Rutgers Scientists Identify Neural Mechanisms of Hunger and Satiety

Researchers at Rutgers University have made significant strides in understanding the complex neural mechanisms that regulate hunger and satiety, revealing two newly identified circuits in the brain that interact in a dynamic tug-of-war over appetite control. Published in the journals *Nature Metabolism* and *Nature Communications*, these findings may lead to advancements in the design of more effective weight-loss medications, including current drugs like Ozempic.

The studies, led by Zhiping Pang and Mark Rossi at the Center for NeuroMetabolism, unveil the intricate relationship between hormones and brain signals that dictate when individuals feel hungry and when they should stop eating. According to Dr. Zhiping Pang, an associate professor at Robert Wood Johnson Medical School, the research highlights a slender bundle of neurons extending from the hypothalamus to the brainstem, densely populated with GLP-1 receptors. These receptors are the target of GLP-1 mimetic drugs that have gained popularity for weight management.

"When we activated this pathway in well-fed mice, they ceased eating; conversely, silencing the circuit or removing the receptor caused weight gain," Dr. Pang explained. The research indicates that fasting diminishes the strength of this neural connection until it is restored by bursts of GLP-1, either natural or synthetic. This discovery could help refine the use of GLP-1 drugs, which have been associated with side effects like nausea and gastrointestinal discomfort.

In the complementary study, Dr. Mark Rossi mapped a different circuit responsible for triggering hunger, focusing on inhibitory neurons in the stria terminalis linked to the lateral hypothalamus. His research demonstrated that stimulating this pathway prompted mice to seek food aggressively, while inhibiting it resulted in lethargy despite prolonged fasting. Hormonal signals, such as ghrelin and leptin, modulate these responses, with ghrelin stimulating food-seeking behavior and leptin signaling satiety.

"The circuits are in different brain regions, but they reveal a fundamental principle: the energy state of an organism quickly alters synaptic connections. During fasting, the hunger circuit becomes more sensitive while the satiety circuit lessens its response, and vice versa after eating," noted Dr. Rossi, co-leader of the research center.

This research represents the first detailed mapping of these opposing circuits operating in parallel, suggesting that current weight-loss drugs that address only one aspect of appetite regulation may lose effectiveness over time. Instead, drugs that target both sides of the hunger-satiety equation could enhance efficacy and reduce adverse effects.

The implications of these findings extend beyond theoretical understanding. As noted by Dr. Pang, future therapies might focus on modulating the brainstem circuit alone, potentially minimizing the side effects associated with peripheral organ interventions. Moreover, restoring the body’s sensitivity to ghrelin could assist individuals who plateau after dieting.

This breakthrough in neural biology employed advanced techniques such as optogenetics, which uses light to manipulate neurons, and chemogenetics for silencing them, alongside traditional patch-clamp recordings to observe individual synapse activity. These methodologies enabled the researchers to fine-tune their investigations into the brain's appetite control mechanisms.

Looking ahead, both research teams plan to further investigate the dynamics of GLP-1 release and its timing, hypothesizing that intermittent bursts may be more effective than constant exposure. Dr. Rossi aims to identify the molecular characteristics of hunger-trigger cells to develop targeted medications that stimulate appetite without impairing the enjoyment of food.

These discoveries underscore the importance of balancing the body's natural appetite regulation mechanisms, moving towards a future where weight-loss prescriptions could offer flexible, individualized approaches to managing hunger and satiety in a healthier manner. As Dr. Rossi aptly stated, "You want to keep the system's flexibility; it's about dimming the lights rather than turning them off completely."

As the field of obesity treatment continues to evolve, these insights from Rutgers University not only pave the way for more sophisticated weight-loss drugs but also contribute to our broader understanding of human appetite regulation, potentially impacting millions struggling with weight management globally.