GLP-1RA Liraglutide and Semaglutide Improves Obesity-Induced Muscle Atrophy via SIRT1 Pathway

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Abstract

Background

Obesity is related to the loss of skeletal muscle mass and function (sarcopenia). The co-existence of obesity and sarcopenia is called sarcopenic obesity (SO). Glucagon like peptide-1 receptor agonists (GLP-1RA) are widely used in the treatment of diabetes and obesity. However, the protective effects of GLP-1RA on skeletal muscle in obesity and SO are not clear. This study investigated the effects of GLP-1RA liraglutide and semaglutide on obesity-induced muscle atrophy and explored the underlying mechanisms.

Methods

Thirty-six male C57BL/6J mice were randomly divided into two groups and fed a regular diet and a high-fat diet for 18 weeks, respectively. After establishing an obesity model, mice were further divided into six groups: control group, liraglutide (LIRA) group, semaglutide (SEMA) group, high-fat diet (HFD) group, HFD + LIRA group, HFD + SEMA group, and subcutaneous injection for 4 weeks. The body weight, muscle mass, muscle strength, glycolipid metabolism, muscle atrophy markers, myogenic differentiation markers, GLUT4 and SIRT1 were analyzed. C2C12 myotube cells treated with palmitic acid (PA) were divided into four groups: control group, PA group, PA + LIRA group, PA + SEMA group. The changes in glucose uptake, myotube diameter, lipid droplet infiltration, markers of muscle atrophy, myogenic differentiation markers, GLUT4 and SIRT1 were analyzed, and the changes in related indicators were observed after the addition of SIRT1 inhibitor EX527.

Results

Liraglutide and semaglutide reduced HFD-induced body weight gain, excessive lipid accumulation and improved muscle atrophy. Liraglutide and semaglutide eliminated the increase of muscle atrophy markers in skeletal muscle and C2C12 myotubes. Liraglutide and semaglutide restored impaired glucose tolerance and insulin resistance. However, these beneficial effects were attenuated by inhibiting SIRT1 expression.

Conclusion

Liraglutide and semaglutide protects skeletal muscle against obesity-induced muscle atrophy via the SIRT1 pathway.

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Most cited references 59

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Skeletal muscle: a brief review of structure and function.

Walter R Frontera, Julien Ochala (2015)

Skeletal muscle is one of the most dynamic and plastic tissues of the human body. In humans, skeletal muscle comprises approximately 40% of total body weight and contains 50-75% of all body proteins. In general, muscle mass depends on the balance between protein synthesis and degradation and both processes are sensitive to factors such as nutritional status, hormonal balance, physical activity/exercise, and injury or disease, among others. In this review, we discuss the various domains of muscle structure and function including its cytoskeletal architecture, excitation-contraction coupling, energy metabolism, and force and power generation. We will limit the discussion to human skeletal muscle and emphasize recent scientific literature on single muscle fibers.

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Sarcopenic obesity in older adults: aetiology, epidemiology and treatment strategies

John A Batsis, Dennis T. Villareal (2018)

The prevalence of obesity in combination with sarcopenia (the age-related loss of muscle mass and strength or physical function) is increasing in adults aged 65 years and older. A major subset of adults over the age of 65 is now classified as having sarcopenic obesity, a high-risk geriatric syndrome predominantly observed in an ageing population that is at risk of synergistic complications from both sarcopenia and obesity. This Review discusses pathways and mechanisms leading to muscle impairment in older adults with obesity. We explore sex-specific hormonal changes, inflammatory pathways and myocellular mechanisms leading to the development of sarcopenic obesity. We discuss the evolution, controversies and challenges in defining sarcopenic obesity and present current body composition modalities used to assess this condition. Epidemiological surveys form the basis of defining its prevalence and consequences beyond comorbidity and mortality. Current treatment strategies, and the evidence supporting them, are outlined, with a focus on calorie restriction, protein supplementation and aerobic and resistance exercises. We also describe weight loss-induced complications in patients with sarcopenic obesity that are relevant to clinical management. Finally, we review novel and potential future therapies including testosterone, selective androgen receptor modulators, myostatin inhibitors, ghrelin analogues, vitamin K and mesenchymal stem cell therapy.

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The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss.

Anna Secher, Jacob Jelsing, Arian Baquero … (2014)

Liraglutide is a glucagon-like peptide-1 (GLP-1) analog marketed for the treatment of type 2 diabetes. Besides lowering blood glucose, liraglutide also reduces body weight. It is not fully understood how liraglutide induces weight loss or to what degree liraglutide acts directly in the brain. Here, we determined that liraglutide does not activate GLP-1-producing neurons in the hindbrain, and liraglutide-dependent body weight reduction in rats was independent of GLP-1 receptors (GLP-1Rs) in the vagus nerve, area postrema, and paraventricular nucleus. Peripheral injection of fluorescently labeled liraglutide in mice revealed the presence of the drug in the circumventricular organs. Moreover, labeled liraglutide bound neurons within the arcuate nucleus (ARC) and other discrete sites in the hypothalamus. GLP-1R was necessary for liraglutide uptake in the brain, as liraglutide binding was not seen in Glp1r(-/-) mice. In the ARC, liraglutide was internalized in neurons expressing proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART). Electrophysiological measurements of murine brain slices revealed that GLP-1 directly stimulates POMC/CART neurons and indirectly inhibits neurotransmission in neurons expressing neuropeptide Y (NPY) and agouti-related peptide (AgRP) via GABA-dependent signaling. Collectively, our findings indicate that the GLP-1R on POMC/CART-expressing ARC neurons likely mediates liraglutide-induced weight loss.

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Author and article information

Journal

Journal ID (nlm-ta): Diabetes Metab Syndr Obes

Journal ID (iso-abbrev): Diabetes Metab Syndr Obes

Journal ID (publisher-id): dmso

Title: Diabetes, Metabolic Syndrome and Obesity

Publisher: Dove

ISSN (Electronic): 1178-7007

Publication date (Electronic): 15 August 2023

Publication date Collection: 2023

Volume: 16

Pages: 2433-2446

Affiliations

[1 ]Department of Clinical Nutrition, The First Affiliated Hospital of Guangxi Medical University , Nanning, People’s Republic of China

[2 ]Department of Geriatric Endocrinology, The First Affiliated Hospital of Guangxi Medical University , Nanning, People’s Republic of China

[3 ]Department of Endocrinology, The Second Affiliated Hospital of Guangxi Medical University , Nanning, People’s Republic of China

Author notes

Correspondence: Yuzhen Liang, Department of Endocrinology, The Second Affiliated Hospital of Guangxi Medical University , Nanning, People’s Republic of China, Email liangyuzhen26@163.com

Ning Xia, Department of Geriatric Endocrinology, The First Affiliated Hospital of Guangxi Medical University , Nanning, People’s Republic of China, Email xianing12@sina.com

Author information

Jie Xiang http://orcid.org/0000-0002-8975-7987

Liyan Qin http://orcid.org/0009-0001-6477-0923

Ning Xia http://orcid.org/0009-0001-6254-7015

Article

Publisher ID: 425642

DOI: 10.2147/DMSO.S425642

PMC ID: 10439806

PubMed ID: 37602204

SO-VID: c43f56c0-ce3a-4a1f-b8a8-b530d37b92b6

License:

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

History

Date received : 12 June 2023

Date accepted : 05 August 2023

Page count

Figures: 6, References: 59, Pages: 14

Funding

Funded by: the National Natural Science Foundation of China;

Funded by: Guangxi Natural Science Foundation, open-funder-registry 10.13039/501100004607;

This work was supported by the National Natural Science Foundation of China (No. 8176030057) and Guangxi Natural Science Foundation (No.2017GXNSFDA198010).

GLP-1RA Liraglutide and Semaglutide Improves Obesity-Induced Muscle Atrophy via SIRT1 Pathway

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Conclusion

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Karger: Nutrition and Dietetics

Most cited references 59

Skeletal muscle: a brief review of structure and function.

Sarcopenic obesity in older adults: aetiology, epidemiology and treatment strategies

The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss.

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