1693-P: Cagrisema-Induced Weight Loss in Diet-Induced Obese Rats Relies on Preserved Mitochondrial Leak Respiration in Skeletal Muscle

Introduction and Objective: Weight management and maintenance is challenged by counter-regulatory mechanisms causing weight regain. One of these mechanisms is a reduction in resting energy expenditure beyond what is explained by the lost weight (termed metabolic adaptation). In rats, CagriSema (CS), a combination of semaglutide (a GLP-1 analogue) and cagrilintide (an amylin analogue), prevents metabolic adaptation, but the mechanisms behind this effect are unknown. Objective: To investigate the effects of CS on metabolic efficiency in two of the most energy consuming organs - liver and skeletal muscle. Methods: Diet-induced obese male rats were subjected to vehicle or CS treatment (2+2 nmol/kg of semaglutide and cagrilintide) for 20 days (n=13). To distinguish weight loss effects from CS effects, a vehicle-treated, food-restricted, weight matched group (WM) was included. At study end, liver and skeletal muscle (soleus) were examined ex vivo for mitochondrial leak respiration (primary endpoint) and lipidomics and metabolomics analyses. Results: To obtain a similar weight loss, WM rats required a ~15% lower calorie intake than CS-treated rats. Prior studies have shown similar difference in calorie intake and also measured a difference in energy expenditure (metabolic adaptation). Liver leak respiration did not differ between groups. In skeletal muscle, leak respiration was similar between the vehicle and the CS-treated group whereas leak respiration was decreased in the WM group compared to the CS-treated group (leak respiration at 0.2 mM succinate: WM: 47.1 ± 3.0 pmol/s⋅mL; CS: 57.8 ± 2.4 pmol/s⋅mL, P = 0.01). Lipidomics and metabolomics revealed remarkably distinct profiles between CS-treated rats and the WM group. Conclusion: CS prevents metabolic adaptation to weight loss partly by preventing a reduction in mitochondrial leak respiration in skeletal muscle. Omics profiles and other functional mechanisms are currently under investigation. Disclosure I. Blom: Employee; Novo Nordisk. J. Jacobsen: Employee; Novo Nordisk. A.T. Hoelker: None. B.D. Eiriksfoss: None. K.K. Lange: None. J. Havelund: None. K. Raun: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. M. Hey-Mogensen: Employee; Novo Nordisk A/S. N.J. Færgeman: None. A. Secher: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. R.E. Kuhre: Employee; Novo Nordisk A/S. S. Larsen: Consultant; PharmaNord, Vejle, Denmark. J.F. Halling: Employee; Novo Nordisk A/S.