Obesity-Associated Chronic Inflammation: A Protective Mechanism against Type 2 Diabetes

Abstract

Chronic inflammation is widely considered a risk factor for T2DM by inducing insulin resistance, but all attempts to translate the concept into clinical therapies have failed in the past 30 years. Anti-inflammatory medicines, including anti-TNF-α antibody (Etanercept), anti-IL1 antibody (Anakinra), anti-IL6 (Ziltivekimab), and NLRP3 inflammasome inhibitor (Colchicine) have excellent activities in the control of inflammation in arthritis. They reduced inflammation in T2DM patients in the clinical trials, but none improved insulin sensitivity. Some of them exhibited a mild and transient activity in the control of blood glucose, but the activities were related to the improvement of insulin secretion by β-cells. The failure may be related to followings: over-interpretation of TNF-α activity; ignoring the role of anti-inflammatory cytokines; differences between mice and humans. However, the species difference cannot fully explain the failure as these therapies did not work in the animal models as well. Moreover, genome-wide association studies (GWAS) show that T2DM is not associated with proinflammatory cytokine genes, including TNF-α, IL-1β, IL-6, and CCL2(MCP1). More studies suggest that inflammation has beneficial activities in the mobilization of energy stores and promotion of energy expenditure to prevent energy surplus, a risk factor of obesity-associated T2DM. Inflammatory cytokines induce lipolysis, thermogenesis, and satiety. In this regard, the inflammatory response is a compensatory event to obesity-associated stress with beneficial effects on energy metabolism. It is time to reconsider inflammation activity in obesity for protective activities.

Keywords

Obesity / Chronic inflammation / Insulin resistance / Type 2 diabetes / Clinical trial

Ethics Statement

Not applicable.

Informed Consent Statement

Not applicable.

Funding

The study is supported by the National Natural Science Foundation of China (Grant No. 32271220 ) to Jianping Ye.

Declaration of Competing Interest

The author declares that he has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References

[1] Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance. Science 1993, 259, 87-91.

[2] Lang CH, Dobrescu C, Bagby GJ. Tumor necrosis factor impairs insulin action on peripheral glucose disposal and hepatic glucose output. Endocrinology 1992, 130, 43-52.

[3] Feinstein R, Kanety H, Papa M, Lunenfeld B, Karasik A. Tumor necrosis factor-alpha suppresses insulin-induced tyrosine phosphorylation of insulin receptor and its substrates.. J. Biol. Chem. 1993, 268, 26055-26058.

[4] Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Investig. 2003, 112, 1796-1808.

[5] Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Investig. 2003, 112, 1821-1830.

[6] Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J. Clin. Endo. Metab. 2004, 89, 2548-2556.

[7] Hu T, Liu C, Lei M, Zeng Q, Li L, Tang H, et al. Metabolic regulation of the immune system in health and diseases: mechanisms and interventions. Sign. Transduct. Target. Ther. 2024, 9, 268.

[8] Gao Z, Zuberi A, Quon MJ, Dong Z, Ye J. Aspirin inhibits serine phosphorylation of insulin receptor substrate 1 in tumor necrosis factor-treated cells through targeting multiple serine kinases. J. Biol. Chem. 2003, 278, 24944-24950.

[9] Rui L, Aguirre V, Kim JK, Shulman GI, Lee A, Corbould A, et al. Insulin/IGF-1 and TNF-α stimulate phosphorylation of IRS-1 at inhibitory Ser 307 via distinct pathways. J. Clin. Investig. 2001, 107, 181-189.

[10] Ye J, McGuinness OP. Inflammation during obesity is not all bad: evidence from animal and human studies. Am. J. Physiol.-Endo. Metab. 2013, 304, E466-E477.

[11] Soták M, Clark M, Suur BE, Börgeson E.Inflammation and resolution in obesity. Nat. Rev. Endo. 2025, 21, 45-61.

[12] Trayhurn P. Hypoxia and adipose tissue function and dysfunction in obesity. Physiol. Rev. 2013, 93, 1-21.

[13] Ye J. Emerging role of adipose tissue hypoxia in obesity and insulin resistance. Int. J. Obes. 2009, 33, 54-66.

[14] Crewe C, An YA, Scherer PE. The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. J. Clin. Investig. 2017, 127, 74-82.

[15] Ye J. Mechanism of insulin resistance in obesity: a role of ATP. Fron. Med. 2021, 15, 372-382.

[16] Ye J. Failure of inflammation hypothesis in the pathogenesis of type 2 diabetes. Obesity Med. 2024, 52, 100565.

[17] Meizlish ML, Franklin RA, Zhou X, Medzhitov R.Tissue Homeostasis and Inflammation. Ann. Rev. Immunol. 2021, 39, 557-581.

[18] Sethi JK, Hotamisligil GS.Metabolic messengers: tumour necrosis factor. Nat. Metab. 2021, 3, 1302-1312.

[19] Bernstein LE, Berry J, Kim S, Canavan B, Grinspoon SK. Effects of etanercept in patients with the metabolic syndrome. Arch. Intern. Med. 2006, 166, 902-908.

[20] Larsen CM, Faulenbach M, Vaag A, Vølund A, Ehses JA, Seifert B, et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 2007, 356, 1517-1526.

[21] Everett BM, Donath MY, Pradhan AD, Thuren T, Pais P, Nicolau JC, et al. Anti-inflammatory therapy with canakinumab for the prevention and management of diabetes. J. Am. Coll. Card. 2018, 71, 2392-2401.

[22] Li D, Zhong J, Zhang Q, Zhang J. Effects of anti-inflammatory therapies on glycemic control in type 2 diabetes mellitus. Fron. Immunol. 2023, 14, 1125116.

[23] Sattar L, Memon RA, Ashfaq F, Hamdani SSQ, Rahim Vohra R, Ashraf J, et al. Efficacy and Safety of Colchicine in Prevention of Secondary Cardiovascular Outcomes Among Patients With Coronary Vessel Disease: A Meta-Analysis. Cureus 2022, 14, e26680.

[24] Cronstein BN, Molad Y, Reibman J, Balakhane E, Levin RI, Weissmann G. Colchicine alters the quantitative and qualitative display of selectins on endothelial cells and neutrophils.. J. Clin. Investig. 1995, 96, 994-1002.

[25] Tang T, Zhang J, Yin J, Staszkiewicz J, Gawronska-Kozak B, Jung DY, et al.Uncoupling of inflammation and insulin resistance by NF-κB in transgenic mice through elevated energy expenditure 2. J. Biol. Chem. 2010, 285, 4637-4644.

[26] Asterholm IW, Tao C, Morley TS, Wang QA, Delgado-Lopez F, Wang ZV, et al. Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling. Cell. Metab. 2014, 20, 103-118.

[27] Zhu Q, An YA, Kim M, Zhang Z, Zhao S, Zhu Y, et al. Suppressing adipocyte inflammation promotes insulin resistance in mice. Mol. Metab. 2020, 39, 101010.

[28] Ye J, Yin J. Type 2 diabetes: a sacrifice program handling energy surplus. Life. Metab. 2024, 3, loae033.

[29] Lee YS, Wollam J, Olefsky JM.An integrated view of immunometabolism. Cell 2018, 172, 22-40.

[30] Kalathookunnel Antony A, Lian Z, Wu H. T Cells in Adipose Tissue in Aging. Front. Immunol. 2018, 9, 2945.

[31] Sárvári AK, Van Hauwaert EL, Markussen LK, Gammelmark E, Marcher A, Ebbesen MF, et al. Plasticity of epididymal adipose tissue in response to diet-induced obesity at single-nucleus resolution. Cell. Metab. 2021, 33, 437-453. e5.

[32] Song A, Dai W, Jang MJ, Medrano L, Li Z, Zhao H, et al. Low-and high-thermogenic brown adipocyte subpopulations coexist in murine adipose tissue. J. Clin. Investig. 2020, 130, 247-257.

[33] Farooqi IS, Xu Y. Translational potential of mouse models of human metabolic disease. Cell 2024, 187, 4129-4143.

[34] Wueest S, Konrad D. The controversial role of IL-6 in adipose tissue on obesity-induced dysregulation of glucose metabolism. Am. J. Physiol.-Endo. Metab. 2020, 319, E607-E613.

[35] Lo J, Bernstein LE, Canavan B, Torriani M, Jackson MB, Ahima RS, et al. Effects of TNF-α neutralization on adipocytokines and skeletal muscle adiposity in the metabolic syndrome. Am. J. Physiol.-Endo. Metab. 2007, 293, E102-E109.

[36] Larsen CM, Faulenbach M, Vaag A, Ehses JA, Donath MY, Mandrup-Poulsen T. Sustained effects of interleukin-1 receptor antagonist treatment in type 2 diabetes. Diabetes Care. 2009, 32, 1663-1668.

[37] Tres GS, Fuchs SC, Piovesan F, Koehler-Santos P, Pereira FDS, Camey S, et al. Effect of diacerein on metabolic control and inflammatory markers in patients with type 2 diabetes using antidiabetic agents: a randomized controlled trial. J. Diabetes Res. 2018, 2018, 4246521.

[38] Garbers C, Heink S, Korn T, Rose-John S. Interleukin-6: designing specific therapeutics for a complex cytokine. Nat. Rev. Drug. Discov. 2018, 17, 395-412.

[39] Schultz O, Oberhauser F, Saech J, Rubbert-Roth A, Hahn M, Krone W, et al. Effects of inhibition of interleukin-6 signalling on insulin sensitivity and lipoprotein (a) levels in human subjects with rheumatoid diseases. PLoS ONE 2010, 5, e14328.

[40] Schreyer SA, Chua SC, LeBoeuf RC. Obesity and diabetes in TNF-alpha receptor-deficient mice. J. Clin. Investig. 1998, 102, 402-411.

[41] Xu H, Hirosumi J, Uysal KT, Guler AD, Hotamisligil GS. Exclusive action of transmembrane TNFα in adipose tissue leads to reduced adipose mass and local but not systemic insulin resistance. Endocrinology 2002, 143, 1502-1511.

[42] Kraakman MJ, Kammoun HL, Allen TL, Deswaerte V, Henstridge DC, Estevez E, et al. Blocking IL-6 trans-signaling prevents high-fat diet-induced adipose tissue macrophage recruitment but does not improve insulin resistance. Cell. Metab. 2015, 21, 403-416.

[43] Findeisen M, Allen TL, Henstridge DC, Kammoun H, Brandon AE, Baggio LL, et al. Treatment of type 2 diabetes with the designer cytokine IC7Fc. Nature 2019, 574, 63-68.

[44] Lambertucci F, Arboatti A, Sedlmeier MG, Motiño O, de Luján Alvarez M, Ceballos MP, et al. Disruption of tumor necrosis factor alpha receptor 1 signaling accelerates NAFLD progression in mice upon a high-fat diet. J. Nutr. Biochem. 2018, 58, 17-27.

[45] Jiao P, Feng B, Ma J, Nie Y, Paul E, Li Y, et al. Constitutive activation of IKKβ in adipose tissue prevents diet-induced obesity in mice. Endocrinology 2012, 153, 154-165.

[46] Kwon H, Laurent S, Tang Y, Zong H, Vemulapalli P, Pessin JE. Adipocyte-specific IKKβ signaling suppresses adipose tissue inflammation through an IL-13-dependent paracrine feedback pathway. Cell. Repo. 2014, 9, 1574-1583.

[47] Moon S, Park Y, Jang S, Kim S, Song D, Shin D, et al. Interleukin-2 improves insulin sensitivity through hypothalamic sympathetic activation in obese mice. J. Neur. 2024, 21, 250.

[48] Gao Z, Ye J. Why do anti-inflammatory therapies fail to improve insulin sensitivity? Acta Pharm. Sinica B 2012, 33, 182-188.

[49] Wang H, Ye J. Regulation of energy balance by inflammation: common theme in physiology and pathology. Rev. Endo. Metab. Disord. 2015, 16, 47-54.

[50] Wang A, Luan HH, Medzhitov R.An evolutionary perspective on immunometabolism. Science 2019, 363, eaar3932.

[51] Medzhitov R.The spectrum of inflammatory responses. Science 2021, 374, 1070-1075.

[52] Rosen ED, Kajimura S. Is it time to rethink the relationship between adipose inflammation and insulin resistance? J. Clin. Investig. 2024, 134.

[53] Maretty L, Gill D, Simonsen L, Soh K, Zagkos L, Galanakis M, et al. Proteomic changes upon treatment with semaglutide in individuals with obesity. Nat. Med. 2025, 31, 266-277.

[54] Yokose C, McCormick N, Abhishek A, Dalbeth N, Pascart T, Lioté F, et al. The clinical benefits of sodium-glucose cotransporter type 2 inhibitors in people with gout. Nat. Rev. Rheumatol. 2024, 20, 216-231.

[55] Lee JH, Zhang Y, Zhao Z, Ye X, Zhang X, Wang H, et al. Intracellular ATP in balance of pro-and anti-inflammatory cytokines in adipose tissue with and without tissue expansion. Int. J. Obes. 2017, 41, 645-651.

[56] Chavakis T, Alexaki VI, Ferrante AW, Jr. Macrophage function in adipose tissue homeostasis and metabolic inflammation. Nat. Immunol. 2023, 24, 757-766.

[57] Salehi Farid A, Rowley JE, Allen HH, Kruger IG, Tavakolpour S, Neeley K, et al. CD45-PET is a robust, non-invasive tool for imaging inflammation. Nature 2025, 639, 214-224.

[58] Goldfine A, Conlin P, Halperin F, Koska J, Permana P, Schwenke D, et al. A randomised trial of salsalate for insulin resistance and cardiovascular risk factors in persons with abnormal glucose tolerance. Diabetologia 2013, 56, 714-723.