Features of the proinflammatory adipose tissue phenotype in experimental metabolic syndrome

Aim. To investigate the proinflammatory activity markers of adipose tissue in a rat model of metabolic syndrome (MetS).
Materials and methods. The experiments were performed on male Wistar rats maintained on either a standard diet or a high-fat, high-carbohydrate diet (HFHCD). Physiological and biochemical parameters were assessed in the respective animal groups. The concentrations of adipokines (leptin and adiponectin) and cytokines: tumor necrosis factor alpha (TNF-α), interleukins (IL-6 and IL-10) and monocyte chemoattractant protein-1 (MCP-1) secreted by adipose tissue cells were determined using enzyme-linked immunosorbent assay. The phenotypic profile of adipose tissue cells expressing the CD68 marker was examined by immunohistochemistry, and the level of CD68 gene expression was additionally assessed using real-time polymerase chain reaction. A histological examination of visceral adipose tissue fragments was performed.
Results. It was found that in rats fed a HFHCD, there was a significant correlation (p < 0.05) between an increase in adipose tissue mass and elevated serum levels of leptin (r = 0.57), glucose (r = 0.62), and insulin (r = 0.61). In the experimental group, the concentrations of proinflammatory cytokines (IL-6, TNF-α, and MCP-1) and leptin produced by adipose tissue cells were higher than in the control group (p < 0.05). Additionally, we demonstrated that rats fed a HFHCD exhibited a significant (p < 0.05) decrease in the secretion of the anti-inflammatory cytokine IL-10 and adiponectin. Histological examination of the experimental group revealed adipocyte hypertrophy and anisocytosis, venous vessel congestion, and thickening of the interlobular connective tissue layer. Furthermore, rats fed an HFHCD exhibited an increased number of CD68-positive cells in visceral fat samples and elevated CD68 gene expression.
Conclusion. Thus, in experimental diet-induced metabolic syndrome, adipose tissue acquires a proinflammatory phenotype due to adipocyte hypertrophy, infiltration by immune-competent cells (CD68+ macrophages), and increased secretion of proinflammatory chemo- and adipokines (TNF-α, IL-6, MCP-1, and leptin).

1. Savulescu-Fiedler I., Mihalcea R., Dragosloveanu S., Scheau C., Baz R.O., Caruntu A. et al. The interplay between obesity and inflammation. Life. 2024;14(7):856. DOI: 10.3390/life14070856.

2. Lee Y.S., Olefsky J. Chronic tissue inflammation and metabolic disease. Genes Dev. 2021;35(5-6):307–328. DOI: 10.1101/gad.346312.120.

3. Landecho M.F., Tuero C., Valentí V., Bilbao I., de la Higuera M., Frühbeck G. Relevance of leptin and other adipokines in obesityassociated cardiovascular risk. Nutrients. 2019;11(11):2664. DOI: 10.3390/nu11112664.

4. Benavides-Aguilar J.A., Torres-Copado A., Isidoro-Sánchez J., Pathak S., Duttaroy A.K., Banerjee A. et al. The regulatory role of microRNAs in obesity and obesity-derived ailments. Genes (Basel). 2023;14(11):2070. DOI: 10.3390/genes14112070.

5. Wu K.K., Cheung S.W., Cheng K.K. NLRP3 Inflammasome activation in adipose tissues and its implications on metabolic diseases. Int. J. Mol. Sci. 2020;21(11):4184. DOI: 10.3390/ijms21114184.

6. Wen X., Zhang B., Wu B., Xiao H., Li Z., Li R. et al. Signaling pathways in obesity: mechanisms and therapeutic interventions. Signal Transduct. Target Ther. 2022;7(1):298. DOI: 10.1038/s41392-022-01149-x.

7. Avtanski D., Pavlov V.A., Tracey K.J., Poretsky L. Characterization of inflammation and insulin resistance in high-fat diet-induced male C57BL/6J mouse model of obesity. Animal Model Exp. Med. 2019;2:252–258. DOI: 10.1002/ame2.12084.

8. Gunawan S., Aulia A., Soetikno V. Development of rat metabolic syndrome models: A review. Vet. World. 2021;14(7): 1774–1783. DOI: 10.14202/vetworld.2021.1774-1783.

9. Birulina J.G., Ivanov V.V., Buyko E.E., Bykov V.V., Smagliy l.V., Nosarev A.V. et al. High-fat, high-carbohydrate diet-induced experimental model of metabolic syndrome in rats. Bulletin of Siberian Medicine. 2020;19(4):14–20. DOI: 10.20538/1682-0363-2020-4-14-20.

10. Reilly S.M., Saltiel A.R. Adapting to obesity with adipose tissue inflammation. Nat. Rev. Endocrinol. 2017;13(11):633–643. DOI: 10.1038/nrendo.2017.90.

11. Sun K., Li X., Scherer P.E. Extracellular matrix (ECM) and fibrosis in adipose tissue: overview and perspectives. Compr. Physiol. 2023;13(1):4387–4407. DOI: 10.1002/cphy.c220020.

12. Kawai T., Autieri M.V., Scalia R. Adipose tissue inflammation and metabolic dysfunction in obesity. Am. J. Physiol. Cell Physiol. 2021;320(3):C375–C391. DOI: 10.1152/ajpcell.00379.2020.

13. Vilariño-García T., Polonio-González M.L., Pérez-Pérez A., Ribalta J., Arrieta F., Aguilar M. et al. Role of leptin in obesity, cardiovascular disease, and type 2 diabetes. Int. J. Mol. Sci. 2024;25(4):2338. DOI: 10.3390/ijms25042338

14. Savulescu-Fiedler I., Mihalcea R., Dragosloveanu S., Scheau C., Baz R.O., Caruntu A. et al. The interplay between obesity and inflammation. Life. 2024;14(7):856. DOI: 10.3390/life14070856.

15. Jaitin D.A., Adlung L., Thaiss C.A., Weiner A., Li B., Descamps H. et al. Lipid-associated macrophages control metabolic homeostasis in a trem2-dependent manner. Cell. 2019;178(3):686–698.e14. DOI: 10.1016/j.cell.2019.05.054.

16. Hildreth A.D., Ma F., Wong Y.Y., Sun R., Pellegrini M., O’Sullivan T.E. Single-cell sequencing of human white adipose tissue identifies new cell states in health and obesity. Nat. Immunol. 2021;22(5):639–653. DOI: 10.1038/s41590-021-00922-4.

17. Yao J., Wu D., Qiu Y. Adipose tissue macrophage in obesity-associated metabolic diseases. Front. Immunol. 2022;13:977485. DOI: 10.3389/fimmu.2022.977485.

18. Michailidou Z., Gomez-Salazar M., Alexaki V.I. Innate immune cells in the adipose tissue in health and metabolic disease. J. Innate Immun. 2022;14(1):4–30. DOI: 10.1159/000515117.

19. Ackermann J., Arndt L., Fröba J., Lindhorst A., Glaß M., Kirstein M. et al. IL-6 signaling drives self-renewal and alternative activation of adipose tissue macrophages. Front. Immunol. 2024;15:1201439. DOI: 10.3389/fimmu.2024.1201439.

20. Singh S., Anshita D., Ravichandiran V. MCP-1: Function, regulation, and involvement in disease. Int. Immunopharmacol. 2021;101(Pt B):107598. DOI: 10.1016/j.intimp.2021.107598.

21. Pérez-Pérez A., Sánchez-Jiménez F., Vilariño-García T., Sánchez-Margalet V. Role of leptin in inflammation and vice versa. Int. J. Mol. Sci. 2020;21(16):5887. DOI: 10.3390/ijms21165887.

22. Park C.S., Shastri N. The role of t cells in obesity-associated inflammation and metabolic disease. Immune Netw. 2022;22(1):e13. DOI:10.4110/in.2022.22.e13.

23. Croce S., Avanzini M.A., Regalbuto C., Cordaro E., Vinci F., Zuccotti G. et al. Adipose tissue immunomodulation and Treg/Th17 imbalance in the impaired glucose metabolism of children with obesity. Children (Basel). 2021;8(7):554. DOI: 10.3390/children8070554.

24. Zhang L., Ai C., Bai M., Niu J., Zhang Z. NLRP3 Inflammasome/pyroptosis: a key driving force in diabetic cardiomyopathy. Int. J. Mol. Sci. 2022;23(18):10632. DOI: 10.3390/ijms231810632.