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Omprakash Singh, Ph.D.

Basic Science Award, 2023

What stood out about your research experience at UT Southwestern, and how did it shape your career?

I am fortunate to have Dr. Jeffrey Zigman as my mentor in diabetes and obesity research, drawing on his expertise as both a researcher and a clinical doctor. My research in the Zigman Lab focuses on ghrelin biology, specifically investigating the role of ghrelin action in the brain. A key aspect of my work has been helping and validating genetically engineered mouse models, which have allowed me to dissect the molecular and neural mechanisms underlying metabolic regulation. Additionally, working closely with Drs. Joel Elmquist and Kevin Williams, as well as other experts in the field, has broadened my perspective on integrating molecular, circuit, and behavioral neuroscience. I have also had the opportunity to present my work alongside experts such as Drs. Joseph Takahashi and William Dauer with the Peter O’Donnell Jr. Brain Institute (OBI), engaging with specialists in circadian rhythms, molecular biology, and neurology, including dystonia and Parkinson’s disease. These experiences have boosted my confidence and strengthened my ability to present my research to diverse audiences of experts. Collaborating with leading researchers, presenting global conferences, and receiving feedback have sharpened my ability to craft impactful research questions and solidified my goal of establishing an independent research program focused on neural mechanisms regulating metabolism, steering me toward an academic career.

How has your basic research bridged the gap between lab discoveries and potential clinical applications?

In the Zigman Lab, I contributed to validating transgenic mouse models, including the LEAP2-knockout line published in Molecular Metabolism, which revealed that LEAP2 deletion increases food intake, body weight, and other metabolic parameters in mice. This work highlights key mechanisms relevant to obesity and metabolic disorders. Building on these findings, we are also developing therapeutic agents targeting obesity using LEAP2. These include treatments for Cancer-Related Anorexia-Cachexia and long-acting LEAP2 analogs, which have demonstrated the ability to reduce hepatic steatosis and inflammation while causing significant weight loss in mice. I recently completed a project using chemogenetic manipulation of ghrelin receptor-expressing neurons in the mediobasal hypothalamus, demonstrating the importance of ghrelin signaling in exercise-induced food intake and endurance. Plasma ghrelin levels were found to correlate with treadmill performance, as published in Journal of Clinical Investigation Insights. These findings suggest that targeting the ghrelin system in conjunction with exercise could offer potential therapeutic strategies for managing obesity, diabetes, and other metabolic disorders. Furthermore, my research on the role of the suprachiasmatic nucleus (SCN) in regulating ghrelin and LEAP2 has led to the discovery that inhibiting SCN ghrelin receptor neurons during the resting phase reduces food intake and results in a modest body weight reduction. This finding presents a significant opportunity to address obesity by targeting time-of-day neuronal pathways. My ongoing research on the sympathetic neural circuits that regulate ghrelin secretion during exercise and caloric restriction. These findings are pivotal for developing strategies to manage and prevent metabolic disorders, providing valuable insights into therapeutic targets for obesity and diabetes.

What unexpected discovery or challenge did you encounter in your basic research, and how did it shape your approach to scientific inquiry?

My research focuses on the role of ghrelin-responsive neurons in regulating exercise endurance, food intake, and metabolic health. Previous studies have demonstrated the hormone ghrelin as a mediator of exercise endurance and the feeding response postexercise. Plasma ghrelin levels nearly double in mice after an hour of high-intensity interval exercise (HIIE) on treadmills, and growth hormone secretagogue receptor–null (GHSR-null) mice show reduced food intake and reduced running distance during an exercise endurance protocol. I investigated whether ghrelin-responsive MBH neurons mediate these effects. I found that intact ghrelin signaling is essential for exercise-induced responses, but inhibiting GHSR-expressing MBH neurons reduces HIIE-induced food intake and exercise endurance. I am now working to enhance the translational impact of the ghrelin system for treating obesity, diabetes, and metabolic disorders. This includes investigating glucose-responsive neurons in MBH-GHSR-expressing neurons that detect hypoglycemia post-exercise and exploring the relationship between exercise, sympathetic activation, and ghrelin secretion through detailed neuronal mapping. Currently, research shows that eating later in the day leads to greater weight gain, and night-shift workers are more prone to obesity and mental disorders. I am studying the role of the SCN in ghrelin action and how ghrelin-responsive SCN neurons contribute to food intake and body weight. The most exciting aspect of our focus is that inhibiting SCN ghrelin receptor neurons during the resting phase reduces food intake, especially at night, resulting in a 7 percent reduction in body weight. These findings present a significant opportunity to address metabolic diseases, such as diabetes and obesity, by targeting the ghrelin system in circadian-specific neuronal pathways that regulate feeding behavior and energy balance, offering valuable insights into potential therapeutic targets for managing and preventing these disorders.

How did participating in the Seldin Symposium impact your research path?

It greatly enhanced my confidence in presenting and discussing my research within this evolving field. The symposium provided an opportunity to receive insightful feedback and engage with fellow researchers addressing similar challenges related to energy balance, diabetes, and obesity. It also opened doors for potential collaborations, broadening the scope of my research and its clinical implications. Engaging with innovative research and leading scientists at the Seldin Symposium helped refine my approach and encouraged me to critically evaluate the wider significance of my findings. This experience not only advanced my research perspective but also allowed me to expand my professional network, shaping the future trajectory of my work.

What are your current research interests and goals?

I am focused on understanding the neuroendocrine mechanisms regulating feeding, energy balance, and circadian rhythms, with a specific emphasis on ghrelin and ghrelin receptor (GHSR) signaling. My goal is to develop integrative strategies combining exercise and targeted therapies to address metabolic disorders like diabetes and obesity. I investigate the interplay between ghrelin, the sympathetic nervous system, exercise, and circadian regulation, focusing on their collective influence on neural circuit plasticity and metabolic health. This work is rooted in the concept of the “Triangle of Health or the Three Pillars of Health,” which highlights the dynamic interplay among nutrition (feeding), exercise, and sleep (circadian rhythms) in regulating energy homeostasis and maintaining overall metabolic health. At the core of this framework is ghrelin, a gut-derived orexigenic hormone that regulates feeding behavior and adapts to fasting, exercise, and neural circuitry. Circadian misalignment, sedentary lifestyles, and irregular feeding schedules have emerged as key drivers of metabolic disorders such as obesity and diabetes. Disruptions in circadian rhythms caused by factors like shift work, irregular sleep patterns, or jet lag can lead to misaligned ghrelin secretion, increasing the risk of overeating and metabolic dysregulation. Understanding these intricate connections is crucial for identifying effective strategies to address lifestyle-related diseases and improve metabolic health and health-span.

What advice would you offer current Internal Medicine trainees about pursuing research?

Stay curious and persistent while addressing complex questions in metabolism, behavior, and circadian biology. Collaborating with interdisciplinary teams and understanding the translational potential of basic research will lead to impactful discoveries and career growth. Identify areas in your clinical work that spark your interest and embrace the challenge of research, as it offers opportunities to ask questions that can change disease understanding and treatment. Actively seek mentorship, step out of your comfort zone to explore new methods, techniques and remain persistent. Research may take time, but the journey is invaluable and highly motivating.

Representative Publications

"Engaging with innovative research and leading scientists at the Seldin Symposium helped refine my approach and encouraged me to critically evaluate the wider significance of my findings."

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