New preclinical research presented at the 2025 European Congress on Obesity (ECO) in Malaga, Spain, reveals that the anti-obesity drugs tirzepatide and semaglutide produce markedly different short-term metabolic responses in mice. While tirzepatide transiently increases energy expenditure, semaglutide initially suppresses it. Both agents, however, converge on enhanced fat oxidation and appetite suppression, with the most pronounced metabolic shifts occurring during active treatment and rapidly waning once dosing ceases.
Background: GLP-1RAs and Dual Agonists in Obesity Management
Anti-obesity pharmacotherapy has been revolutionized by glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual incretin agonists. Semaglutide, a GLP-1RA, and tirzepatide, a dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, have demonstrated substantial efficacy in weight reduction and glycaemic control in clinical trials. They foster a negative energy balance primarily through appetite suppression and improved glucose metabolism, yet their direct effects on energy expenditure and long-term metabolic adaptations have remained underexplored.
Design and Methods of the Study
Researchers at Gubra, a Danish preclinical contract research organization, conducted a controlled laboratory experiment involving 24 age-matched mice subjected to a high-fat diet for 20 weeks. The mice were then randomized into three groups (n=8 per group): a vehicle-treated control group, a semaglutide-treated group (10 nmol/kg), and a tirzepatide-treated group (10 nmol/kg). Treatments were administered once daily for four weeks, followed by a two-week washout period during which the high-fat diet was maintained.
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Energy expenditure was monitored continuously via indirect calorimetry, measuring oxygen consumption (VO₂) and carbon dioxide production (VCO₂) to estimate metabolic rate. Simultaneously, researchers tracked food and water intake as well as spontaneous physical activity. The entire protocol was performed at thermoneutral ambient temperatures (~30°C) to eliminate confounding cold-induced thermogenesis.
Weight Loss and Appetite Suppression
After four weeks of treatment, the control mice gained an average of 2.7 grams, whereas the tirzepatide and semaglutide groups lost an average of 15.6 g and 8.3 g respectively. The most significant weight loss occurred within the first week of dosing, underscoring the rapid onset of pharmacological action. Both active treatments also led to marked reductions in food intake compared to controls: tirzepatide recipients consumed approximately 35% fewer calories, while semaglutide recipients ate about 25% less. These findings align with clinical observations of robust appetite suppression with GLP-1RAs and highlight tirzepatide’s superior efficacy in the early phase of therapy.
Energy Expenditure: Divergent Early Responses
One of the study’s pivotal discoveries was the divergence in energy expenditure trajectories between the two drugs:
- Tirzepatide-Induced Hypermetabolism
Within four days of initiating tirzepatide, mice exhibited a statistically significant uptick in energy expenditure relative to controls. This elevation persisted through the second week of dosing before gradually regressing to baseline by week four. Notably, the surge in metabolic rate occurred without any concomitant increase in physical activity, indicating a direct thermogenic or substrate-cycling effect of tirzepatide. - Semaglutide-Mediated Metabolic Suppression
In contrast, semaglutide treatment led to a pronounced decrease in energy expenditure during the first three days of dosing. Energy utilization then gradually normalized to control levels for the remainder of the treatment period. This transient metabolic slowdown likely reflects the body’s adaptive response to rapid negative energy balance, a phenomenon known to blunt long-term weight loss by conserving calories.
Respiratory Exchange Ratio and Substrate Utilization
Both tirzepatide and semaglutide prompted significant shifts in the respiratory exchange ratio (RER), a marker of substrate oxidation. During the first two weeks of treatment, RER values declined in both active treatment groups, signaling a switch toward increased fat oxidation and reduced carbohydrate utilization. This metabolic reprogramming facilitates weight loss by mobilizing lipid stores. By the third week of therapy, RER values returned to control levels, suggesting a homeostatic rebalancing of fuel preference.
However, during the two-week washout period, RER spiked above baseline in both groups as mice resumed higher caloric intake, reflecting rapid reversion to carbohydrate preference and potential rebound weight gain.
Mechanistic Insights and Clinical Implications
Dr Simone Bossi, co-lead author and pharmacology researcher at Gubra, emphasized the significance of these divergent energy-expenditure profiles: “Weight regulation is a function of energy intake versus expenditure. While both tirzepatide and semaglutide tip the balance toward a negative energy state by lowering appetite, tirzepatide uniquely amplifies energy expenditure acutely, offering a potential dual mechanism for enhanced weight loss.”
The transient rise in energy expenditure with tirzepatide could translate into greater durability of weight reduction in human patients. Conversely, semaglutide’s initial metabolic suppression underscores the challenge of adaptive thermogenesis—a well-documented barrier to sustained weight loss in diet-and-exercise interventions.
Washout Dynamics and the Reality of Treatment Cessation
A critical takeaway from the washout data is the rapid dissipation of metabolic benefits once pharmacotherapy stops. Both drugs’ effects on energy expenditure and substrate selection vanished within days of treatment withdrawal, while hyperphagia (increased eating) accelerated. This rebound underscores the necessity of continued therapy or adjunctive lifestyle interventions to maintain weight loss and metabolic health.
Expert Commentary on Translational Relevance
Obesity specialists in attendance at ECO noted that the preclinical findings mirror clinical trial observations, where tirzepatide has consistently achieved greater mean weight reductions than semaglutide over comparable periods. Dr Rebecca Nguyen, an endocrinologist at the University of Munich not involved in the study, commented: “These animal data provide mechanistic context for tirzepatide’s superior efficacy. The transient hypermetabolic phase may narrow the gap between pharmacological and physiological weight-loss plateaus.”
However, Dr Nguyen also cautioned, “Rodent metabolism differs from humans in thermogenic capacity and substrate handling. We need controlled clinical studies measuring indirect calorimetry and RER in patients to validate these preclinical insights.”
Implications for Future Drug Development
The differential metabolic signatures of tirzepatide and semaglutide highlight the evolving landscape of incretin-based obesity treatments. Dual agonists that target multiple hormone pathways may offer combinatorial advantages—appetite suppression coupled with enhanced energy expenditure. Pharmaceutical research is likely to explore tri-agonists (e.g., GLP-1/GIP/glucagon) or agents combining incretin effects with mitochondrial uncoupling to sustain hypermetabolism without compromising safety.
Beyond Weight Loss: Metabolic Health and Comorbidities
Weight reduction alone does not fully capture obesity treatment success. Improvements in insulin sensitivity, cardiovascular risk markers, and inflammatory profiles are equally critical. Dual agonists such as tirzepatide have demonstrated superior glycaemic control in type 2 diabetes trials, raising the possibility that transient hypermetabolism also ameliorates lipid profiles and hepatic steatosis more robustly than GLP-1RAs alone.
Conclusions and Next Steps
The study presented at ECO 2025 furnishes compelling evidence that tirzepatide and semaglutide diverge in their acute metabolic impacts despite shared appetite-suppressing properties. Tirzepatide’s capacity to transiently boost energy expenditure, independent of physical activity, may confer a therapeutic edge in achieving and maintaining weight loss. Semaglutide’s initial metabolic suppression, conversely, exemplifies the physiological hurdles that undermine long-term efficacy.
Critically, both drugs’ metabolic enhancements are reversible within days of treatment cessation, reinforcing the imperative of sustained therapy and comprehensive lifestyle programs to secure durable outcomes. Future clinical research should incorporate metabolic phenotyping—quantifying energy expenditure, substrate oxidation, and adaptive thermogenesis—to optimize drug selection and dosing regimens.
As obesity rates climb globally, mechanistic insights from preclinical models will guide precision medicine approaches, tailoring pharmacotherapy to individual metabolic profiles. The tirzepatide versus semaglutide comparison marks a pivotal step in deciphering how incretin-based therapies can be harnessed most effectively to curb the obesity epidemic and its attendant health burdens.
