Dinghui Liu1, Jianqiu Gu2, Weijuan Shao3, Juan Pang4, Xiaoxian Qian5, Tianru Jin6. 1. Department of Cardiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China; Division of Advanced Diagnostics, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada. 2. Division of Advanced Diagnostics, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Endocrinology and Metabolism and Institute of Endocrinology, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China. 3. Division of Advanced Diagnostics, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada. 4. Division of Advanced Diagnostics, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China. 5. Department of Cardiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China. 6. Division of Advanced Diagnostics, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Banting and Best Diabetes Centre, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address: tianru.jin@utoronto.ca.
Abstract
OBJECTIVES: Semaglutide and liraglutide are glucagon-like peptide-1 (GLP-1)-based diabetes drugs. Semaglutide possesses a longer half-life. Utilizing relatively lower doses, we compared the beneficial metabolic effects of these 2 drugs in mice fed a high-fat diet (HFD), aiming to deepen our mechanistic understanding on their energy homeostatic functions. METHODS: Male C57BL/6J mice were fed an HFD for 10 weeks, followed by daily phosphate-buffered saline (PBS, as control); liraglutide (150 μg/kg body weight); or semaglutide (12 μg/kg body weight, low dose [LD]; or 60 μg/kg body weight, high dose [HD]) injection for 4 weeks. Metabolic tolerance and other tests were conducted within the 4-week period. Expression of metabolism-related genes, including Fgf21 in the liver and adipose tissues, was assessed after mice were euthanized. RESULTS: HFD-induced body weight gain, increasing inguinal fat tissue mass, glucose defects and insulin intolerance were effectively and comparably attenuated in the 3 experimental groups. HD semaglutide showed an even better effect on attenuating hyperleptinemia. Liraglutide but not semaglutide treatment enhanced hepatic fibroblast growth factor 21 (FGF21) protein level. All 3 experimental groups showed elevated expression of genes that encode pyruvate dehydrogenase kinase 4 and enoyl-CoA hydratase and 3-hydroxyacyl-coenzyme A dehydrogenase, associated with reduced plasma triglyceride levels. Finally, the plasma "GLP-1" level in HD semaglutide-treated mice was 14-fold higher than in HFD-fed control mice. CONCLUSIONS: Liraglutide, but not semaglutide, increased hepatic FGF21 protein level, whereas semaglutide had a greater effect on attenuating hyperleptinemia. Thus, these 2 GLP-1-based diabetes drugs may target metabolic organs, including liver and adipose tissue, with differing levels of efficacy.
OBJECTIVES: Semaglutide and liraglutide are glucagon-like peptide-1 (GLP-1)-based diabetes drugs. Semaglutide possesses a longer half-life. Utilizing relatively lower doses, we compared the beneficial metabolic effects of these 2 drugs in mice fed a high-fat diet (HFD), aiming to deepen our mechanistic understanding on their energy homeostatic functions. METHODS: Male C57BL/6J mice were fed an HFD for 10 weeks, followed by daily phosphate-buffered saline (PBS, as control); liraglutide (150 μg/kg body weight); or semaglutide (12 μg/kg body weight, low dose [LD]; or 60 μg/kg body weight, high dose [HD]) injection for 4 weeks. Metabolic tolerance and other tests were conducted within the 4-week period. Expression of metabolism-related genes, including Fgf21 in the liver and adipose tissues, was assessed after mice were euthanized. RESULTS: HFD-induced body weight gain, increasing inguinal fat tissue mass, glucose defects and insulin intolerance were effectively and comparably attenuated in the 3 experimental groups. HD semaglutide showed an even better effect on attenuating hyperleptinemia. Liraglutide but not semaglutide treatment enhanced hepatic fibroblast growth factor 21 (FGF21) protein level. All 3 experimental groups showed elevated expression of genes that encode pyruvate dehydrogenase kinase 4 and enoyl-CoA hydratase and 3-hydroxyacyl-coenzyme A dehydrogenase, associated with reduced plasma triglyceride levels. Finally, the plasma "GLP-1" level in HD semaglutide-treated mice was 14-fold higher than in HFD-fed control mice. CONCLUSIONS: Liraglutide, but not semaglutide, increased hepatic FGF21 protein level, whereas semaglutide had a greater effect on attenuating hyperleptinemia. Thus, these 2 GLP-1-based diabetes drugs may target metabolic organs, including liver and adipose tissue, with differing levels of efficacy.
Authors: Louise S Dalbøge; Michael Christensen; Martin Rønn Madsen; Thomas Secher; Nicole Endlich; Vedran Drenic'; Alba Manresa-Arraut; Henrik H Hansen; Ida Rune; Lisbeth N Fink; Mette V Østergaard Journal: Biomedicines Date: 2022-07-11