An Effective Glucagon-Like Peptide-1 Receptor Agonists, Semaglutide, Improves Sarcopenic Obesity in Obese Mice by Modulating Skeletal Muscle Metabolism

Abstract

Purpose This study aimed to investigate the effect of Semaglutide on skeletal muscle and its metabolomics. Methods A total of 18 male C57BL/6 mice were randomly divided into normal control (NC) group, high-fat diet (HFD) group and HFD+Semaglutide group, and were given standard diet, HFD diet, HFD diet plus Semaglutide, respectively. The body weight, gastrocnemius weight, serum lipid, blood glucose and inflammatory index levels of mice in each group were observed and compared, and the morphological and structural changes of gastrocnemius were also analyzed. Meanwhile, gastrocnemius metabolite changes were analyzed by untargeted metabolomics. Results After Semaglutide treatment, the food intake and body weight of mice were evidently decreased, while the relative gastrocnemius weight ratio were conversely increased. Meanwhile, the levels of TG, CHO, LDL, HDL, TNF-α, IL-6, IL-1β and HOMA-IR were all observed to decrease remarkably after Semaglutide intervention. Histological analysis showed that Semaglutide significantly improved the pathological changes of gastrocnemius, manifested as increased type I/type II muscle fiber ratio, total muscle fiber area, muscle fiber density, sarcomere length, mitochondrial number and mitochondrial area. Furthermore, metabolic changes of gastrocnemius after Semaglutide intervention were analyzed, and 141 kinds of differential metabolites were screened out, mainly embodied in lipids and organic acids, and enriched in 9 metabolic pathways including a variety of amino acids. Conclusion Semaglutide can significantly reduce the body weight and the accumulation of intramuscular fat, promote muscle protein synthesis, increase the relative proportion of skeletal muscle, and improve muscle function of obese mice, possibly by altering the metabolism of muscle lipids and organic acids.

Anti-inflammatory benefits of semaglutide: State of the art

“… Effects Model Treatment Ref. Reduced the TNF-α, IL-6 and Nf-κB signalings LPS-induced lung injury in rats Semaglutide [73] Blocked the NLRP3 activity PTT-induced seizure in C57/BL6J mouse Semaglutide [70] Reduced the TNF-α, IL-6, and IL-1β levels in brain tissues Endo-toxemia in male Swiss albino mice Semaglutide [72] Reduced p38 MAPK, c-Jun- NF-κB p65 inflammation signaling pathway in brain tissues Animal model of seizure Semaglutide [71] Reduced intramuscular fat and improved muscle function by lowering the, TNF-α, IL-6, IL-1β levels Male C57BL/6 mice Semaglutide [78] Declined TNF-α, and IL-6 serum and heart tissues Obese mouse Semaglutide [62] Decreased vascular inflammation and micro-calcifications Obese rabbit Semaglutide [79] Attenuated inflammatory markers and improved cardiac function Obese mice Semaglutide [80] …”

GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives

“…Furthermore, GLP-1 RAs have recently been shown to improve sarcopenic obesity in obese mice by influencing the skeletal muscle metabolism [ 140 , 141 , 142 ]. In addition to weight loss, semaglutide has been shown to lower the intramuscular accumulation of fat and promote protidosynthesis in these mouse models, increasing both mass and muscle function [ 140 ].…”

“…Furthermore, GLP-1 RAs have recently been shown to improve sarcopenic obesity in obese mice by influencing the skeletal muscle metabolism [ 140 , 141 , 142 ]. In addition to weight loss, semaglutide has been shown to lower the intramuscular accumulation of fat and promote protidosynthesis in these mouse models, increasing both mass and muscle function [ 140 ]. Furthermore, GLP-1 RAs have been shown to improve muscle wasting both by suppressing myostatin expression and promoting the expression of myogenic factors, as well as through anti-inflammatory and anti-apoptotic effects [ 141 , 142 ].…”

Sarcopenic obesity: epidemiology, pathophysiology, cardiovascular disease, mortality, and management

“…Weight-loss therapies such as those using GLP-1 receptor agonists (RA) have shown to be beneficial for sarcopenic obesity, however the data are mainly produced in preclinical studies and proper specific parameters of sarcopenic obesity assessed before and after the introduction of GLP-1 RA are required ( 92 ). Bariatric surgery induced weight-loss by a malabsorptive and/or restrictive mechanism with a consistent effect on adipose tissue mass, but its benefit for skeletal muscle remain to be determined ( 93 )…”