Abstract

Obesity puts people at risk for a variety of IL-1-driven metabolic disorders, such as atherosclerosis and type 2 diabetes mellitus (T2D) [1]. Moreover, the activation of adipose tissue macrophages (ATMs) inside fat deposits has been associated to an obesity-induced inflammatory state [2]. Furthermore, a new study found that obesity promotes the NLRP3 inflammasome to assemble in ATMs, resulting in insulin resistance in early T2D patients [3]. Higher level of both NLRP3 and IL-1 in visceral adipose tissue in free-feeding mice on a conventional chow diet was observed to associate significantly with body weight and adiposity when matched to mice fed a calorie-restricted diet. Weight loss in obese T2D patients was linked to lower NLRP3 and IL-1β expression in subcutaneous adipose tissue, which was similar to the findings in mice. Gene-deficient mice fed a high fat diet demonstrated lower caspase-1 activation and pro-IL-1β expression in adipose tissue, as well as a loss in serum IL-18 synthesis, compared to their wildtype counterparts. Furthermore, NLRP3- and caspase-1-deficient animals are more resistant to insulin resistance caused by a high-fat diet [3,4]. Insulin sensitivity was observed to be reduced as a result of NLRP3 inflammasome-mediated activation of effector adipose T cells, which then mediate downstream insulin resistance pathways via releasing interferon-gamma [5].

References

1. Ellulu MS., et al. “Obesity and inflammation: the linking mechanism and the complications”. Archives of Medical Science4 (2017): 851-863.
2. Van Dierendonck XAMH., et al. “The role of uncoupling protein 2 in macrophages and its impact on obesity-induced adipose tissue inflammation and insulin resistance”. Journal of Biological Chemistry51 (2020): 17535-17548.
3. Vandanmagsar B., et al. “The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance”. Nature Medicine2 (2011): 179-188.
4. Li Y., et al. “Inflammasomes as therapeutic targets in human diseases”. Signal Transduction and Targeted Therapy1 (2021): 247.
5. Gora IM., et al. “NLRP3 Inflammasome at the Interface of Inflammation, Endothelial Dysfunction, and Type 2 Diabetes”. Cells 2 (2021): 314.
6. Reginato A., et al. “The Role of Fatty Acids in Ceramide Pathways and Their Influence on Hypothalamic Regulation of Energy Balance: A Systematic Review”. International Journal of Molecular Sciences 22.10 (2021): 5357.
7. Russo L and Lumeng CN. “Properties and functions of adipose tissue macrophages in obesity”. Immunology4 (2018): 407-417.
8. Karasawa T and Takahashi M. “Saturated fatty acid-crystals activate NLRP3 inflammasome”. Aging 6 (2019): 1613-1614.
9. Tzeng HT., et al. “Shaping of Innate Immune Response by Fatty Acid Metabolite Palmitate”. Cells 12 (2019): 1633.
10. Guo X., et al. “AKT controls NLRP3 inflammasome activation by inducing DDX3X phosphorylation”. FEBS Letters (2021).
11. Li D., et al. “Reactive oxygen species induced by uric acid promote NRK 52E cell apoptosis through the NEK7 NLRP3 signaling pathway”. Molecular Medicine Reports 4 (2021): 729.
12. Snodgrass RG., et al. “Inflammasome-mediated secretion of IL-1β in human monocytes through TLR2 activation; modulation by dietary fatty acids”. Journal of Immunology8 (2013): 4337-4347.
13. Sokolova M., et al. “Palmitate promotes inflammatory responses and cellular senescence in cardiac fibroblasts”. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids2 (2017): 234-245.
14. Finelli C. “Obesity, COVID-19 and immunotherapy: the complex relationship!”. Immunotherapy15 (2020): 1105-1109.
15. Fusco R., et al. “Focus on the Role of NLRP3 Inflammasome in Diseases”. International Journal of Molecular Sciences12 (2020): 4223.
16. Kelley N., et al. “The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation”. International Journal of Molecular Sciences12 (2019): 3328.
17. Rocha DM., et al. “Saturated fatty acids trigger TLR4-mediated inflammatory response”. Atherosclerosis 244 (2016): 211-215.
18. Rogero MM and Calder PC. “Obesity, Inflammation, Toll-Like Receptor 4 and Fatty Acids”. Nutrients4 (2018): 432.
19. He W., et al. “Ageing potentiates diet-induced glucose intolerance, β-cell failure and tissue inflammation through TLR4”. Scientific Reports1 (2018): 2767.
20. Hasan A., et al. “TNF-α in Combination with Palmitate Enhances IL-8 Production via The MyD88- Independent TLR4 Signaling Pathway: Potential Relevance to Metabolic Inflammation”. International Journal of Molecular Sciences17 (2019): 4112.