Brain RAP is a Critical Mediator of Leptin Resistance and Obesity Interview with:

Makoto Fukuda Ph.D. Assistant Professor Children's Nutrition Research Center Department of Pediatrics Baylor College of Medicine Houston, Texas 77030

Dr. Makoto Fukuda

Makoto Fukuda Ph.D.
Assistant Professor
Children’s Nutrition Research Center
Department of Pediatrics
Baylor College of Medicine
Houston, Texas 77030 What is the background for this study? What are the main findings?

Response: A hallmark characteristic of obesity is diminished actions of metabolic hormones that are critically required to maintain whole body energy balance and glucose homeostasis. Leptin is a crucial and powerful hormone that keeps body weight normal. It was hoped that leptin might be a “magic bullet” that could cure obesity. Shortly after the discovery, however, obese individuals were found to have little or no response to exogenously administered leptin, a state of “leptin resistance”. These observations created a central question to be addressed in the field, which would help our understanding of the core of pathophysiology of obesity. While we and other groups previously demonstrated that Epac, a signaling molecule known as a GTP/GDP exchange factor directly activated by cAMP, is involved in cellular leptin resistance, the role of brain Epac signaling in the whole body metabolism has not yet established.

We approached this question by using brain-specific knockout mice of Rap1, a direct activator of Epac. As expected from previous results, mice with brain-specific deficiency of Rap1 failed to develop leptin resistance even when they were challenged with a hypercaloric diet. What impressed us most in this study was that Rap1 in the brain plays a key role in the whole body metabolic control, beyond its role in controlling leptin sensitivity. Loss of brain Rap1 protects mice from diet-induced obesity and disordered glucose balance, whereas these knockout mice maintained a similar body weight to that of control mice on a normal regular diet. Further, pharmacological inhibition of this pathway reversed leptin resistance and reduced the body weight of dietary obese mice. At the cellular level, we found an unexpected link between Rap1 and endoplasmic reticulum (ER) stress that has emerged as a causative contributor to the development of leptin resistance. What should readers take away from your report?

Response: A key message from this study is that brain Rap is a critical signaling mediator of leptin resistance and obesity. Additionally, in the proof-of-concept study with an Epac2 inhibitor, acute suppression of brain Epac-Rap1 signaling indeed displayed an anticipated beneficial effect in reducing body weight of diet-induced obese mice. Providing a potential mechanic insights into the action of Rap1 in mediating leptin resistance, we also showed that reciprocal interactions between Rap1 and ER stress in the brain of diet-induced obese mice, which implies that Rap1 may be a key molecule that links ER stress to neural leptin resistance. What recommendations do you have for future research as a result of this study?

Response: This study is the first, basic research conclusively providing evidence that Rap1 in the brain is a key molecule that links excess energy intake and the biological responses associated with obesity, but further study is required. For example, further validation of our results from multiple different research groups is necessary for future translational studies aimed to treat obesity. Another intriguing question is to determine the molecular link between Rap1 and overfeeding. If Rap1 is really proven to be a critical mediator of obesity, the next logical step is to determine what activates Rap1 and drives leptin resistance under overnutrition. Addressing this question will advance our understanding of how the brain contributes to the pathophysiology of obesity. Thank you for your contribution to the community.


Kentaro Kaneko et al. Neuronal Rap1 Regulates Energy Balance, Glucose Homeostasis, and Leptin Actions. Cell Reports, September 2016 DOI: 10.1016/j.celrep.2016.08.039

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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