Study reveals distinct mechanisms of action of tirzepatide and semaglutide

(Press-News.org) New animal research being presented at this year’s European Congress on Obesity (ECO) in Malaga, Spain (11-14 May), reveals distinct metabolic adjustments to tirzepatide and semaglutide treatment, with tirzepatide temporarily increasing energy expenditure and semaglutide initially reducing energy expenditure. Importantly, the biggest metabolic changes happen directly after treatment and disappear quickly after treatment is stopped.

Anti-obesity drugs like tirzepatide and semaglutide have shown substantial promise in promoting weight loss and improving metabolic health. These GLP-1 receptor agonists (GLP-1RAs) and dual agonists primarily act by suppressing appetite and improving glucose metabolism.

As co-leading author Dr Simone Bossi from Pharmacology Research department at Gubra, a preclinical contract research organisation and biotech company, in Denmark explained, “Weight is largely determined by the balance between the energy consumed and the amount of energy expended. Eating more and burning less energy creates a positive energy balance leading to weight gain, while eating less and burning more creates a negative balance, resulting in weight loss. We know that tirzepatide and semaglutide tip the scales towards a negative energy balance by lowering appetite and food intake.”

However, their acute and long-term effects on energy expenditure and metabolic adaptations—the physiological adjustments the body makes to conserve energy in response to a reduction in calorie intake—after treatment cessation remain poorly understood.

In this study, researchers fed a group of 24 mice of the same age a high-fat diet for 20 weeks Then they were divided into three groups (8 per group): a vehicle control (no treatment), a semaglutide group (10 nmol/kg), and a tirzepatide group (10 nmol/kg). The mice were given the drugs once a day for four weeks, followed by a two-week washout period, and the fatty diet was maintained throughout the period.

Energy expenditure was continuously monitored in real time with indirect calorimetry (which measures oxygen consumption and exhaled carbon dioxide and helps estimate energy usage) alongside measurements of food and water intake and physical activity levels.

The experiment was conducted at thermoneutrality (ambient temperatures where metabolic rate is at a minimum) to minimize confounding effects of cold-induced thermogenesis (burning calories to generate heat).

After four weeks of treatment, the control animals (given no treatment) displayed a weight gain of 2.7 grams (g) on average, while those given tirzepatide and semaglutide lost on average 15.6g and 8.3g respectively, with the most pronounced effects occurring in the first week. Both tirzepatide and semaglutide also led to a notable reduction in food intake.

The study found a significant increase in energy expenditure after four days of tirzepatide treatment, which remained elevated throughout the second week before gradually returning to control levels. Importantly, this increase was not accompanied by a rise in physical activity, indicating a direct metabolic effect. However, the washout period after treatment stopped revealed no lasting differences in metabolic profiles as the mice started to eat more than before.

In contrast, treatment with semaglutide resulted in a significant reduction in energy expenditure during the first three days of dosing, followed by a return to control levels.

“When people lose a lot of weight, their bodies often use less energy, which can make it harder to keep weight off,” explained Dr Bossi. “As seen in this study, mice receiving semaglutide did show a slowing down of burning energy during weight loss.”

Nevertheless, tirzepatide and semaglutide both led to a decrease in the respiratory exchange ratio [1] during the first two weeks of treatment, suggesting an increase in fat oxidation and a decrease in carbohydrate oxidation rates, thereby aiding weight loss. Respiratory exchange ratio levels returned to control levels after three weeks of dosing but increased again during the washout period when the mice started to eat a lot again.

According to Dr Bossi, “Our findings suggest distinct metabolic adaptations to semaglutide and tirzepatide treatment. Both medications facilitate substantial weight loss and also enhance fat oxidation. But while semaglutide initially appears to slow down the burning of energy during weight loss, tirzepatide temporarily increases the burning of energy. It is this effect on energy expenditure at the beginning of dosing that might help explain why tirzepatide has a stronger effect on weight loss.”She adds, “This preliminary work opens exciting avenues for future research to clarify the underlying mechanisms and to develop new improved therapies focusing on increasing energy expenditure for long-term weight maintenance.”

 

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