Scientists Map Brain Circuits That Drive Food Cravings Based on Energy Needs

Two teams of Rutgers researchers have discovered complementary brain pathways that function like a neurological tug-of-war, with one circuit stepping on the hunger accelerator while another applies the brakes.

The findings, published in Nature Metabolism and Nature Communications, reveal how the brain dynamically rewires itself to match food-seeking behavior with the body’s actual energy requirements.

The research goes beyond current weight-loss medications by mapping specific neural circuits that could be targeted to reduce side effects while maintaining therapeutic benefits. Unlike today’s GLP-1 drugs that keep appetite signals constantly suppressed, these newly identified pathways suggest a more nuanced approach that preserves the brain’s natural eating rhythms.

Two Opposing Circuits Control Food Drive

Mark Rossi and Zhiping Pang, who co-lead Rutgers’ Center for NeuroMetabolism, traced separate but interconnected brain circuits. Pang’s team identified neurons running from the hypothalamus to the brainstem that shut down eating when activated. These cells are packed with GLP-1 receptors, the same proteins targeted by weight-loss drugs like Ozempic and Wegovy.

When researchers used light pulses to activate this pathway in well-fed mice, the animals immediately stopped eating. But when scientists silenced the circuit or deleted the receptors, mice gained weight rapidly.

“The synapse is a volume knob that only turns up when energy stores are low,” Pang explained. He cautioned that drugs keeping these signals high around the clock could disrupt normal brain rhythms and trigger side effects like nausea and muscle wasting.

Rossi’s team mapped the opposing circuit that triggers hunger. They traced inhibitory neurons that, when activated, sent mice sprinting toward sugar water even after they’d been well-fed. When blocked, animals remained inactive even after long fasts.

“Pang’s pathway shuts things down,” Rossi said. “Ours steps on the accelerator.”

Brain Rewires Itself Based on Energy Status

The most striking discovery was how quickly these circuits adapt. During fasting, the hunger circuit becomes hypersensitive while the satiety circuit weakens. After eating, the relationship completely flips. This dynamic rewiring happens through changes in synaptic strength—the connections between neurons literally become stronger or weaker based on the body’s energy state.

The hunger circuit showed particularly dramatic state-dependent changes. When mice were fasted, 22% of neurons in this pathway became excited during food consumption, compared to just 2% in well-fed animals. The same neurons tracked across both conditions showed significantly stronger responses when mice were hungry.

Hormone injections confirmed the circuits’ sensitivity to metabolic signals. Ghrelin, the gut’s hunger messenger, supercharged food-seeking behavior through the hunger circuit. Leptin, the satiety hormone, slammed it shut. These hormonal effects disappeared when researchers removed key neurons from the pathways.

Obesity Disrupts the System

The researchers discovered that three weeks of high-fat diet feeding completely eliminated the circuits’ ability to adjust based on energy needs. Overfed mice showed blunted responses in both pathways, with their brains essentially stuck in a dysregulated state regardless of actual hunger levels.

However, the dysfunction proved reversible. When mice returned to regular chow for three weeks, their brain circuits recovered normal sensitivity to fasting and feeding states. This finding suggests that dietary interventions might restore proper neural function even after periods of overnutrition.

The study revealed an important detail missing from current understanding: the hunger-promoting circuit’s sensitivity depends entirely on specific neurons that express growth hormone secretagogue receptors. When researchers eliminated these neurons, ghrelin could no longer enhance food-seeking behavior, though leptin’s appetite-suppressing effects remained intact.

Implications for Better Drugs

Current GLP-1 medications trigger weight loss but cause significant side effects including nausea, diarrhea, and muscle wasting in some patients. The new circuit maps suggest more targeted approaches.

Pang’s research indicates that drugs targeting only the brainstem circuit while sparing peripheral organs might curb appetite without gastrointestinal side effects. Meanwhile, Rossi’s work suggests restoring sensitivity to ghrelin could help dieters who plateau after months of calorie restriction.

The researchers used sophisticated techniques including optogenetics to control neurons with laser light, chemogenetics to silence specific cells, and real-time calcium imaging to watch neural activity unfold. These tools allowed unprecedented precision in manipulating individual pathways.

Key Findings Include:

• Two complementary brain circuits control food seeking and stopping
• Neural connections strengthen and weaken within hours based on energy status
• High-fat diets temporarily disable the brain’s ability to match appetite with need
• Circuit function can be restored by returning to healthier diets
• Specific hormone receptors are required for hunger circuit activation

Maintaining Flexibility

Both research teams plan follow-up studies to refine drug development. Pang wants to measure GLP-1 release in real-time to determine whether short bursts rather than constant exposure could calm appetite more effectively. Rossi is cataloging the molecular signatures of hunger-trigger cells to find drug targets that reduce cravings without eliminating eating pleasure.

“You want to keep the system’s flexibility,” Rossi noted. “It’s the difference between dimming the lights and flicking them off.”

The research suggests that allowing the brain to correctly rebalance eating desires throughout the day, rather than using drugs to keep appetite constantly suppressed, may prove crucial for developing the next generation of weight-loss treatments. By understanding how natural hunger and satiety circuits normally coordinate, scientists may finally develop therapies that work with the brain’s existing systems rather than against them.