Deciphering the role of lipocalin 13 in obesity and diabetes: from molecular analysis to physiological relevance


Grant Data
Project Title
Deciphering the role of lipocalin 13 in obesity and diabetes: from molecular analysis to physiological relevance
Principal Investigator
Dr Wong, Chi Ming   (Principal investigator)
Co-Investigator(s)
Professor Xu Aimin   (Co-Investigator)
Duration
24
Start Date
2013-06-01
Completion Date
2015-05-31
Amount
117700
Conference Title
Presentation Title
Keywords
lipocalin, obesity, diabetes, LCN13, metabolic hormone
Discipline
Endocrinology,Diabetes/Metabolism
Panel
Medicine
Sponsor
Block Grant Earmarked for Research (104)
HKU Project Code
201211159084
Grant Type
Seed Fund for Basic Research
Funding Year
2012/2013
Status
Completed
Objectives
In addition to the regulation of glucose metabolism, previous studies also demonstrated the protective role of LCN13 against hepatic steatosis(1). Overexpression of LCN13 in primary mouse hepatocytes and in the liver of transgenic mice reduces hepatic lipogenesis and stimulates fatty acid β-oxidation(1). Subsequent study, of neutralizing endogenous LCN13 with anti-LCN13 serum exacerbates diet-induced hepatic steatosis(1), further suggested the beneficial role of LCN13 in lipid metabolism. To summarize, these findings collectively suggested that LCN13 has therapeutic potential to treat obesity-related diseases. However, up to date, only two scientific papers from the same group of researchers reported the benefits of mouse LCN13 on glucose and lipid metabolism. Their findings remain to be validated. In addition, the previous findings were based on the transgenic mouse and cultured cell models. There is no loss-of-function study to support their findings. The detail molecular mechanism for the action of LCN13 is still not clear. Aims and Hypotheses to be Tested: Generally consistent with previous findings, the expression level of LCN13 mRNA in liver is much lower in the mice fed with high fat diet than their lean controls in our microarray study (Fig. 1A). However, low LCN13 protein was detected in the liver by the immunoblotting (Fig. 1C). In contrast, LCN13 protein is abundantly expressed, although no LCN13 mRNA (Cut-off for positive result with cycle threshold Ct ? 37), was detected, in pancreas (Fig. 1B-C). Therefore, we hypothesize that the LCN13 protein is mainly produced in liver and is transported to pancreas via bloodstream. In addition, previous studies only focused on the impact of LCN13 on glucose and lipid metabolism in liver and adipose tissue, the role of LCN13 on pancreas has NOT been determined. As pancreas the major targeted organ for the actions of LCN13 (Fig 1C-E), it is necessary to further explore the physiological role(s) of LCN13 in pancreas by both in-vivo and ex-vivo approaches. The long-term goal of this study is to fully elucidate the mechanism of mouse LCN13 involved in obesity and diabetes, and explore the possibility to apply our knowledge learned from the mouse to treat obesity and its related comorbidities in human. Specific to this project, the objectives are listed as followings: 1: To investigate the expression pattern of circulating LCN13 in different pathophysiological conditions 2: To investigate the function of LCN13 by loss-of-function study 3: To explore the role of LCN13 on the pancreatic functions. Key references 1. Sheng, L., Cho, K. W., Zhou, Y., Shen, H., and Rui, L. (2011) The Journal of biological chemistry 286, 38128-38135 2. Cho, K. W., Zhou, Y., Sheng, L., and Rui, L. (2011) Molecular and cellular biology 31, 450-457 3. Ezzati, M., and Riboli, E. (2012) Science 337, 1482-1487 4. Ko, G. T., So, W. Y., Chow, C. C., Wong, P. T., Tong, S. D., Hui, S. S., Kwok, R., Chan, A., Chan, C. L., Chan, J. C., and Committee, B. R. (2010) Eur J Clin Nutr 64, 1386-1392 5. Macfarlane, D. J., and Thomas, G. N. (2010) British journal of sports medicine 44, 1197-1201 6. Bray, G. A., and Ryan, D. H. (2012) Circulation 125, 1695-1703 7. Ortega, F. B., Lee, D. C., Katzmarzyk, P. T., Ruiz, J. R., Sui, X., Church, T. S., and Blair, S. N. (2012) Eur Heart J 8. Chen, W., Hoo, R. L., Konishi, M., Itoh, N., Lee, P. C., Ye, H. Y., Lam, K. S., and Xu, A. (2011) The Journal of biological chemistry 286, 34559-34566 9. Xu, A., Lam, M. C., Chan, K. W., Wang, Y., Zhang, J., Hoo, R. L., Xu, J. Y., Chen, B., Chow, W. S., Tso, A. W., and Lam, K. S. (2005) Proceedings of the National Academy of Sciences of the United States of America 102, 6086-6091 10. Hui, X., Zhu, W., Wang, Y., Lam, K. S., Zhang, J., Wu, D., Kraegen, E. W., Li, Y., and Xu, A. (2009) The Journal of biological chemistry 284, 14050-14057 11. Zhou, M., Xu, A., Lam, K. S., Tam, P. K., Che, C. M., Chan, L., Lee, I. K., Wu, D., and Wang, Y. (2010) J Hepatol 53, 1108-1116 12. Kaneko, K., Ueki, K., Takahashi, N., Hashimoto, S., Okamoto, M., Awazawa, M., Okazaki, Y., Ohsugi, M., Inabe, K., Umehara, T., Yoshida, M., Kakei, M., Kitamura, T., Luo, J., Kulkarni, R. N., Kahn, C. R., Kasai, H., Cantley, L. C., and Kadowaki, T. (2010) Cell metabolism 12, 619-632 13. Cheng, K. K., Lam, K. S., Wu, D., Wang, Y., Sweeney, G., Hoo, R. L., Zhang, J., and Xu, A. (2012) Proceedings of the National Academy of Sciences of the United States of America 109, 8919-8924 14. Xu, G., Ahn, J., Chang, S., Eguchi, M., Ogier, A., Han, S., Park, Y., Shim, C., Jang, Y., Yang, B., Xu, A., Wang, Y., and Sweeney, G. (2012) The Journal of biological chemistry 287, 4808-4817