The treatment landscape for obesity and type 2 diabetes has been transformed by GLP-1 receptor agonists, offering substantial and sustained weight loss for patients around the globe. Yet despite their widespread clinical use, key questions remain about how these drugs reshape patient behavior around food, their metabolism over time, and why individual responses to the drug vary so widely.
In a new study published in Diabetes, Vanderbilt researchers reported that prolonged treatment with the GLP-1R agonist semaglutide induces changes in feeding behavior and fuel use that correspond with three distinct stages. The findings offer new insight into the behavioral and metabolic adaptations that accompany semaglutide-induced weight loss and weight maintenance, and the rapid weight regain seen after stopping treatment.
“GLP-1R agonists are incredibly effective drugs, but we still don’t fully understand how they work beyond the basic observation that they reduce food intake,” said Julio Ayala, associate professor of molecular physiology and biophysics. “We wanted to break that down further—how often do animals eat, how much do they eat at each meal, and what happens to metabolism over longer periods of treatment that more closely resemble the human experience.” Ayala spearheaded the study along with Harsh Shah, a postdoctoral fellow in his lab.
Most preclinical studies of GLP-1R agonists to date examine short-term responses, often after a single dose or brief treatment window. Ayala and colleagues took a different approach, administering semaglutide to mice for three weeks and conducting continuous, high-resolution measurements of feeding behavior and energy expenditure throughout and after treatment.
“This type of work simply wouldn’t be possible without the specialized infrastructure at Vanderbilt,” Ayala said. “The Mouse Metabolic Phenotyping Center allowed us to make measurements with a level of precision that’s difficult to achieve elsewhere.”
The extended timeline revealed a striking parallel between mice and humans treated with GLP-1R agonists: weight loss that unfolds in three distinct stages. Mice experienced an initial period of rapid weight loss, followed by a slower, more gradual decline, and ultimately a phase of weight maintenance. When semaglutide treatment stopped, weight regain occurred rapidly.
Distinct Feeding Behaviors Across Stages
A central goal of the study was to determine how different components of feeding behavior contribute to each stage of weight change. Rather than treating food intake as a single variable, the researchers examined meal size and meal frequency independently.
They found that meal size dropped sharply when first starting treatment with semaglutide and remained small throughout all three stages of weight loss and maintenance. Meal frequency, however, followed a more dynamic pattern: the number of meals the mice consumed initially decreased but rebounded during the weight maintenance phase, even while overall body weight remained stable.
“These drugs don’t just make animals eat less overall—they fundamentally change how feeding behavior is organized,” Ayala said. “Meal size stays low, but over time the animals compensate by eating more frequently. That balance appears to be part of how weight loss eventually plateaus.”
Once semaglutide treatment ended, both meal size and meal number increased, corresponding with the rapid regain of lost weight. The findings suggest that different neural mechanisms may dominate at different stages of drug response.
In addition to feeding behavior, the researchers closely examined energy expenditure and source—how the body chooses between burning fat or carbohydrates and how much is used.
Contrary to what might be expected, the total number of calories burned remained largely unchanged throughout semaglutide treatment. Early in treatment, the mice burned more fat, which was consistent with active weight loss. However, as they transitioned into the weight maintenance stage, they also shifted toward burning less fat and more carbohydrates.
“This switch in fuel utilization was one of the more surprising findings,” Ayala said. “Even though body weight was stable, the underlying metabolism was still changing. That suggests the system is actively adapting to defend the new body weight.”
These metabolic shifts may help explain why weight loss eventually plateaus despite continued drug treatment—and why weight regain can occur so rapidly once treatment stops.
Implications for Different Patient Responses
Clinically, GLP-1R agonists are known for their variability: Some patients lose substantial amounts of weight, while others respond modestly or not at all. Ayala believes that understanding the behavioral and metabolic adaptations revealed in this study may help explain that heterogeneity.
“If we can identify the mechanisms that drive these different stages—and the transitions between them—we may be able to understand why some individuals respond better than others,” he said. “Ultimately, that could inform more personalized treatment strategies.”
The findings also underscore the importance of studying drug effects over extended periods. Short-term studies may capture only the initial phase of weight loss, missing the adaptive responses that shape long-term outcomes.
Building on this work, Ayala’s lab is now investigating how brain activity changes across the different stages of semaglutide-induced weight loss, maintenance, and regain. Because GLP-1R agonists primarily act in the brain to suppress appetite, identifying stage-specific neural activity patterns is a key next step.
“We’re particularly interested in how neuronal circuits evolve over time,” Ayala said. “The brain doesn’t respond to these drugs in a static way—it adapts.”
The team is also exploring molecular changes in peripheral tissues, such as liver, fat, and muscle, that may underlie the observed shift from fat to carbohydrate use during weight maintenance.
As GLP-1R agonists continue to shape the future of obesity treatment, studies like this one provide a deeper understanding of the biological complexity underlying their success—and their limitations.
“Weight loss isn’t a single process,” Ayala said. “It’s a series of stages, each with its own biology. Recognizing that complexity is essential if we want to improve outcomes for patients.”
Go deeper
The paper “Prolonged Semaglutide Treatment Reveals Stage-Dependent Changes to Feeding Behavior and Metabolic Adaptations in Male Mice” was published in Diabetes in December 2025.
Funding
This research was supported by funds from the National Institutes of Health and the Vanderbilt Diabetes Research and Training Center.
School of Medicine Basic Sciences shared resources
This research made use of the Vanderbilt Mouse Metabolic Phenotyping Center.