What Rodents Teach Us About Weight Loss and Hunger

Do we truly possess free will in our dietary choices? This perplexing question lies at the core of why so many struggle to adhere to their diets.

To explore this, neuroscientist Harvey J. Grill from the University of Pennsylvania turned to rats, investigating what would occur if all brains except the brainstem were removed. The brainstem regulates essential functions like heart rate and breathing, yet these animals lost their ability to smell, see, and remember.

Did they burn enough calories?

To assess this, Dr. Grill administered liquid food directly into their mouths.

“Once they reached a certain point, they allowed the food to flow out,” he explained.

Beginning decades ago, these studies laid the groundwork for ongoing research that continuously astonished scientists, challenging the notion that perfect animals are linked to consciousness. This is particularly relevant considering the GLP-1 drugs, such as Ozempic, which complicate our understanding of how weight-loss medications impact the brain’s feeding control system.

Emerging narratives do not clarify why some individuals become obese while others do not. Rather, they hint at when we begin eating and when we cease.

Obesity researcher Dr. Jeffrey Friedman from Rockefeller University in New York noted that although most studies involve rodents, it is a misconception to assume that humans are fundamentally different. We are shaped by billions of years of evolution, he stated.

As researchers delved into dietary control, they discovered that the brain receives consistent signals indicating that the body is adequately supplied with food. The body requires a specific calorie intake, and these signals ensure that it is fulfilled.

This process initiates even before an animal consumes its first bite. Light exposure from potential food prompts predictions regarding the caloric density of what is being offered. Neurons react more vigorously to high-calorie foods like peanut butter than to low-calorie options such as mouse chow.

Key control points emerge when an animal tastes food, as neurons recalculate calorie density based on signals transmitted from the mouth to the brainstem.

Ultimately, as food enters the intestines, a new wave of signals reaches the brain, allowing neurons to reassess the calorie content.

Zachary Knight, a neuroscientist at the University of California, San Francisco, found that the gut’s evaluation revolves around calorie content.

He observed this phenomenon when three distinct foods were injected directly into a mouse’s stomach—one being fatty food, another carbohydrate, and the third protein—each infusion containing the same caloric value.

In all cases, the brain received a uniform message regarding calorie levels, indicating that neurons registered energy in calorie terms rather than by food source.

When the brain concludes that sufficient calories have been consumed, neurons relay signals to halt feeding.

Dr. Knight expressed his surprise at these findings, having previously believed that satiety signals emanated from a “gut-brain communication” process, reflecting fullness and a conscious decision to stop eating.

Based on this understanding, some diets suggest drinking a large glass of water before meals or focusing on low-calorie foods like celery.

Nonetheless, these strategies often fail for many since they don’t address how the brain governs dietary habits. Dr. Knight found that mice do not send satiety signals to the brain; they only receive water.

It remains true that individuals can choose to eat even when satiated or refrain from eating while trying to lose weight. Dr. Grill noted exerting control not only on the brainstem but also on other areas of the brain.

However, Dr. Friedman ultimately suggested that brain control often overrides a person’s conscious choice regarding their feelings of hunger or fullness. He likened this to holding one’s breath—possible, but only for a limited duration—or suppressing a cough until unavoidable.

Scott Sternson, a neuroscientist at the University of California, San Diego, echoed this sentiment.

“We’re eager to help people initiate change,” said Dr. Sternson, co-founder of Penguin Bio, a startup focused on developing obesity treatments. While individuals can choose whether or not to eat in given moments, maintaining that control demands considerable mental resources.

“Ultimately, other things often overshadow these conscious decisions,” he remarked.

Researchers continuously uncover surprising insights into the brain’s dietary control system.

They gained knowledge about the brain’s rapid reactions to food stimuli, for instance.

Neuroscientists unearthed thousands of neurons within the hypothalamus of mice that respond to hunger. Yet how are these neurons regulated? Previous work confirmed that fasting activated these hunger neurons while neuronal activity was diminished post-feeding.

Their hypothesis posited that neurons reacted to existing fat storage in the body. For instance, low fat storage, as seen during fasting—accompanied by decreased leptin levels, a hormone released from fat—would activate hunger neurons. The assumption was that fat replenishment during eating would raise leptin levels and quiet neuronal activity.

The entire system was expected to respond gradually based on the body’s energy reserves.

However, three research groups, led by Dr. Knight, Dr. Sternson, and Mark Anderman of Beth Israel Deaconess Medical Center, investigated the immediate activity of hunger neurons.

Starting with hungry mice, they noted rapid firing of hunger neurons, signaling a need for food.

Surprisingly, when food was presented, those neurons ceased activation.

“Even before the first bite, those neurons powered down,” Dr. Knight observed. “Neurons were forecasting. Mice anticipate how many calories they would consume.”

The more calorie-dense the food presented, the more neurons silenced.

“All three laboratories were astonished,” recalled Dr. Bradford B. Lowell, who collaborated with Andermann at Beth Israel Deaconess. “It was remarkably unexpected.”

Dr. Lowell then investigated the outcome of intentionally deactivating hunger neurons, even when mice had limited food access. This was done using genetic modifications that allow for neuron activation and deactivation via drugs or blue light.

The mice refrained from eating for hours, despite the food present.

Dr. Lowell and Dr. Sternson independently executed opposite studies, activating neurons in mice post-meal, akin to a Thanksgiving feast. The animals were relaxed and satisfied.

However, Dr. Andermann, who replicated the experiment, noted “mice would rise and consume an additional 10-15% of their body weight” when their hunger neurons were activated, emphasizing that “these neurons compel focus on food.”

Researchers continue to be amazed by their findings. The complexities of brain control ensure meticulous regulation of dietary intake, leading to insights for developing new diet-controlling medications.

One notable discovery was made by Amber Aradeff, a neuroscientist at the Monell Chemical Senses Center and the University of Pennsylvania. She recently identified two distinct groups of neurons in the brainstem that respond to GLP-1 obesity medications.

One neuronal group indicated satiety, while the other triggered nausea in the rodents. Current obesity treatments target both neuronal groups, she notes. She proposes that drug development could focus on activating satiety neurons rather than those inducing nausea.

Columbia University’s Alexander Nectow made another surprising finding, identifying a distinct group of neurons in the brainstem that regulate meal volume based on bite size. “I am unsure how this functions,” he stated.

“I have spent over ten years studying this area of the brain,” Dr. Nectow shared.

He is currently exploring whether these neurons could become targets for a new class of weight loss drugs that may involve GLP-1.

“This is truly remarkable,” Dr. Nectow concluded.