (BMI) values. Prediabetic patients had lower serum cathelicidin protein levels than non-diabetic subjects. CONCLUSIONS: Cathelicidin inhibits the CD36 fat receptor and lipid accumulation in adipocytes and hepatocytes, leading to a reduction of fat mass and hepatic steatosis in vivo. Circulating cathelicidin levels are associated with increased BMI. Our results demonstrate that cathelicidin modulates the development of obesity.
Subject(s)
Antimicrobial Cationic Peptides/pharmacology , Fatty Liver/drug therapy , Fatty Liver/prevention & control , Lipid Metabolism/drug effects , 3T3-L1 Cells , Adipocytes/cytology , Adipocytes/drug effects , Adipocytes/metabolism , Animals , CD36 Antigens/biosynthesis , CD36 Antigens/genetics , Cell Differentiation/drug effects , Diabetes Mellitus, Experimental , Diet, High-Fat/adverse effects , Disease Models, Animal , Fatty Liver/complications , Fatty Liver/metabolism , Gene Expression Regulation/drug effects , Hepatocytes/drug effects , Humans , Immunohistochemistry , Liver/pathology , Male , Mice , Mice, Inbred C57BL , Obesity/complications , Obesity/metabolism , Prediabetic State/complications , Prediabetic State/metabolism , CathelicidinsABSTRACT
Intestinal fibrostenosis is among the hallmarks of severe Crohn's disease. Patients with certain TNFSF15 (gene name for TL1A) variants over-express TL1A and have a higher risk of developing strictures in the small intestine. In addition, sustained Tl1a expression in mice leads to small and large intestinal fibrostenosis under colitogenic conditions. The aim of this study was to determine whether established murine colonic fibrosis could be reversed with Tl1a antibody (Ab). Treatment with neutralizing Tl1a Ab reversed colonic fibrosis back to the original pre-inflamed levels, potentially as a result of lowered expression of connective tissue growth factor, Il31Ra, transforming growth factor ß1 and insulin-like growth factor-1. In addition, blocking Tl1a function by either neutralizing Tl1a Ab or deletion of death domain receptor 3 (Dr3) reduced the number of fibroblasts and myofibroblasts, the primary cell types that mediate tissue fibrosis. Primary intestinal myofibroblasts expressed Dr3 and functionally responded to direct Tl1a signaling by increasing collagen and Il31Ra expression. These data demonstrated a direct role for TL1A-DR3 signaling in tissue fibrosis and that modulation of TL1A-DR3 signaling could inhibit gut fibrosis.
Subject(s)
Colon/immunology , Crohn Disease/immunology , Signal Transduction/immunology , Tumor Necrosis Factor Ligand Superfamily Member 15/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/pharmacology , Colon/pathology , Crohn Disease/genetics , Crohn Disease/pathology , Fibrosis , Humans , Mice , Mice, Knockout , Myofibroblasts/immunology , Myofibroblasts/pathology , Receptors, Interleukin/genetics , Receptors, Interleukin/immunology , Receptors, Tumor Necrosis Factor, Member 25/genetics , Receptors, Tumor Necrosis Factor, Member 25/immunology , Signal Transduction/drug effects , Signal Transduction/genetics , Tumor Necrosis Factor Ligand Superfamily Member 15/antagonists & inhibitors , Tumor Necrosis Factor Ligand Superfamily Member 15/geneticsABSTRACT
No final conclusion has yet been achieved on whether the area postrema (AP) is involved in the regulation of cardiovascular activity in the rats. The aim of the present study was to investigate the role of the AP in the regulation of basal blood pressure under normal as well as abnormal (cold stress) conditions in Sprague-Dawley rats. The lesion of AP was performed by the electrolytic-lesion method. Stressed animals were subjected to chronic intermittent cold stress (2 degrees C, 3 h/day for 14 days). The systolic blood pressure was measured by the indirect tail-cuff transducer method. The results showed that no significant difference was found between systolic blood pressure measured before and after AP-lesion surgery. The AP-lesion group had similar systolic blood pressure to both sham-operation and the control groups under normal environmental conditions. However, it was found that cold stress resulted in a significant increase in systolic blood pressure in the AP-lesion rats, but not in sham-lesion animals, within two weeks. Furthermore, there was no significant difference between blood pressures of sham-lesion rats with or without cold stress and the control animals. These results support the view that the AP plays no role in keeping basal blood pressure under normal condition and indicate as well that the AP is important in maintaining normal blood pressure under the conditions of stress (cold).
