Q&A: Penn State nutritional sciences researcher discusses implications of recent metabolic receptor study

Approximately one in eight American adults reports that they have taken an anti-obesity drug, like Ozempic or Wegovy, according to the KFF’s 2024 Health Tracking Poll. These GLP-1 receptor agonist drugs help the body to regulate blood sugar and promote a feeling of fullness when eating, which is why many have turned to them for weight loss. While these drugs have produced positive effects in many patients, GLP-1 receptor agonists often cause undesired side effects such as nausea, vomiting, constipation, and diarrhea.

A new study from researchers in the Penn State Department of Nutritional Sciences has uncovered new receptor signaling mechanisms at a metabolic receptor that could pave the way for new obesity treatment approaches that help avoid undesired side effects, while potentially still producing similar physiological responses to GLP-1 receptor agonists.

Joshua Gross, assistant professor of nutritional sciences and biobehavioral health, recently discovered and characterized a rare genetic mutation (L149P) in the receptor for ‘the hunger hormone’ ghrelin. Through examining biochemical processes in cell models, the researchers showed that the natural L149P mutation reprograms how the ghrelin receptor works at the molecular level compared to the native version of it.

The ghrelin receptor is a G protein-coupled receptor (GPCR), which is the most common receptor family targeted by pharmaceutical drugs, including GLP-1 receptor agonists. GPCRs receive signals from outside the cell and activate G proteins inside the cell, which, in turn, trigger adaptive biological responses. When the ghrelin receptor is activated, it engages G protein signaling inside the cell, ultimately causing hunger, an increase in body weight, and a disruption of glucose control. While these unhealthy metabolic effects are likely mediated through the G protein pathway, the mutated L149P receptor is unique in that it selectively uses a different intercellular signaling pathway to produce distinct effects on receptor function in cells.

The researchers believe that drugs utilizing this alternative signaling pathway might help to avoid the negative metabolic side effects that ghrelin produces when the usual G protein pathway is activated.

This finding by Gross and his research team may have implications for future drug development for metabolic and eating disorders, as deviation from the usual signaling pathway may enable researchers to selectively target specific receptor signaling pathways that avoid undesirable side effects while still producing desired therapeutic outcomes, such as reducing hunger and controlling blood glucose levels.

This study, published in Molecular Pharmacology, is the first step in Gross’s investigation into understanding how metabolic GPCR signaling can be manipulated and controlled using a natural receptor mutation as a model. Their long-term goal is to use this information to design new drugs that maximize the therapeutic effects of new medications while also minimizing the side effects.

Gross recently discussed how GPCR signaling works and the implications of the L149P mutation for future targeted medicine development.

Q: What is GPCR signaling, and how does it impact eating behavior?

Gross: GPCRs are receptor proteins embedded in cell membranes that act as an interface between the extracellular and intracellular environments, transferring information from molecules (such as metabolic hormones) into the cell via G proteins located inside the cell. The activated G protein then transfers the signal through amplification, which ultimately culminates in a certain biological response that helps organisms adapt to constantly changing environments.

>One example of these receptors at work is when we are fasting or hungry. When we are in this state, our body releases hunger hormones from the gut into the blood, such as ghrelin, that bind to their receptors to initiate adaptive responses. To accomplish this, the ghrelin-bound receptor signals to brain cells that we are hungry and to now enact several bodily processes that trigger behavioral and physiological changes. These changes cumulatively stimulate appetite, reduce metabolic rate, and shift food preferences towards calorie-dense foods. Altogether, these effects drive us to start eating, resist ending a meal, and start planning how to find more food to quench our hunger and restore our calorie reserves.

Work from our lab and others supports the idea that these effects are elicited by a specific signaling pathway, the G protein pathway, activated by the ghrelin receptor. But my previous work, along with many others, has found that there are many different cellular pathways that GPCRs, including the ghrelin receptor, can use to convey more nuanced and fine-tuned molecular information to more appropriately respond to hunger or other stimuli.

Q: What is L149P, and how is it different from other GPCRs?

Gross: The L149P mutation is an ultra-rare genetic variation in the ghrelin receptor. You typically do not find a genetic variant in this part of the receptor because, as we are learning, it is evolutionarily ancient and critical to basic receptor functions. What excites us about this new receptor model is that we can simultaneously learn more about fundamental molecular mechanisms of GPCRs while also providing a novel and generalizable target for GPCR drug development.

Even though it is a mutation found in humans, it is so rare that we have yet to find anyone with it to observe its clinical effects. Do they have any clinical issues? Are they protected against obesity or diabetes? Our recent study indicated that the L149P mutation dramatically dysregulates ghrelin receptor function, so we suspect that it would clinically impact humans. However, we still need to verify how it presents in people carrying this mutation or similar mutations in related metabolic receptors.

Q: How can L149P aid in improving medications and human health?

Gross: The prescription medications we would seek to produce based on this study would strive to precisely manipulate the conformation and orientation of the receptor to produce the same effects observed in the mutated L149P receptor. This would allow us to develop more targeted medications for metabolic or neurological conditions, without the undesired side effects that some of them cause by indiscriminately activating all signaling pathways in the cell.

For example, GLP-1 receptor agonists cause gastrointestinal side effects that negatively impact the person taking the medication. In some cases, the side effects can be severe enough that they have to stop taking these medications entirely before seeing the positive impacts.

Developing medications that better treat obesity, diabetes, and other eating disorders, or as a potential add-on therapy with existing medications, is the goal of continuing our research in this area. Our work provides the potential to develop better medications that may be safer and more effective for those looking to treat chronic metabolic disorders and improve their overall health.

Originally published in March 2026.