Abstract Body: Introduction: Early onset of type 2 diabetes mellitus in obese children is a growing concern in the USA. Despite great advances in the treatment for diabesity in recent years, there is still an urgent need to find novel therapies to control the disease. Ion channels are promising therapeutic targets for metabolic disorders by modulating ionic homeostasis as they regulate cellular physiology and hormone secretion.
Methods: To decipher the role of novel ion channel, CLIC1 in HFD-induced juvenile diabesity and associated cardiac dysfunction, we incorporated the binge eating mouse model. 6 weeks old wild type and mice lacking clic1 were fed with high fat diet (60% HFD-ad libitum) for 20 weeks to induce obesity. We recorded food intake, body weight, blood glucose levels, tolerance for glucose and insulin, fat composition, metabolism and cardiac function of both sexes. To establish the mechanism in HFD-induced diabesity, we incorporated biochemical, immuno cyto/histo-chemistry and molecular biology approaches.
Results: We discovered that the ablation of CLIC1 promotes juvenile obesity in HFD-fed mice in both sexes. Echo-MRI revealed that null mutant mice had increased fat composition but decreased lean mass. In contrast, we observed that lack of CLIC1 in male mice are prone to develop type 2 diabetes, whereas female mice are protected. Whilst there were no differences in whole body metabolism, we found a decreased expression of GLUT4 in HFD-fed clic1^-/- as compared to normal diet fed clic1^-/-. High-resolution echocardiography shows that HFD-fed wt mice have compromised cardiac function. We observed decreased E/A ratio (diastolic dysfunction) in HFD fed WT mice compared to normal diet fed WT mice. Mice lacking CLIC1 presented no cardiac dysfunction.
Conclusion: For the first time, we show that the expression of CLIC1 is vital for preventing juvenile diabesity. Further we discovered that though morbidly obese mice lacking clic1 had normal cardiac function. These observations pave the way for the development of CLIC1 specific novel therapeutic strategy in juvenile model of diabesity.