The Major Goals of this award are to: 1) allow me to build upon my current knowledge base in metabolism research by gaining expertise in the fields of neurophysiology and adipose tissue physiology, 2) further develop my overall scientific skills to become a successful independent diabetes researcher, and 3) achieve 1 and 2 through investigating role the endocannabinoid system in the development of diabetes and obesity to provide novel insight for future therapies. Because the complications of metabolic diseases, such as diabetes and obesity, are not isolated to one tissue in the body, it is imperative to investigate metabolic disorders utilizing an integrative physiology approach. Therefore, to build upon my expertise in skeletal muscle metabolism, I will receive training from my Mentor Dr. Joel Elmquist (expert in neuroanatomy and neurophysiology) and Co-mentor Dr. Philipp Scherer (expert in adipose tissue physiology). Drs. Elmquist and Scherer are leaders in diabetes and obesity research, and routinely utilize advanced cellular and molecular biology techniques to utilize a multidisciplinary approach to address innovative questions regarding obesity and diabetes. They have provided me with sophisticated mouse models that allow for the specific deletion or reactivation of cannabinoid 1 receptor (CB1R) from specific neuronal populations within the central nervous system (CNS) and from peripheral tissues. The endocannabinoid system, consisting of the CB1R and lipid derived endogenous cannabinoid molecules, has been shown to contribute to the development of diabetes and obesity. Although CB1R antagonist are effective at improving insulin sensitivity and protecting against diet induced obesity, these drugs have severe side effects associated with the widespread distribution of CB1Rs in the body. Therefore, the overarching aim of experiments within this application is to investigate distinct sites (neuronal and peripheral) of CB1R expression that are critical for metabolic regulation. We anticipate the results from our investigation will provide novel insight to the development of effective therapies to combat metabolic disease while circumventing major side effects. My Mentors have all necessary resources to complete the proposed experiments, and the rigorous training plan will provide me with the necessary skills to become an independent researcher. The training afforded by this fellowship will serve as the foundation for my career path to becoming a tenured research faculty with a laboratory that makes meaningful contributions to obesity and diabetes researcher. By combining all of my training, I will possess a unique skillset to utilize an integrative physiology (skeletal muscle <-> CNS <-> adipose tissue) allowing me to fill in a niche in diabetes research. The result obtained from this proposal will not result in competing interests with my mentors, the findings obtained are my own independent line of research to launch my independent career, and the models generated from this award will be made available to the scientific community.
The endogenous cannabinoid system is a key regulation of whole body energy balance. Over activation of this system contributes to the development of Type 2 Diabetes and obesity. However, the sites of action that are most important for these effects are poorly understood. The purpose of this project is to identify sites of action in the central nervous system and peripheral organs that are most important for these harmful effects. The results from this research will improve the understanding of the development of Type 2 Diabetes and obesity, and aid in the development of future therapies to better address these diseases.
| Mani, Bharath K; Castorena, Carlos M; Osborne-Lawrence, Sherri et al. (2018) Ghrelin mediates exercise endurance and the feeding response post-exercise. Mol Metab 9:114-130 |
| He, Zhenyan; Gao, Yong; Alhadeff, Amber L et al. (2018) Cellular and synaptic reorganization of arcuate NPY/AgRP and POMC neurons after exercise. Mol Metab 18:107-119 |
| Caron, Alexandre; Dungan Lemko, Heather M; Castorena, Carlos M et al. (2018) POMC neurons expressing leptin receptors coordinate metabolic responses to fasting via suppression of leptin levels. Elife 7: |
