March 2020
What makes us hungry? What satisfies our hunger? The complex cellular processes controlling appetite begin when hormones such as ghrelin, melanocortin and others interact with cell surface receptors in the brain, initiating signaling pathways that stimulate or suppress appetite and prepare the body for digestion, resulting in the storage or release of energy from food.
It is in the intricate details of these pathways that some researchers hope to find solutions to the problems of obesity and diabetes. The laboratory of Fraternal Order of Eagles Diabetes Research Center member, Julien Sebag, PhD, Assistant Professor of Molecular Physiology and Biophysics, studies cell surface receptors and accessory proteins in the brain that signal hunger, communicate “fullness”, and control energy balance—the processes that tell us when we need to eat, cause us to stop eating when full, and stimulate the body to produce and store energy.
The “hunger hormone” ghrelin is secreted by the stomach during fasting to promote food intake. Ghrelin increases appetite by activating its receptor GHSR1a in the hunger sensing neurons in the brain and for that reason is a promising avenue for the development of anti-obesity treatments. In a study recently published in the Journal Science Signaling, the Sebag lab found that the Melanocortin Receptor Accessory Protein 2 (MRAP2) interacts with GHSR1a in a way that drastically alters the cellular signals triggered by ghrelin. Whereas, in the presence of MRAP2, ghrelin activates the cellular signal responsible for hunger sensing, in the absence of MRAP2, ghrelin triggers an alternative pathway with unknown physiological function. This finding has important implications towards understanding how ghrelin may carry different functions in different tissues depending on the presence or absence of MRAP2. Specifically, if an approach or therapy can be discovered to prevent the interaction of the ghrelin receptor and MRAP2 in hunger sensing brain neurons, then this could lead to the development of treatments that could produce weight loss by reducing appetite. This deeper understanding of GHSR1a signaling and regulation by MRAP2 may inform future drug discovery efforts targeting GHSR1a to treat obesity and improve their likelihood of being successful. With this knowledge, scientists hope to identify new and better drugs for treating obesity and diabetes.