A team of two Rutgers researchers discovered complementary brain channels that work like a tug of war, one circuit stepping on the starvation accelerator while the other applied brakes.
These findings, published in natural metabolism and natural transmission, reveal how the brain dynamically rewires to match food-seeking behaviors with the body’s actual energy needs.
The study goes beyond current weight loss medications by mapping specific neural circuits that can target reduced side effects while maintaining therapeutic benefits. With today’s GLP-1 drugs constantly suppressing the signal of appetite, these newly discovered pathways suggest a more nuanced approach that can preserve the brain’s natural dietary rhythm.
Two opposing circuits control the food driver
Mark Rossi and Zhiping Pang are co-led by Rutgers’ Neuro-Metabolic Center, who track individual but interconnected brain circuits. Pang’s team identified neurons from the hypothalamus to the brainstem, which turned off diet when activated. The cells are packed with GLP-1 receptors, targeting the same proteins as weight loss drugs such as Ozempic and Wegovy.
When the researchers used light pulses to activate this pathway in well-fed mice, the animals stopped feeding immediately. However, when scientists silence or delete the receptor, the mice gained rapidly.
“Synapses are volume knobs that appear only when energy storage is low,” Ponger explained. He warned that drugs that keep these signals high around the clock disrupt normal brain rhythms and trigger side effects such as nausea and muscle waste.
Rossi’s team draws the opposite track that triggers hunger. They tracked inhibitory neurons, and even after being activated, they rushed the mice towards sugar water even after feeding. When blocked, the animal remains invalid even after a long period of fasting.
“Pang’s road shuts things down,” Rosie said. “Our steps on the accelerator.”
The brain rewires according to its energy state
The most striking discovery is how fast these circuits adapt. During fasting, the hunger circuit becomes allergic, while the satiety circuit becomes weakened. After eating, the relationship completely flips. This dynamic rewiring occurs through changes in synaptic strength – depending on the body’s energy state, the connection between neurons becomes stronger or weaker.
The hunger circuit exhibits particularly severe state-dependent changes. When fasting mice, 22% of neurons in this pathway become excited during food consumption, while only 2% of animals were fed well. When mice were hungry, the same neurons tracked in both cases showed significantly stronger responses.
Hormone injections confirm the sensitivity of the circuit to metabolic signals. Ghrelin, the intestinal hunger messenger, supercharges food behavior through the Hunger Tour. Leptin, satiety hormone, turn it off. These hormone effects disappeared when researchers removed key neurons from the pathway.
Obesity can damage the system
The researchers found that three weeks of high-fat diet feeding completely eliminated the circuit’s ability to adjust based on energy demands. Overeating mice showed blunt responses in both pathways, with their brains basically in a dysregulated state regardless of actual hunger levels.
However, dysfunction proves reversible. When mice returned to regular food for three weeks, their brain circuits restored normal sensitivity to fasting and feeding status. This finding suggests that dietary interventions may restore appropriate neurological function even during the nutritional period.
The study reveals an important detail missing from current understanding: the sensitivity of promoting starvation circuits is entirely dependent on specific neurons expressing the secret receptor of the growth hormone. When the researchers eliminated these neurons, ghrelin could no longer enhance food-seeking behavior, although leptin’s appetite suppression was still intact.
Impact on better medicines
Current GLP-1 drugs can cause weight loss but can cause major side effects, including nausea, diarrhea and muscle waste in some patients. The new circuit diagram proposes more targeted methods.
Pang’s research shows that drugs targeting brainstem circuits only may suppress appetite while retaining peripheral organs without gastrointestinal side effects. Meanwhile, Rossi’s work shows that restoring sensitivity to autropin can help dieters go through months of calorie restriction.
The researchers used complex techniques including optogenetics to control neurons with laser light, chemical genetics to silencing specific cells, and real-time calcium imaging to observe the unfolding of neural activity. These tools can be more accurate than ever before when manipulating a single pathway.
Key findings include:
- Two complementary brain circuits control food seeking and stopping
- Neural connections are enhanced and weakened within hours according to energy state
- A high-fat diet temporarily disables the brain’s ability to need appetite
- Circuit functionality can be restored by returning to a healthier diet
- Hunger circuit activation requires specific hormone receptors
Stay flexible
Both research teams plan follow-up research to improve drug development. Pang hopes to measure GLP-1 release in real time to determine whether short bursts rather than continuous exposure can calm appetite more effectively. Rossi is classifying molecular characteristics of starvation-triggered cells to find drug targets that reduce cravings without eliminating dietary pleasure.
“You want to keep the system flexible,” Rossi noted. “It’s the difference between dimming the light and throwing it away.”
The study shows that getting the brain to correctly rebalance dietary expectations throughout the day, rather than using drugs to keep appetite suppressed, may be crucial in developing the next generation of weight loss treatments. By understanding how natural hunger and fullness are often coordinated, scientists may eventually develop treatments that work with existing systems in the brain, rather than confront them.
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