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Review
. 2024 Dec 23;46(12):14514-14541.
doi: 10.3390/cimb46120872.

Spotlight on the Mechanism of Action of Semaglutide

Ilias Papakonstantinou  1 , Konstantinos Tsioufis  2 , Vasiliki Katsi  2
Affiliations
Review

Spotlight on the Mechanism of Action of Semaglutide

Ilias Papakonstantinou et al. Curr Issues Mol Biol. .

Abstract

Initially intended to control blood glucose levels in patients with type 2 diabetes, semaglutide, a potent glucagon-like peptide 1 analogue, has been established as an effective weight loss treatment by controlling appetite. Integrating the latest clinical trials, semaglutide in patients with or without diabetes presents significant therapeutic efficacy in ameliorating cardiometabolic risk factors and physical functioning, independent of body weight reduction. Semaglutide may modulate adipose tissue browning, which enhances human metabolism and exhibits possible benefits in skeletal muscle degeneration, accelerated by obesity and ageing. This may be attributed to anti-inflammatory, mitochondrial biogenesis, antioxidant and autophagy-regulating effects. However, most of the supporting evidence on the mechanistic actions of semaglutide is preclinical, demonstrated in rodents and not actually confirmed in humans, therefore warranting caution in the interpretation. This article aims to explore potential innovative molecular mechanisms of semaglutide action in restoring the balance of several interlinking aspects of metabolism, pointing to distinct functions in inflammation and oxidative stress in insulin-sensitive musculoskeletal and adipose tissues. Moreover, possible applications in protection from infections and anti-aging properties are discussed. Semaglutide enhancement of the core molecular mechanisms involved in the progress of obesity and diabetes, although mostly preclinical, may provide a framework for future research applications in human diseases overall.

Keywords: adipose; aging; autophagy; browning; diabetes; infections; inflammation; obesity; sarcopenia; semaglutide.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Semaglutide and transcriptional regulation of WAT to BAT conversion and BAT activation. Because of primitive experimental research in humans, data were acquired from reviews and from experimental evidence in rodents. Semaglutide activates the AMPK/SIRT1 axis which presents a crucial role for promoting the differentiation process into BAT by increasing the expression levels of UCP1. AMPK/SIRT1 activates PGC1α and via the transcriptional regulator PRDM16, the enzyme CIDEA. CIDEA controls the development of brown adipocytes in BAT and interacts with PGC1α to differentiate BeAT. Semaglutide may activate FGF21 produced by BAT which enhances the browning of WAT by increasing the expression of UCP1 and CIDEA. FGF21 exerts further anti-inflammatory effects by stimulation of adiponectin secretion. Semaglutide may induce FNDC5 expression in pancreatic β-cells via CREB, promoting the conversion of WAT to BAT, but also insulin secretion and autophagy while reducing apoptosis. Semaglutide may mediate glucose transport through AMPK/SIRT1 activation and GLUT4 upregulation. Upward arrows symbolize increase or upregulation, while downward arrows indicate decrease or downregulation of the mentioned mechanisms. Abbreviations: BAT, brown adipose tissue; BeAT, beige adipose tissue; WAT, white adipose tissue; UCP1, uncoupling protein 1; PRDM16, PR domain-containing 16; PGC1a, peroxisome proliferator activated receptor gamma coactivator 1 alpha; FGF21, fibroblast growth factor 21; FNDC5, protein fibronectin type III domain-containing protein 5; CREB, cAMP-response element binding protein; CIDEA, cell death-inducing DNA fragmentation factor-α-like effector A; GLUT4, glucose transporter type 4; AMPK, adenosine monophosphate–activated protein kinase; SIRT1, sirtuin 1.
Figure 2
Figure 2
Possible mechanisms of semaglutide on oxidative stress and inflammation. Semaglutide activates AMPK/SIRT1 to deacetylate the NF-kB and possibly interacts with AGE/RAGEs to mediate critical anti- inflammatory responses and ROS reduction. Also PGC1α activated by SIRT1 regulates factors like NRF2 to diminish oxidative stress, aberrant UPR and ROS. In addition, semaglutide may promote autophagy and mitophagy through AMPK/TFEB and AMPK/parkin activation respectively. Upward arrows symbolize increase or upregulation, while downward arrows indicate decrease or downregulation of the mentioned mechanisms. Abbreviations: AMPK, adenosine monophosphate–activated protein kinase; SIRT1, sirtuin 1; NF-kB, nuclear factor kB; TFEB, transcription factor EB; UPR, unfolded protein response; ROS, reactive oxygen species; NRF2, nuclear factor (erythroid-derived 2)-like 2; AGEs, advanced glycation end-products; RAGE, AGE receptors.
Figure 3
Figure 3
Possible anti-aging mechanisms of semaglutide, hypothesis-generating from preclinical research. Semaglutide through AMPK/SIRT1 activation may blockade the NF-kB critical mediator of inflammation and FOXO transcription factors through SIRT1/PGC-1α. This activates autophagy and may regulate the UPS and autophagy-lysosomal system for removal of senescent cells and SASP. Semaglutide may upregulate transcriptional responses to oxidative stress and ROS production like NRF2 which decrease with ageing. In addition, possible PTBP1 depletion by semaglutide downmodulates the NF-kB pathway. Upward arrows symbolize increase or upregulation, while downward arrows indicate decrease or downregulation of the mentioned mechanisms. Abbreviations: UPS, ubiquitin–proteasome system; SASP, senescence-associated secretory phenotype; PTP1B, protein tyrosine phosphatase 1B or polypyrimidine tract binding protein 1; PGC1a, peroxisome proliferator activated receptor gamma coactivator 1 alpha; FOXO, forkhead box O proteins.
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References

    1. Bu T., Sun Z., Pan Y., Deng X., Yuan G. Glucagon-like Peptide-1: New Regulator in Lipid Metabolism. Diabetes Metab. J. 2024;48:354–372. doi: 10.4093/dmj.2023.0277. - DOI - PMC - PubMed
    1. Chobot A., Górowska-Kowolik K., Sokołowska M., Jarosz-Chobot P. Obesity and diabetes-Not only a simple link between two epidemics. Diabetes Metab. Res. Rev. 2018;34:e3042. doi: 10.1002/dmrr.3042. - DOI - PMC - PubMed
    1. Klein S., Gastaldelli A., Yki-Järvinen H., Scherer P.E. Why does obesity cause diabetes? Cell Metab. 2022;34:11–20. doi: 10.1016/j.cmet.2021.12.012. - DOI - PMC - PubMed
    1. Masenga S.K., Kabwe L.S., Chakulya M., Kirabo A. Mechanisms of Oxidative Stress in Metabolic Syndrome. Int. J. Mol. Sci. 2023;24:7898. doi: 10.3390/ijms24097898. - DOI - PMC - PubMed
    1. Davies M.J., Aroda V., Collins B.S., Gabbay R.A., Green J., Maruthur N.M., Rosas S.E., Del Prato S., Mathieu C., Mingrone G., et al. Management of hyperglycemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) Diabetes Care. 2022;45:2753–2786. doi: 10.2337/dci22-0034. - DOI - PMC - PubMed

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