(T1430-05-30) Effect of Semaglutide on Muscle Mass Loss in Rats on a High-Fat Diet

Purpose: Semaglutide (a glucagon-like peptide-1 (GLP-1) receptor agonists, is approved by the US Food and Drug Administration primarily for enhancing glycemic control in adults with and without T2DM (Ozempic^®) and promoting weight loss in individuals dealing with obesity and overweight (Wegovy^®)¹. About 2% of all adults (~5 million) are estimated to be currently using a GLP-1 medication in the United States, with a 40-fold increase from 2017 to 2021. This number is expected to reach 6% (~15 million adults) by 2030². Recently, there has been a significant increase in public interest in the off-label use of Ozempic and related GLP-1 agonists for cosmetic weight loss³. Clinical studies have shown notable reductions in muscle mass in obese individuals⁴; however, the impact on non-obese individuals consuming a high-fat diet (HFD) and receiving semaglutide for cosmetic weight loss and pediatric patients with obesity and T2DM⁵ is unclear. In this study, we investigated the impact of semaglutide on body weight reduction and muscle mass loss in male and female rats.

Methods: 23 male and female Pirc rats were fed a normal diet of Teklad F6 rodent diet (W) from Harlan Laboratories (Madison, WI) (ad libitum) since weaning. At 7 weeks, rats were divided into five groups: a control group (2 females, 1 male), an HFD group (2 females, 5 males), an HFD group treated with semaglutide 240 μg/kg daily (equivalent to 1.2 mg in human dose) (3 females, 3 males), an HFD group treated with semaglutide 400 μg/kg twice weekly (equivalent to 2 mg in human dose) (4 females), and an HFD group treated with 400 μg/kg/daily daily (3 females). Rats in control group continued normal diet, whereas the remaining rats (n=20) were fed with a HFD (Research Diet #D12492; 60% kcal from fat, 5.24 kcal/g, ad libitum) for two months. Rats in HFD with semaglutide treatment were injected subcutaneously. Body weight was measured weekly, and rats were euthanized at the end of week 15. Skeletal muscles tibialis anterior (TA), and extensor digitorum longus (EDL) were extracted and weighed using an electronic balance (PB153, Mettler Toledo, USA). We used one-way analysis of variance (ANOVA) followed by Tukey's test to compare TA/body weight and EDL/body weight ratios between experimental groups.

Results: The results showed that two months of treatment with 240 µg/kg semaglutide decreased the HFD-induced increase in body weight by 15.7% in male rats and 8.8% in female rats (Figure 1). In female rats, daily administration of semaglutide at 400 µg/kg significantly reduced body weight by 18.6% compared to the HFD group, whereas the same dose administered twice weekly resulted in a modest reduction of 2% (Figure 1) More rats are needed in each group to show statistical significance. Compared to the control group, rats on the HFD exhibited a significant reduction in the muscle mass-to-body weight ratios for both the TA and EDL muscles, which was reversed by semaglutide treatment for both male and female rats (Figure 2).

Conclusion: Both TA/body weight and EDL/body weight ratios were significantly decreased in rats consuming HFD; however, semaglutide treatment for 2 months increased these ratios mainly due to a decrease in body weight with no significant loss in muscle mass. In conclusion, 2-month semaglutide treatment (at 240 and 400 μg/kg) did not result in muscle mass loss, indicating that short-term and lower doses of semaglutide treatment are safer to use in the non-obese population.

References: 1. Jason Powell and James Taylor. Use of Dulaglutide, Semaglutide, and Tirzepatide in Diabetes and Weight Management. Clin Ther. 2024 Mar;46(3):289-292.
2. Schafer, J. Goldman: 15 million Americans will be taking weight loss drugs by 2030. Yahoo Finance.
3. Sabrina H Han, Rachel Safeek, Kyle Ockerman, Nhan Trieu, Patricia Mars, Audrey Klenke, Heather Furnas, Sarah Sorice-Virk. Public Interest in the Off-Label Use of Glucagon-like Peptide 1 Agonists (Ozempic) for Cosmetic Weight Loss: A Google Trends Analysis. Aesthet Surg J. 2023 Dec 14;44(1):60-67.
4. Alexia Bikou , Foteini Dermiki-Gkana , Michail Penteris , Theodoros K Constantinides , Christos Kontogiorgis. A systematic review of the effect of semaglutide on lean mass: insights from clinical trials. Expert Opin Pharmacother. 2024 Apr;25(5):611-619.
5. Daniel Weghuber, Timothy Barrett, Margarita Barrientos Pérez, Inge Gies, Dan Hesse, Ole K. Jeppesen, Aaron S. Kelly, Lucy D. Mastrandrea, Rasmus Sørrig, and Silva Arslanian. Once-Weekly Semaglutide in Adolescents with Obesity. N Engl J Med 2022;387:2245-2257

Acknowledgements: Rashim Singh is supported by the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health under award number K12TR004522.