The endocannabinoid system, consisting of the CB1R and lipid derived endogenous cannabinoid molecules, has been shown to significantly contribute to the development of diabetes and obesity. Although CB1R inverse agonists 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 CNS and the periphery. The goal of this application is to investigate the role of CB1Rs in the SF1 neurons of the ventromedial hypothalamus to regulate energy homeostasis. We will also examine if this subset of neurons is responsible for the metabolic improvements associated with CB1R inverse agonists. We anticipate the results from our investigation will provide novel insight to the development of effective therapies to combat metabolic disease while circumventing potential side effects.

Public Health Relevance

The endogenous cannabinoid system is a key regulator of whole body energy balance. Activation of this system contributes to the development of diabetes and obesity, whereas drugs that block the cannabinoid system can protect from diabetes and obesity. While effective, these drugs also have severe side effects. We believe that the cannabinoid system in a small subset of neurons regulates energy and glucose balance. Studying these neurons will aid in the development of novel therapies, without side effects, to better treat or prevent diabetes and obesity

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Cooke, Brad
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Sw Medical Center Dallas
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Caron, Alexandre; Lee, Syann; Elmquist, Joel K et al. (2018) Leptin and brain-adipose crosstalks. Nat Rev Neurosci 19:153-165
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
Fujikawa, T; Castorena, C M; Lee, S et al. (2017) The hypothalamic regulation of metabolic adaptations to exercise. J Neuroendocrinol 29:
Xu, Yong; O'Malley, Bert W; Elmquist, Joel K (2017) Brain nuclear receptors and body weight regulation. J Clin Invest 127:1172-1180
Fujikawa, Teppei; Castorena, Carlos M; Pearson, Mackenzie et al. (2016) SF-1 expression in the hypothalamus is required for beneficial metabolic effects of exercise. Elife 5:
Lee, Jiwon; Yang, Dong Joo; Lee, Syann et al. (2016) Nutritional conditions regulate transcriptional activity of SF-1 by controlling sumoylation and ubiquitination. Sci Rep 6:19143
Zhu, Yi; Gao, Yong; Tao, Caroline et al. (2016) Connexin 43 Mediates White Adipose Tissue Beiging by Facilitating the Propagation of Sympathetic Neuronal Signals. Cell Metab 24:420-433
Sohn, Jong-Woo; Oh, Youjin; Kim, Ki Woo et al. (2016) Leptin and insulin engage specific PI3K subunits in hypothalamic SF1 neurons. Mol Metab 5:669-79