Epigenetic modifications in obesity-associated diseases

Abstract

The global prevalence of obesity has reached epidemic levels, significantly elevating the susceptibility to various cardiometabolic conditions and certain types of cancer. In addition to causing metabolic abnormalities such as insulin resistance (IR), elevated blood glucose and lipids, and ectopic fat deposition, obesity can also damage pancreatic islet cells, endothelial cells, and cardiomyocytes through chronic inflammation, and even promote the development of a microenvironment conducive to cancer initiation. Improper dietary habits and lack of physical exercise are important behavioral factors that increase the risk of obesity, which can affect gene expression through epigenetic modifications. Epigenetic alterations can occur in early stage of obesity, some of which are reversible, while others persist over time and lead to obesity-related complications. Therefore, the dynamic adjustability of epigenetic modifications can be leveraged to reverse the development of obesity-associated diseases through behavioral interventions, drugs, and bariatric surgery. This review provides a comprehensive summary of the impact of epigenetic regulation on the initiation and development of obesity-associated cancers, type 2 diabetes, and cardiovascular diseases, establishing a theoretical basis for prevention, diagnosis, and treatment of these conditions.

Keywords

cancer / cardiovascular diseases / epigenetics / obesity / prevention / therapy / type 2 diseases

References

[1] Obesity and overweight. Updated 9 June 2021. Accessed 10 January, 2024. https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight

[2] Oliveros E, Somers VK, Sochor O, Goel K, Lopez-Jimenez F. The concept of normal weight obesity. Prog Cardiovasc Dis. 2014;56(4):426-433.

[3] Pluta W, Dudzińska W, Lubkowska A. Metabolic obesity in people with normal body weight (MONW)-review of diagnostic criteria. Int J Environ Res Public Health. 2022;19(2).

[4] Sung H, Siegel RL, Torre LA, et al. Global patterns in excess body weight and the associated cancer burden. CA Cancer J Clin. 2019;69(2):88-112.

[5] Arnold M, Leitzmann M, Freisling H, et al. Obesity and cancer: an update of the global impact. Cancer Epidemiol. 2016;41:8-15.

[6] Sun M, Fritz J, Häggström C, et al. Metabolically (un)healthy obesity and risk of obesity-related cancers: a pooled study. J Natl Cancer Inst. 2023;115(4):456-467.

[7] Ligibel JA, Alfano CM, Courneya KS, et al. American Society of Clinical Oncology position statement on obesity and cancer. J Clin Oncol. 2014;32(31):3568-3574.

[8] Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17-48.

[9] Apovian CM, Okemah J, O'Neil PM. Body weight considerations in the management of type 2 diabetes. Adv Ther. 2019;36(1):44-58.

[10] Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet. 2014;383(9922):1068-1083.

[11] Liu Y, Douglas PS, Lip GYH, et al. Relationship between obesity severity, metabolic status and cardiovascular disease in obese adults. Eur J Clin Invest. 2023;53(3):e13912.

[12] Powell-Wiley TM, Poirier P, Burke LE, et al. Obesity and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2021;143(21):e984-e1010.

[13] Jin X, Qiu T, Li L, et al. Pathophysiology of obesity and its associated diseases. Acta Pharm Sin B. 2023;13(6):2403-2424.

[14] Liu L, Shi Z, Ji X, et al. Adipokines, adiposity, and atherosclerosis. Cell Mol Life Sci. 2022;79(5):272.

[15] Rojas E, Rodríguez-Molina D, Bolli P, et al. The role of adiponectin in endothelial dysfunction and hypertension. Curr Hypertens Rep. 2014;16(8):463.

[16] Ruze R, Liu T, Zou X, et al. Obesity and type 2 diabetes mellitus: connections in epidemiology, pathogenesis, and treatments. Front Endocrinol (Lausanne). 2023;14:1161521.

[17] Kim DS, Scherer PE. Obesity, diabetes, and increased cancer progression. Diabetes Metab J. 2021;45(6):799-812.

[18] Hill MA, Yang Y, Zhang L, et al. Insulin resistance, cardiovascular stiffening and cardiovascular disease. Metabolism. 2021;119:154766.

[19] Cavalli G, Heard E. Advances in epigenetics link genetics to the environment and disease. Nature. 2019;571(7766):489-499.

[20] Li R, Grimm SA, Mav D, et al. Transcriptome and DNA methylome analysis in a mouse model of diet-induced obesity predicts increased risk of colorectal cancer. Cell Rep. 2018;22(3):624-637.

[21] Izquierdo-Torres E, Hernández-Oliveras A, Lozano-Arriaga D, Zarain-Herzberg Á. Obesity, the other pandemic: linking diet and carcinogenesis by epigenetic mechanisms. J Nutr Biochem. 2022;108:109092.

[22] Ling C, Rönn T. Epigenetics in human obesity and type 2 diabetes. Cell Metab. 2019;29(5):1028-1044.

[23] Jurkowska RZ, Jurkowski TP, Jeltsch A. Structure and function of mammalian DNA methyltransferases. Chembiochem. 2011;12(2):206-222.

[24] Chen Z, Zhang Y. Role of mammalian DNA methyltransferases in development. Annu Rev Biochem. 2020;89:135-158.

[25] Jones PA. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet. 2012;13(7):484-492.

[26] Wu X, Zhang Y. TET-mediated active DNA demethylation: mechanism, function and beyond. Nat Rev Genet. 2017;18(9):517-534.

[27] Bochtler M, Kolano A, Xu GL. DNA demethylation pathways: additional players and regulators. Bioessays. 2017;39(1):1-13.

[28] Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128(4):683-692.

[29] Huang T, Huang X, Nie Y, Shi X, Shu C. A combined effect of expression levels of obesity-related genes and clinical factors on cancer survival rate. BioMed Res Int. 2020;2020:8838676.

[30] Torres-Gutierrez CJ, Heckman MG, Hlady RA, et al. Association of clinical epidemiologic exposures and overall survival with genome-wide DNA methylation profiles in acute myeloid leukemia: analysis of the mayo clinic AML epidemiology cohort. Blood. 2018;132:3987.

[31] Crujeiras AB, Morcillo S, Diaz-Lagares A, et al. Identification of an episignature of human colorectal cancer associated with obesity by genome-wide DNA methylation analysis. Int J Obes (Lond). 2019;43(1):176-188.

[32] Crujeiras AB, Diaz-Lagares A, Stefansson OA, et al. Obesity and menopause modify the epigenomic profile of breast cancer. Endocr Relat Cancer. 2017;24(7):351-363.

[33] Lorenzo PM, Izquierdo AG, Diaz-Lagares A, et al. ZNF577 methylation levels in leukocytes from women with breast cancer is modulated by adiposity, menopausal state, and the mediterranean diet. Front Endocrinol. 2020;11:245.

[34] Cabrera-Mulero A, Crujeiras AB, Izquierdo AG, et al. Novel SFRP2 DNA methylation profile following neoadjuvant therapy in colorectal cancer patients with different grades of BMI. J Clin Med. 2019;8(7):1041.

[35] Castellano-Castillo D, Morcillo S, Crujeiras AB, et al. Association between serum 25-hydroxyvitamin D and global DNA methylation in visceral adipose tissue from colorectal cancer patients. BMC Cancer. 2019;19(1):93.

[36] Frederick ALM, Guo C, Meyer A, Yan L, Schneider SS, Liu Z. The influence of obesity on folate status, DNA methylation and cancer-related gene expression in normal breast tissues from premenopausal women. Epigenetics. 2021;16(4):458-467.

[37] Bao B, Teslow EA, Mitrea C, Boerner JL, Dyson G, Bollig-Fischer A. Role of TET1 and 5hmC in an obesity-linked pathway driving cancer stem cells in triple-negative breast cancer. Mol Cancer Res. 2020;18(12):1803-1814.

[38] Dong L, Ma L, Ma GH, Ren H. Genome-wide analysis reveals DNA methylation alterations in obesity associated with high risk of colorectal cancer. Sci Rep. 2019;9(1):5100.

[39] Rodríguez-Miguel C, Moral R, Escrich R, Vela E, Solanas M, Escrich E. The role of dietary extra virgin olive oil and corn oil on the alteration of epigenetic patterns in the rat DMBA-induced breast cancer model. PLoS One. 2015;10(9):e0138980.

[40] Sedaghat F, Cheraghpour M, Hosseini SA, et al. Hypomethylation of NANOG promoter in colonic mucosal cells of obese patients: a possible role of NF-κB. Br J Nutr. 2019;122(5):499-508.

[41] Milner JJ, Chen ZF, Grayson J, Shiao SPK. Obesity-associated differentially methylated regions in colon cancer. J Pers Med. 2022;12(5):660.

[42] Tian Y, Arai E, Makiuchi S, et al. Aberrant DNA methylation results in altered gene expression in non-alcoholic steatohepatitis-related hepatocellular carcinomas. J Cancer Res Clin Oncol. 2020;146(10):2461-2477.

[43] Cheng Y, Monteiro C, Matos A, et al. Epigenome-wide DNA methylation profiling of periprostatic adipose tissue in prostate cancer patients with excess adiposity-a pilot study. Clin Epigenet. 2018;10(1):54.

[44] Boughanem H, Ruiz-Limon P, Crujeiras AB, de Luque V, Tinahones FJ, Macias-Gonzalez M. 25-Hydroxyvitamin D status is associated with interleukin-6 methylation in adipose tissue from patients with colorectal cancer. Food Funct. 2021;12(20):9620-9631.

[45] Spyrou N, Avgerinos KI, Mantzoros CS, Dalamaga M. Classic and novel adipocytokines at the intersection of obesity and cancer: diagnostic and therapeutic strategies. Curr Obes Rep. 2018;7(4):260-275.

[46] Herrera-Vargas AK, García-Rodríguez E, Olea-Flores M, Mendoza-Catalán MA, Flores-Alfaro E, Navarro-Tito N. Pro-angiogenic activity and vasculogenic mimicry in the tumor microenvironment by leptin in cancer. Cytokine Growth Factor Rev. 2021;62:23-41.

[47] Hsieh YY, Shen CH, Huang WS, et al. Resistin-induced stromal cell-derived factor-1 expression through Toll-like receptor 4 and activation of p38 MAPK/NFκB signaling pathway in gastric cancer cells. J Biomed Sci. 2014;21(1):59.

[48] Shi Y, Zhu N, Qiu Y, et al. Resistin-like molecules: a marker, mediator and therapeutic target for multiple diseases. Cell Commun Signal. 2023;21(1):18.

[49] Polusani SR, Huang YW, Huang G, et al. Adipokines deregulate cellular communication via epigenetic repression of gap junction loci in obese endometrial cancer. Cancer Research. 2019;79(1):196-208.

[50] Bokobza E, Hinault C, Tiroille V, Clavel S, Bost F, Chevalier N. The adipose tissue at the crosstalk between EDCs and cancer development. Front Endocrinol (Lausanne). 2021;12:691658.

[51] Basak S, Das MK, Duttaroy AK. Plastics derived endocrine-disrupting compounds and their effects on early development. Birth Defects Res. 2020;112(17):1308-1325.

[52] Kahn LG, Philippat C, Nakayama SF, Slama R, Trasande L. Endocrine-disrupting chemicals: implications for human health. Lancet Diabetes Endocrinol. 2020;8(8):703-718.

[53] Shafei A, Ramzy MM, Hegazy AI, et al. The molecular mechanisms of action of the endocrine disrupting chemical bisphenol A in the development of cancer. Gene. 2018;647:235-243.

[54] Leung YK, Govindarajah V, Cheong A, et al. Gestational high-fat diet and bisphenol A exposure heightens mammary cancer risk. Endocr Relat Cancer. 2017;24(7):365-378.

[55] Darbre PD. Endocrine disruptors and obesity. Curr Obes Rep. 2017;6(1):18-27.

[56] Stern JH, Rutkowski JM, Scherer PE. Adiponectin, leptin, and fatty acids in the maintenance of metabolic homeostasis through adipose tissue crosstalk. Cell Metab. 2016;23(5):770-784.

[57] Sinha MK, Opentanova I, Ohannesian JP, et al. Evidence of free and bound leptin in human circulation. Studies in lean and obese subjects and during short-term fasting. J Clin Invest. 1996;98(6):1277-1282.

[58] Saxena NK, Vertino PM, Anania FA, Sharma D. leptin-induced growth stimulation of breast cancer cells involves recruitment of histone acetyltransferases and mediator complex to CYCLIN D1 promoter via activation of Stat3. J Biol Chem. 2007;282(18):13316-13325.

[59] Milosevic VS, Vukmirovic FC, Krstic MS, Zindovic MM, Lj Stojanovic D, Jancic SA. Involvement of leptin receptors expression in proliferation and neoangiogenesis in colorectal carcinoma. J buon. 2015;20(1):100-108.

[60] Wei X, Liu Y, Gong C, et al. Targeting leptin as a therapeutic strategy against ovarian cancer peritoneal metastasis. Anticancer Agents Med Chem. 2017;17(8):1093-1101.

[61] Ray A, Cleary MP. The potential role of leptin in tumor invasion and metastasis. Cytokine Growth Factor Rev. 2017;38:80-97.

[62] Jiménez-Cortegana C, López-Saavedra A, Sánchez-Jiménez F, et al. Leptin, both bad and good actor in cancer. Biomolecules. 2021;11(6):913.

[63] de Candia P, Prattichizzo F, Garavelli S, Alviggi C, La Cava A, Matarese G. The pleiotropic roles of leptin in metabolism, immunity, and cancer. J Exp Med. 2021;218(5):e20191593.

[64] Mendoza-Pérez J, Gu J, Herrera LA, et al. Prognostic significance of promoter CpG island methylation of obesity-related genes in patients with nonmetastatic renal cell carcinoma. Cancer. 2017;123(18):3617-3627.

[65] Assidi M, Yahya FM, Al-Zahrani MH, et al. Leptin protein expression and promoter methylation in ovarian cancer: a strong prognostic value with theranostic promises. Int J Mol Sci. 2021;22(23):12872.

[66] Zhang TJ, Xu ZJ, Gu Y, et al. Identification and validation of obesity-related gene LEP methylation as a prognostic indicator in patients with acute myeloid leukemia. Clin Epigenet. 2021;13(1):16.

[67] Pasha HF, Mohamed RH, Toam MM, Yehia AM. Genetic and epigenetic modifications of adiponectin gene: potential association with breast cancer risk. J Gene Med. 2019;21(10):e3120.

[68] Parida S, Siddharth S, Sharma D. Adiponectin, obesity, and cancer: clash of the bigwigs in health and disease. Int J Mol Sci. 2019;20(10):2519.

[69] Messaggio F. Increasing adiponectin receptor levels improves anti-proliferative effects of adiporon in pancreatic cancer. Pancreas. 2017;46(10):1419.

[70] Cicekdal MB, Kazan BT, Tuna BG, et al. Effects of two types of energy restriction on methylation levels of adiponectin receptor 1 and leptin receptor overlapping transcript in a mouse mammary tumour virus-transforming growth factor-alpha breast cancer mouse model. Br J Nutr. 2021;125(1):1-9.

[71] Yamaji T, Iwasaki M, Sasazuki S, Tsugane S. Interaction between adiponectin and leptin influences the risk of colorectal adenoma. Cancer Res. 2010;70(13):5430-5437.

[72] Baca P, Barajas-Olmos F, Mirzaeicheshmeh E, et al. DNA methylation and gene expression analysis in adipose tissue to identify new loci associated with T2D development in obesity. Nutr Diabetes. 2022;12(1):50.

[73] Ouni M, Eichelmann F, Jähnert M, et al. Differences in DNA methylation of HAMP in blood cells predicts the development of type 2 diabetes. Mol Metab. 2023;75:101774.

[74] Touré M, Hichami A, Sayed A, Suliman M, Samb A, Khan NA. Association between polymorphisms and hypermethylation of CD36 gene in obese and obese diabetic Senegalese females. Diabetol Metab Syndr. 2022;14(1):117.

[75] Krause C, Geißler C, Tackenberg H, et al. Multi-layered epigenetic regulation of IRS2 expression in the liver of obese individuals with type 2 diabetes. Diabetologia. 2020;63(10):2182-2193.

[76] Wu L, Jiao Y, Li Y, et al. Hepatic Gadd45β promotes hyperglycemia and glucose intolerance through DNA demethylation of PGC-1α. J Exp Med. 2021;218(5):e20201475.

[77] Mirzaeicheshmeh E, Zerrweck C, Centeno-Cruz F, et al. Alterations of DNA methylation during adipogenesis differentiation of mesenchymal stem cells isolated from adipose tissue of patients with obesity is associated with type 2 diabetes. Adipocyte. 2021;10(1):493-504.

[78] Schrader S, Perfilyev A, Ahlqvist E, et al. Novel subgroups of type 2 diabetes display different epigenetic patterns that associate with future diabetic complications. Diabetes Care. 2022;45(7):1621-1630.

[79] Veloso Pereira BM, Charleaux de Ponte M, Malavolta Luz AP, Thieme K. DNA methylation enzymes in the kidneys of male and female BTBR ob/ob mice. Front Endocrinol (Lausanne). 2023;14:1167546.

[80] Yang L, Zhang Q, Wu Q, et al. Effect of TET2 on the pathogenesis of diabetic nephropathy through activation of transforming growth factor β1 expression via DNA demethylation. Life Sci. 2018;207:127-137.

[81] Li KY, Tam CHT, Liu H, et al. DNA methylation markers for kidney function and progression of diabetic kidney disease. Nat Commun. 2023;14(1):2543.

[82] Milluzzo A, Maugeri A, Barchitta M, Sciacca L, Agodi A. Epigenetic mechanisms in type 2 diabetes retinopathy: a systematic review. Int J Mol Sci. 2021;22(19):10502.

[83] Rautenberg EK, Hamzaoui Y, Coletta DK. Mini-review: mitochondrial DNA methylation in type 2 diabetes and obesity. Front Endocrinol (Lausanne). 2022;13:968268.

[84] Cao K, Lv W, Wang X, et al. Hypermethylation of hepatic mitochondrial ND6 provokes systemic insulin resistance. Adv Sci (Weinh). 2021;8(11):2004507.

[85] Giglio RV, Stoian AP, Patti AM, et al. Genetic and epigenetic biomarkers for diagnosis, prognosis and treatment of metabolic syndrome. Curr Pharm Des. 2021;27(35):3729-3740.

[86] Masi S, Ambrosini S, Mohammed SA, et al. Epigenetic remodeling in obesity-related vascular disease. Antioxid Redox Signal. 2021;34(15):1165-1199.

[87] Sumi MP, Mahajan B, Sattar RSA, et al. Elucidation of epigenetic landscape in coronary artery disease: a review on basic concept to personalized medicine. Epigenet Insights. 2021;14:2516865720988567.

[88] Do WL, Gohar J, McCullough LE, Galaviz KI, Conneely KN, Narayan KMV. Examining the association between adiposity and DNA methylation: a systematic review and meta-analysis. Obes Rev. 2021;22(10):e13319.

[89] Fernández-Sanlés A, Sayols-Baixeras S, Subirana I, Degano IR, Elosua R. Association between DNA methylation and coronary heart disease or other atherosclerotic events: a systematic review. Atherosclerosis. 2017;263:325-333.

[90] Guo Y, Fan Y, Zhang J, et al. Perhexiline activates KLF14 and reduces atherosclerosis by modulating ApoA-I production. J Clin Invest. 2015;125(10):3819-3830.

[91] Wu S, Hsu LA, Teng MS, Chou HH, Ko YL. Differential genetic and epigenetic effects of the KLF14 gene on body shape indices and metabolic traits. Int J Mol Sci. 2022;23(8):4165.

[92] Yeung BH, Griffiths K, Berger L, et al. Leptin induces epigenetic regulation of transient receptor potential melastatin 7 in rat adrenal pheochromocytoma cells. Am J Respir Cell Mol Biol. 2021;65(2):214-221.

[93] Fontanella RA, Scisciola L, Rizzo MR, et al. Adiponectin related vascular and cardiac benefits in obesity: is there a role for an epigenetically regulated mechanism? Front Cardiovasc Med. 2021;8:768026.

[94] Indumathi B, Oruganti SS, Sreenu B, Kutala VK. Association of promoter methylation and expression of inflammatory genes IL-6 and TNF-α with the risk of coronary artery disease in diabetic and obese subjects among Asian Indians. Indian J Clin Biochem. 2022;37(1):29-39.

[95] Geißler C, Krause C, Neumann AM, et al. Dietary induction of obesity and insulin resistance is associated with changes in Fgf21 DNA methylation in liver of mice. J Nutr Biochem. 2022;100:108907.

[96] Kouzarides T. Chromatin modifications and their function. Cell. 2007;128(4):693-705.

[97] Zhang Y, Reinberg D. Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. Genes Dev. 2001;15(18):2343-2360.

[98] Labbe DP, Zadra G, Yang M, et al. High-fat diet fuels prostate cancer progression by rewiring the metabolome and amplifying the MYC program. Nat Commun. 2019;10:4358.

[99] Wagner EJ, Carpenter PB. Understanding the language of Lys36 methylation at histone H3. Nat Rev Mol Cell Biol. 2012;13(2):115-126.

[100] Li XJ, Li QL, Ju LG, et al. Deficiency of histone methyltransferase SET domain-containing 2 in liver leads to abnormal lipid metabolism and HCC. Hepatology. 2021;73(5):1797-1815.

[101] Assante G, Chandrasekaran S, Ng S, et al. Acetyl-CoA metabolism drives epigenome change and contributes to carcinogenesis risk in fatty liver disease. Genome Med. 2022;14(1):67.

[102] Rajan PK, Utibe-Abasi U, Sanabria JD, et al. The role of histone acetylation/methylation mediated epigenetic modifications in the pathogenesis of non-alcoholic steatohepatitisassociated liver carcinogenesis. Am J Transplant. 2021;21(4):769.

[103] de Conti A, Dreval K, Tryndyak V, et al. Inhibition of the cell death pathway in nonalcoholic steatohepatitis (NASH)-related hepatocarcinogenesis is associated with histone H4 lysine 16 deacetylation. Mol Cancer Res. 2017;15(9):1163-1172.

[104] Qin Y, Roberts JD, Grimm SA, et al. An obesity-associated gut microbiome reprograms the intestinal epigenome and leads to altered colonic gene expression. Genome Biol. 2018;19(1):7.

[105] Porcuna J, Mínguez-Martínez J, Ricote M. The PPARα and PPARγ epigenetic landscape in cancer and immune and metabolic disorders. Int J Mol Sci. 2021;22(19):10573.

[106] Mayoral R, Osborn O, McNelis J, et al. Adipocyte SIRT1 knockout promotes PPARγ activity, adipogenesis and insulin sensitivity in chronic-HFD and obesity. Mol Metab. 2015;4(5):378-391.

[107] Jiang X, Ye X, Guo W, Lu H, Gao Z. Inhibition of HDAC3 promotes ligand-independent PPARγ activation by protein acetylation. J Mol Endocrinol. 2014;53(2):191-200.

[108] Xu Z, Tong Q, Zhang Z, et al. Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathway. Clin Sci (Lond). 2017;131(15):1841-1857.

[109] Zhang J, Xu Z, Gu J, et al. HDAC3 inhibition in diabetic mice may activate Nrf2 preventing diabetes-induced liver damage and FGF21 synthesis and secretion leading to aortic protection. Am J Physiol Endocrinol Metab. 2018;315(2):E150-E162.

[110] Adhikari N, Jha T, Ghosh B. Dissecting histone deacetylase 3 in multiple disease conditions: selective inhibition as a promising therapeutic strategy. J Med Chem. 2021;64(13):8827-8869.

[111] Longo M, Zatterale F, Spinelli R, et al. Altered H3K4me3 profile at the TFAM promoter causes mitochondrial alterations in preadipocytes from first-degree relatives of type 2 diabetics. Clin Epigenetics. 2023;15(1):144.

[112] Jetton TL, Flores-Bringas P, Leahy JL, Gupta D. SetD7 (Set7/9) is a novel target of PPARγ that promotes the adaptive pancreatic β-cell glycemic response. J Biol Chem. 2021;297(5):101250.

[113] Dubois-Deruy E, El Masri Y, Turkieh A, Amouyel P, Pinet F, Annicotte JS. Cardiac acetylation in metabolic diseases. Biomedicines. 2022;10(8):1834.

[114] Dhagia V, Kitagawa A, Jacob C, et al. G6PD activity contributes to the regulation of histone acetylation and gene expression in smooth muscle cells and to the pathogenesis of vascular diseases. Am J Physiol Heart Circ Physiol. 2021;320(3):H999-H1016.

[115] Grootaert MOJ, Finigan A, Figg NL, Uryga AK, Bennett MR. SIRT6 protects smooth muscle cells from senescence and reduces atherosclerosis. Circ Res. 2021;128(4):474-491.

[116] Lecce L, Xu Y, V'Gangula B, et al. Histone deacetylase 9 promotes endothelial-mesenchymal transition and an unfavorable atherosclerotic plaque phenotype. J Clin Invest. 2021;131(15):e131178.

[117] Ponting CP, Oliver PL, Reik W. Evolution and functions of long noncoding RNAs. Cell. 2009;136(4):629-641.

[118] Rey F, Messa L, Pandini C, et al. Transcriptome analysis of subcutaneous adipose tissue from severely obese patients highlights deregulation profiles in coding and non-coding oncogenes. Int J Mol Sci. 2021;22(4):1989.

[119] Tait S, Baldassarre A, Masotti A, et al. Integrated transcriptome analysis of human visceral adipocytes unravels dysregulated microRNA-long non-coding RNA-mRNA networks in obesity and colorectal cancer. Front Oncol. 2020;10:1089.

[120] Cao XH, Yang K, Liang MX, et al. Variation of long non-coding RNA and mRNA profiles in breast cancer cells with influences of adipocytes. Front Oncol. 2021;11:631551.

[121] De la Fuente-Hernandez MA, Alanis-Manriquez EC, Ferat-Osorio E, et al. Molecular changes in adipocyte-derived stem cells during their interplay with cervical cancer cells. Cell Oncol (Dordr). 2022;45(1):85-101.

[122] Wang LL, Wang RR, Ye Z, et al. PVT1 affects EMT and cell proliferation and migration via regulating p21 in triple-negative breast cancer cells cultured with mature adipogenic medium. Acta Biochim Biophys Sin. 2018;50(12):1211-1218.

[123] Choudhry H, Hassan MA, Al-Malki AL, Al-Sakkaf KA. Suppression of circulating AP001429.1 long non-coding RNA in obese patients with breast cancer. Oncol Lett. 2021;22(1):508.

[124] Wu H, Zhong Z, Wang A, et al. LncRNA FTX represses the progression of non-alcoholic fatty liver disease to hepatocellular carcinoma via regulating the M1/M2 polarization of Kupffer cells. Cancer Cell Int. 2020;20:266.

[125] Wang B, Li X, Hu W, Zhou Y, Din Y. Silencing of lncRNA SNHG20 delays the progression of nonalcoholic fatty liver disease to hepatocellular carcinoma via regulating liver Kupffer cells polarization. IUBMB Life. 2019;71(12):1952-1961.

[126] Shetty A, Suresh PS. A synergy of estradiol with leptin modulates the long non-coding RNA NEAT1/mmu-miR-204-5p/IGF1 axis in the uterus of high-fat-diet-induced obese ovariectomized mice. J Steroid Biochem Mol Biol. 2021;209:105843.

[127] Liu Y, Wang L, Liu H, Li C, He J. The prognostic significance of metabolic syndrome and a related six-lncRNA signature in esophageal squamous cell carcinoma. Front Oncol. 2020;10:61.

[128] Liu Y, Li C, Fang L, et al. Lipid metabolism-related lncRNA SLC25A21-AS1 promotes the progression of oesophageal squamous cell carcinoma by regulating the NPM1/c-Myc axis and SLC25A21 expression. Clin Transl Med. 2022;12(6):e944.

[129] de Klerk JA, Beulens JWJ, Mei H, et al. Altered blood gene expression in the obesity-related type 2 diabetes cluster may be causally involved in lipid metabolism: a Mendelian randomisation study. Diabetologia. 2023;66(6):1057-1070.

[130] Liu B, Zhong Y, Huang D, et al. LncRNA Nron deficiency protects mice from diet-induced adiposity and hepatic steatosis. Metabolism. 2023;148:155609.

[131] Kerr AG, Wang Z, Wang N, et al. The long noncoding RNA ADIPINT regulates human adipocyte metabolism via pyruvate carboxylase. Nat Commun. 2022;13(1):2958.

[132] Alvarez-Dominguez JR, Winther S, Hansen JB, Lodish HF, Knoll M. An adipose lncRAP2-Igf2bp2 complex enhances adipogenesis and energy expenditure by stabilizing target mRNAs. iScience. 2022;25(1):103680.

[133] Li Y, Chen Y, Liu Z, et al. Downregulation of Kcnq1ot1 attenuates β-cell proliferation and insulin secretion via the miR-15b-5p/Ccnd1 and Ccnd2 axis. Acta Diabetol. 2022;59(7):885-899.

[134] Zhang F, Yang Y, Chen X, et al. The long non-coding RNA βFaar regulates islet β-cell function and survival during obesity in mice. Nat Commun. 2021;12(1):3997.

[135] Weiss E, Schrüfer A, Tocantins C, et al. Higher gestational weight gain delays wound healing and reduces expression of long non-coding RNA KLRK1-AS1 in neonatal endothelial progenitor cells. J Physiol. 2023;601(17):3961-3974.

[136] Zhao W, Yin Y, Cao H, Wang Y. Exercise improves endothelial function via the lncRNA MALAT1/miR-320a axis in obese children and adolescents. Cardiol Res Pract. 2021;2021:8840698.

[137] Li R, Yu X, Chen Y, et al. Association of lncRNA PVT1 gene polymorphisms with the risk of essential hypertension in chinese population. Biomed Res Int. 2022;2022:9976909.

[138] Liu Y, Xu XY, Shen Y, et al. Ghrelin protects against obesity-induced myocardial injury by regulating the lncRNA H19/miR-29a/IGF-1 signalling axis. Exp Mol Pathol. 2020;114:104405.

[139] Lang YY, Xu XY, Liu YL, et al. Ghrelin relieves obesity-induced myocardial injury by regulating the epigenetic suppression of miR-196b mediated by lncRNA HOTAIR. Obes Facts. 2022;15(4):540-549.

[140] Heyn GS, Corrêa LH, Magalhães KG. The impact of adipose tissue-derived miRNAs in metabolic syndrome, obesity, and cancer. Front Endocrinol (Lausanne). 2020;11:563816.

[141] Cheng L, Zhu Y, Han H, et al. MicroRNA-148a deficiency promotes hepatic lipid metabolism and hepatocarcinogenesis in mice. Cell Death Dis. 2017;8(7):e2916.

[142] Gjorgjieva M, Sobolewski C, Ay AS, et al. Genetic ablation of MiR-22 fosters diet-induced obesity and NAFLD development. J Pers Med. 2020;10(4):170.

[143] Feige JN, Gelman L, Michalik L, Desvergne B, Wahli W. From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions. Prog Lipid Res. 2006;45(2):120-159.

[144] Hsu HT, Sung MT, Lee CC, et al. Peroxisome proliferator-activated receptor γ expression is inversely associated with macroscopic vascular invasion in human hepatocellular carcinoma. Int J Mol Sci. 2016;17(8):1226.

[145] Motawi TK, Shaker OG, Ismail MF, Sayed NH. Peroxisome proliferator-activated receptor gamma in obesity and colorectal cancer: the role of epigenetics. Sci Rep. 2017;7(1):10714.

[146] Rajarajan D, Selvarajan S, Charan Raja MR, Kar Mahapatra S, Kasiappan R. Genome-wide analysis reveals miR-3184-5p and miR-181c-3p as a critical regulator for adipocytes-associated breast cancer. J Cell Physiol. 2019;234(10):17959-17974.

[147] Belaiba F, Medimegh I, Ammar M, et al. Expression and polymorphism of micro-RNA according to body mass index and breast cancer presentation in Tunisian patients. J Leukoc Biol. 2019;105(2):317-327.

[148] Meerson A, Eliraz Y, Yehuda H, et al. Obesity impacts the regulation of miR-10b and its targets in primary breast tumors. BMC Cancer. 2019;19(1):86.

[149] Ahmed FE. miRNA as markers for the diagnostic screening of colon cancer. Expert Rev Anticancer Ther. 2014;14(4):463-485.

[150] Jeon J, Olkhov-Mitsel E, Xie H, et al. Temporal stability and prognostic biomarker potential of the prostate cancer urine miRNA transcriptome. J Natl Cancer Inst. 2020;112(3):247-255.

[151] Donkers H, Hirschfeld M, Weiss D, et al. Detection of microRNA in urine to identify patients with endometrial cancer: a feasibility study. Int J Gynecol Cancer. 2021;31(6):868-874.

[152] Jasinski-Bergner S, Kielstein H. Adipokines regulate the expression of tumor-relevant microRNAs. Obesity Facts. 2019;12(2):211-225.

[153] Nagalingam A, Siddharth S, Parida S, et al. Hyperleptinemia in obese state renders luminal breast cancers refractory to tamoxifen by coordinating a crosstalk between Med1, miR205 and ErbB. Npj Breast Cancer. 2021;7(1):105.

[154] Rios-Colon L, Chijioke J, Niture S, et al. Leptin modulated microRNA-628-5p targets Jagged-1 and inhibits prostate cancer hallmarks. Sci Rep. 2022;12(1).

[155] Ma L, Fan Z, Du G, Wang H. Leptin-elicited miRNA-342-3p potentiates gemcitabine resistance in pancreatic ductal adenocarcinoma. Biochem Biophys Res Commun. 2019;509(3):845-853.

[156] Al-Khalaf HH, Amir M, Al-Mohanna F, Tulbah A, Al-Sayed A, Aboussekhra A. Obesity and p16(INK4A) downregulation activate breast adipocytes and promote their protumorigenicity. Mol Cell Biol. 2017;37(17):e00101-17.

[157] Moraes JA, Encarnação C, Franco VA, et al. Adipose tissue-derived extracellular vesicles and the tumor microenvironment: revisiting the hallmarks of cancer. Cancers (Basel). 2021;13(13):3328.

[158] Liu Y, Tan J, Ou S, Chen J, Chen L. Adipose-derived exosomes deliver miR-23a/b to regulate tumor growth in hepatocellular cancer by targeting the VHL/HIF axis. J Physiol Biochem. 2019;75(3):391-401.

[159] Wu Q, Sun S, Li Z, et al. Breast cancer-released exosomes trigger cancer-associated cachexia to promote tumor progression. Adipocyte. 2019;8(1):31-45.

[160] Cao M, Isaac R, Yan W, et al. Cancer-cell-secreted extracellular vesicles suppress insulin secretion through miR-122 to impair systemic glucose homeostasis and contribute to tumour growth. Nat Cell Biol. 2022;24(6):954-967.

[161] Cariello M, Piccinin E, Pasculli E, et al. Platelets from patients with visceral obesity promote colon cancer growth. Commun Biol. 2022;5(1).

[162] Cirillo F, Catellani C, Sartori C, Lazzeroni P, Amarri S, Street ME. Obesity, insulin resistance, and colorectal cancer: could miRNA dysregulation play a role? Int J Mol Sci. 2019;20(12):2922.

[163] Taroeno-Hariadi KW, Hardianti MS, Sinorita H, Aryandono T. Obesity, leptin, and deregulation of microRNA in lipid metabolisms: their contribution to breast cancer prognosis. Diabetol Metab Syndr. 2021;13(1):10.

[164] Lou G, Song X, Yang F, et al. Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma. J Hematol Oncol. 2015;8:122.

[165] Sheykhhasan M, Kalhor N, Sheikholeslami A, Dolati M, Amini E, Fazaeli H. Exosomes of mesenchymal stem cells as a proper vehicle for transfecting miR-145 into the breast cancer cell line and its effect on metastasis. Biomed Res Int. 2021;2021:5516078.

[166] Lou G, Chen L, Xia C, et al. MiR-199a-modified exosomes from adipose tissue-derived mesenchymal stem cells improve hepatocellular carcinoma chemosensitivity through mTOR pathway. J Exp Clin Cancer Res. 2020;39(1):4.

[167] Zhou Y, Yamamoto Y, Takeshita F, Yamamoto T, Xiao Z, Ochiya T. Delivery of miR-424-5p via extracellular vesicles promotes the apoptosis of MDA-MB-231 TNBC cells in the tumor microenvironment. Int J Mol Sci. 2021;22(2):844.

[168] Santos D, Porter-Gill P, Goode G, et al. Circulating microRNA levels differ in the early stages of insulin resistance in prepubertal children with obesity. Life Sci. 2023;312:121246.

[169] Zhu J, Wang C, Zhang X, et al. Correlation analysis of microribonucleic acid-155 and microribonucleic acid-29 with type 2 diabetes mellitus, and the prediction and verification of target genes. J Diabetes Investig. 2021;12(2):165-175.

[170] Chu X, Hou Y, Zhang X, et al. Hepatic glucose metabolism disorder induced by adipose tissue-derived miR-548ag via DPP4 upregulation. Int J Mol Sci. 2023;24(3):2964.

[171] Catanzaro G, Conte F, Trocchianesi S, et al. Network analysis identifies circulating miR-155 as predictive biomarker of type 2 diabetes mellitus development in obese patients: a pilot study. Sci Rep. 2023;13(1):19496.

[172] Dracheva KV, Pobozheva IA, Anisimova KA, et al. Downregulation of exosomal hsa-miR-551b-3p in obesity and its link to type 2 diabetes mellitus. Noncoding RNA. 2023;9(6):67.

[173] Li JM, Li X, Chan LWC, et al. Lipotoxicity-polarised macrophage-derived exosomes regulate mitochondrial fitness through Miro1-mediated mitophagy inhibition and contribute to type 2 diabetes development in mice. Diabetologia. 2023;66(12):2368-2386.

[174] Shan Z, Fa WH, Tian CR, Yuan CS, Jie N. Mitophagy and mitochondrial dynamics in type 2 diabetes mellitus treatment. Aging (Albany NY). 2022;14(6):2902-2919.

[175] Karere GM, Glenn JP, Li G, Konar A, VandeBerg JL, Cox LA. Potential miRNA biomarkers and therapeutic targets for early atherosclerotic lesions. Sci Rep. 2023;13(1):3467.

[176] Elmoselhi AB, Seif Allah M, Bouzid A, et al. Circulating microRNAs as potential biomarkers of early vascular damage in vitamin D deficiency, obese, and diabetic patients. PLoS One. 2023;18(3):e0283608.

[177] Wan F, Ma X, Wang J, An Z, Xue J, Wang Q. Evaluation of left ventricular dysfunction by three-dimensional speckle-tracking echocardiography and bioinformatics analysis of circulating exosomal miRNA in obese patients. BMC Cardiovasc Disord. 2023;23(1):450.

[178] Dogan N, Ozuynuk-Ertugrul AS, Balkanay OO, et al. Examining the effects of coronary artery disease- and mitochondrial biogenesis-related genes' and microRNAs' expression levels on metabolic disorders in epicardial adipose tissue. Gene. 2023;895:147988.

[179] Tang Y, Yang LJ, Liu H, et al. Exosomal miR-27b-3p secreted by visceral adipocytes contributes to endothelial inflammation and atherogenesis. Cell Rep. 2023;42(1):111948.

[180] Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP. A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell. 2011;146(3):353-358.

[181] Kristensen LS, Andersen MS, Stagsted LVW, Ebbesen KK, Hansen TB, Kjems J. The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet. 2019;20(11):675-691.

[182] Zhang Y, Tian Z, Ye H, et al. Emerging functions of circular RNA in the regulation of adipocyte metabolism and obesity. Cell Death Discov. 2022;8(1):268.

[183] Chen C, Zhang X, Deng Y, et al. Regulatory roles of circRNAs in adipogenesis and lipid metabolism: emerging insights into lipid-related diseases. FEBS J. 2021;288(12):3663-3682.

[184] Li G, Zhang H, Cao K, et al. Transcriptome of visceral adipose tissue identifies an inflammation-related ceRNA network that regulates obesity. Mol Cell Biochem. 2022;;477(4):1095-1106.

[185] Zhang Z, Zhang T, Feng R, Huang H, Xia T, Sun C. circARF3 alleviates mitophagy-mediated inflammation by targeting miR-103/TRAF3 in mouse adipose tissue. Mol Ther Nucleic Acids. 2019;14:192-203.

[186] Zhang PP, Han Q, Sheng MX, et al. Identification of circular RNA expression profiles in white adipocytes and their roles in adipogenesis. Front Physiol. 2021;12:728208.

[187] Zhang P, Sheng M, Du C, et al. Assessment of CircRNA expression profiles and potential functions in brown adipogenesis. Front Genet. 2021;12:769690.

[188] Liu Y, Liu H, Li Y, et al. Circular RNA SAMD4A controls adipogenesis in obesity through the miR-138-5p/EZH2 axis. Theranostics. 2020;10(10):4705-4719.

[189] Arcinas C, Tan W, Fang W, et al. Adipose circular RNAs exhibit dynamic regulation in obesity and functional role in adipogenesis. Nat Metab. 2019;1(7):688-703.

[190] Firoozi Z, Mohammadisoleimani E, Shahi A, et al. Potential roles of hsa_circ_000839 and hsa_circ_0005986 in breast cancer. J Clin Lab Anal. 2022;36(3): e24263.

[191] Takenaka K, Olzomer EM, Hoehn KL, et al. Investigation of circular RNA transcriptome in obesity-related endometrial cancer. Gene. 2023;855:147125.

[192] Li Y, Jiang B, Zeng L, et al. Adipocyte-derived exosomes promote the progression of triple-negative breast cancer through circCRIM1-dependent OGA activation. Environ Res. 2023:117266.

[193] Dai Y, Ma X, Zhang J, Yu S, Zhu Y, Wang J. hsa_circ_0115355 promotes pancreatic β-cell function in patients with type 2 diabetes through the miR-145/SIRT1 axis. J Clin Lab Anal. 2022;36(8):e24583.

[194] Ma J, Wu Y, He Y. Silencing circRNA LRP6 down-regulates PRMT1 to improve the streptozocin-induced pancreatic β-cell injury and insulin secretion by sponging miR-9-5p. J Bioenerg Biomembr. 2021;53(3):333-342.

[195] Teaney NA, Cyr NE. FoxO1 as a tissue-specific therapeutic target for type 2 diabetes. Front Endocrinol (Lausanne). 2023;14:1286838.

[196] Cai H, Jiang Z, Yang X, Lin J, Cai Q, Li X. Circular RNA HIPK3 contributes to hyperglycemia and insulin homeostasis by sponging miR-192-5p and upregulating transcription factor forkhead box O1. Endocr J. 2020;67(4):397-408.

[197] Dandare A, Khan MJ, Naeem A, Liaquat A. Clinical relevance of circulating non-coding RNAs in metabolic diseases: emphasis on obesity, diabetes, cardiovascular diseases and metabolic syndrome. Genes Dis. 2023;10(6):2393-2413.

[198] Zhao Z, Li X, Gao C, et al. Peripheral blood circular RNA hsa_circ_0124644 can be used as a diagnostic biomarker of coronary artery disease. Sci Rep. 2017;7:39918.

[199] Wen C, Li B, Nie L, Mao L, Xia Y. Emerging roles of extracellular vesicle-delivered circular RNAs in atherosclerosis. Front Cell Dev Biol. 2022;10:804247.

[200] Clapier CR, Cairns BR. The biology of chromatin remodeling complexes. Annu Rev Biochem. 2009;78:273-304.

[201] Clapier CR, Iwasa J, Cairns BR, Peterson CL. Mechanisms of action and regulation of ATP-dependent chromatin-remodelling complexes. Nat Rev Mol Cell Biol. 2017;18(7):407-422.

[202] Ebot EM, Gerke T, Labbé DP, et al. Gene expression profiling of prostate tissue identifies chromatin regulation as a potential link between obesity and lethal prostate cancer. Cancer. 2017;123(21):4130-4138.

[203] Pant R, Alam A, Choksi A, Shah VK, Firmal P, Chattopadhyay S. Chromatin remodeling protein SMAR1 regulates adipogenesis by modulating the expression of PPAR gamma. Biochim Biophys Acta Mol Cell Biol Lipids. 2021;1866(12):159045.

[204] Taye N, Alam A, Ghorai S, et al. SMAR1 inhibits Wnt/β-catenin signaling and prevents colorectal cancer progression. Oncotarget. 2018;9(30):21322-21336.

[205] Moore A, Wu L, Chuang J-C, et al. Arid1a loss drives nonalcoholic steatohepatitis in mice through epigenetic dysregulation of hepatic lipogenesis and fatty acid oxidation. Hepatology. 2019;69(5):1931-1945.

[206] Sun X, Wang SC, Wei Y, et al. Arid1a has context-dependent oncogenic and tumor suppressor functions in liver cancer. Cancer Cell. 2017;32(5):574-589. e6.

[207] Yang P-B, Hou P-P, Liu F-Y, et al. Blocking PPAR gamma interaction facilitates Nur77 interdiction of fatty acid uptake and suppresses breast cancer progression. Proc Natl Acad Sci USA. 2020;117(44):27412-27422.

[208] Liu XZ, Rulina A, Choi MH, et al. C/EBPB-dependent adaptation to palmitic acid promotes tumor formation in hormone receptor negative breast cancer. Nat Commun. 2022;13(1):69.

[209] Wei Z, Yoshihara E, He N, et al. Vitamin D switches BAF complexes to protect β cells. Cell. 2018;173(5):1135-1149. e15.

[210] Wang RR, Qiu X, Pan R, et al. Dietary intervention preserves β cell function in mice through CTCF-mediated transcriptional reprogramming. J Exp Med. 2022;219(7):e20211779.

[211] Kong Q, Zou J, Zhang Z, et al. BAF60a deficiency in macrophage promotes diet-induced obesity and metabolic inflammation. Diabetes. 2022;71(10):2136-2152.

[212] Iyengar NM, Gucalp A, Dannenberg AJ, Hudis CA. Obesity and cancer mechanisms: tumor microenvironment and inflammation. J Clin Oncol. 2016;34(35):4270-4276.

[213] Cani PD, Jordan BF. Gut microbiota-mediated inflammation in obesity: a link with gastrointestinal cancer. Nat Rev Gastroenterol Hepatol. 2018;15(11):671-682.

[214] Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112(12):1796-1808.

[215] Harman-Boehm I, Blüher M, Redel H, et al. Macrophage infiltration into omental versus subcutaneous fat across different populations: effect of regional adiposity and the comorbidities of obesity. J Clin Endocrinol Metab. 2007;92(6):2240-2247.

[216] Iyengar NM, Zhou XK, Gucalp A, et al. Systemic correlates of white adipose tissue inflammation in early-stage breast cancer. Clin Cancer Res. 2016;22(9):2283-2289.

[217] Gucalp A, Iyengar NM, Zhou XK, et al. Periprostatic adipose inflammation is associated with high-grade prostate cancer. Prostate Cancer Prostatic Dis. 2017;20(4):418-423.

[218] Ley K. M1 means kill; M2 means heal. J Immunol. 2017;199(7):2191-2193.

[219] Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. 2007;117(1):175-184.

[220] Kern L, Mittenbühler MJ, Vesting AJ, Ostermann AL, Wunderlich CM, Wunderlich FT. Obesity-induced TNFα and IL-6 signaling: the missing link between obesity and inflammation-driven liver and colorectal cancers. Cancers (Basel). 2018;11(1):24.

[221] Liu X-L, Pan Q, Cao H-X, et al. Lipotoxic hepatocyte-derived exosomal MicroRNA 192–5p activates macrophages through rictor/Akt/Forkhead box transcription factor O1 signaling in nonalcoholic fatty liver disease. Hepatology. 2020;72(2):454-469.

[222] Liu H, Niu Q, Wang T, Dong H, Bian C. Lipotoxic hepatocytes promote nonalcoholic fatty liver disease progression by delivering microRNA-9-5p and activating macrophages. Int J Biol Sci. 2021;17(14):3745-3759.

[223] Phu TA, Ng M, Vu NK, Bouchareychas L, Raffai RL. IL-4 polarized human macrophage exosomes control cardiometabolic inflammation and diabetes in obesity. Mol Ther. 2022;30(6):2274-2297.

[224] Li L, Zuo H, Huang X, et al. Bone marrow macrophage-derived exosomal miR-143-5p contributes to insulin resistance in hepatocytes by repressing MKP5. Cell Proliferation. 2021;54(12):e13140.

[225] Li D, Yang C, Zhu J-Z, et al. Berberine remodels adipose tissue to attenuate metabolic disorders by activating sirtuin 3. Acta Pharmacol Sin. 2021;43(5):1285-1298.

[226] Han Y-B, Tian M, Wang X-X, et al. Berberine ameliorates obesity-induced chronic inflammation through suppression of ER stress and promotion of macrophage M2 polarization at least partly via downregulating lncRNA Gomafu. Int Immunopharmacol. 2020;86:106741.

[227] Chen L, Zhang J, Zou Y, et al. Kdm2a deficiency in macrophages enhances thermogenesis to protect mice against HFD-induced obesity by enhancing H3K36me2 at the Pparg locus. Cell Death Different. 2021;28(6):1880-1899.

[228] Sprenkle NT, Winn NC, Bunn KE, et al. The miR-23-27-24 clusters drive lipid-associated macrophage proliferation in obese adipose tissue. Cell Rep. 2023;42(8):112928.

[229] Ying W, Gao H, Dos Reis FCG, et al. MiR-690, an exosomal-derived miRNA from M2-polarized macrophages, improves insulin sensitivity in obese mice. Cell Metabolism. 2021;33(4):781.

[230] Quail DF, Dannenberg AJ. The obese adipose tissue microenvironment in cancer development and progression. Nat Rev Endocrinol. 2019;15(3):139-154.

[231] Wang Z, Aguilar EG, Luna JI, et al. Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. Nat Med. 2019;25(1):141-151.

[232] Zhou D, Hlady RA, Schafer MJ, et al. High fat diet and exercise lead to a disrupted and pathogenic DNA methylome in mouse liver. Epigenetics. 2017;12(1):55-69.

[233] Prasad M, Rajagopal P, Devarajan N, et al. A comprehensive review on high -fat diet-induced diabetes mellitus: an epigenetic view. J Nutr Biochem. 2022;107:109037.

[234] Viraragavan A, Willmer T, Patel O, Basson A, Johnson R, Pheiffer C. Cafeteria diet induces global and Slc27a3-specific hypomethylation in male Wistar rats. Adipocyte. 2021;10(1):108-118.

[235] Romagnolo DF, Donovan MG, Doetschman TC, Selmin OI. N-6 linoleic acid induces epigenetics alterations associated with colonic inflammation and cancer. Nutrients. 2019;11(1):171.

[236] Wahab NA, Elias MH, Ali RAR, Mokhtar NM. Chronic consumption of fructose dysregulates genes related to glucose and lipid metabolism in prostate tissue. Sains Malaysiana. 2018;47(10):2501-2507.

[237] Petito G, Giacco A, Cioffi F, et al. Short-term fructose feeding alters tissue metabolic pathways by modulating microRNAs expression both in young and adult rats. Front Cell Dev Biol. 2023;11:1101844.

[238] Li X, Shao X, Bazzano LA, et al. Blood DNA methylation at TXNIP and glycemic changes in response to weight-loss diet interventions: the POUNDS lost trial. Int J Obes (Lond). 2022;46(6):1122-1127.

[239] Domínguez-Barragán J, Fernández-Sanlés A, Hernáez Á, et al. Blood DNA methylation signature of diet quality, and association with cardiometabolic traits. Eur J Prev Cardiol. 2023;31(2):191-202.

[240] Joshi T, Patel I, Kumar A, Donovan V, Levenson AS. Grape powder supplementation attenuates prostate neoplasia associated with pten haploinsufficiency in mice fed high-fat diet. Mol Nutr Food Res. 2020;64(16):e2000326.

[241] Li Y, Chen M, Tollefsbol T. The epigenetic influence of maternal dieton prevention of high-fat diet induced obesity and breastcancer in later life. Cancer Res. 2020;80(16):2440.

[242] Chen M, Li S, Arora I, et al. Maternal soybean diet on prevention of obesity-related breast cancer through early-life gut microbiome and epigenetic regulation. J Nutr Biochem. 2022;110:109119.

[243] Deng X, Liang J, Wang L, et al. Whole grain proso millet (Panicum miliaceum L.) attenuates hyperglycemia in type 2 diabetic mice: involvement of miRNA profile. J Agric Food Chem. 2023;71(24):9324-9336.

[244] Jiang Y, Sun-Waterhouse D, Chen Y, Li F, Li D. Epigenetic mechanisms underlying the benefits of flavonoids in cardiovascular health and diseases: are long non-coding RNAs rising stars? Crit Rev Food Sci Nutr. 2022;62(14):3855-3872.

[245] Potenza MA, Iacobazzi D, Sgarra L, Montagnani M. The intrinsic virtues of EGCG, an extremely good cell guardian, on prevention and treatment of diabesity complications. Molecules. 2020;25(13):3061.

[246] Mishra SP, Wang B, Jain S, et al. A mechanism by which gut microbiota elevates permeability and inflammation in obese/diabetic mice and human gut. Gut. 2023;72(10):1848-1865.

[247] Okuka N, Schuh V, Krammer U, et al. Epigenetic aspects of a new probiotic concept—a pilot study. Life (Basel). 2023;13(9):1912.

[248] Gershuni VM, Yan SL, Medici V. Nutritional ketosis for weight management and reversal of metabolic syndrome. Curr Nutr Rep. 2018;7(3):97-106.

[249] Choi YJ, Jeon SM, Shin S. Impact of a ketogenic diet on metabolic parameters in patients with obesity or overweight and with or without type 2 diabetes: a meta-analysis of randomized controlled trials. Nutrients. 2020;12(7):2005.

[250] Weber DD, Aminzadeh-Gohari S, Tulipan J, Catalano L, Feichtinger RG, Kofler B. Ketogenic diet in the treatment of cancer—Where do we stand? Mol Metab. 2020;33:102-121.

[251] Ellenbroek JH, van Dijck L, Töns HA, et al. Long-term ketogenic diet causes glucose intolerance and reduced β- and α-cell mass but no weight loss in mice. Am J Physiol Endocrinol Metab. 2014;306(5):E552-E558.

[252] O'Neill B, Raggi P. The ketogenic diet: pros and cons. Atherosclerosis. 2020;292:119-126.

[253] Dmitrieva-Posocco O, Wong AC, Lundgren P, et al. β-Hydroxybutyrate suppresses colorectal cancer. Nature. 2022;605(7908):160-165.

[254] Xie Z, Zhang D, Chung D, et al. Metabolic regulation of gene expression by histone lysine β-hydroxybutyrylation. Mol Cell. 2016;62(2):194-206.

[255] Zhang H, Chang Z, Qin LN, et al. MTA2 triggered R-loop trans-regulates BDH1-mediated β-hydroxybutyrylation and potentiates propagation of hepatocellular carcinoma stem cells. Signal Transduct Target Ther. 2021;6(1):135.

[256] Liu K, Li F, Sun Q, et al. p53 β-hydroxybutyrylation attenuates p53 activity. Cell Death Dis. 2019;10(3):243.

[257] Koronowski KB, Greco CM, Huang H, et al. Ketogenesis impact on liver metabolism revealed by proteomics of lysine β-hydroxybutyrylation. Cell Rep. 2021;36(5):109487.

[258] Ferrer M, Mourikis N, Davidson EE, et al. Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia. Cell Metab. 2023;

[259] Friedenreich CM, Ryder-Burbidge C, McNeil J. Physical activity, obesity and sedentary behavior in cancer etiology: epidemiologic evidence and biologic mechanisms. Mol Oncol. 2021;15(3):790-800.

[260] Donovan MG, Wren SN, Cenker M, Selmin OI, Romagnolo DF. Dietary fat and obesity as modulators of breast cancer risk: focus on DNA methylation. Br J Pharmacol. 2020;177(6):1331-1350.

[261] Kanaley JA, Colberg SR, Corcoran MH, et al. Exercise/physical activity in individuals with type 2 diabetes: a consensus statement from the American College of Sports Medicine. Med Sci Sports Exerc. 2022;54(2):353-368.

[262] Tucker WJ, Fegers-Wustrow I, Halle M, Haykowsky MJ, Chung EH, Kovacic JC. Exercise for primary and secondary prevention of cardiovascular disease: JACC Focus Seminar 1/4. J Am Coll Cardiol. 2022;80(11):1091-1106.

[263] Duggan C, Tapsoba JD, Scheel J, Wang CY, McTiernan A. Weight loss reduces circulating micro-RNA related to obesity and breast cancer in postmenopausal women. Epigenetics. 2022;17(13):2082-2095.

[264] Mastrototaro L, Roden M. The effects of extracellular vesicles and their cargo on metabolism and its adaptation to physical exercise in insulin resistance and type 2 diabetes. Proteomics. 2023:e2300078.

[265] Trettel CDS, Pelozin BRA, Barros MP, et al. Irisin: an anti-inflammatory exerkine in aging and redox-mediated comorbidities. Front Endocrinol (Lausanne). 2023;14:1106529.

[266] Aas V, Øvstebø R, Brusletto BS, et al. Distinct microRNA and protein profiles of extracellular vesicles secreted from myotubes from morbidly obese donors with type 2 diabetes in response to electrical pulse stimulation. Front Physiol. 2023;14:1143966.

[267] Dogan S, Cicekdal MB, Ozorhan U, et al. Roles of adiponectin and leptin signaling-related microRNAs in the preventive effects of calorie restriction in mammary tumor development. Appl Physiol Nutr Metab. 2021;46(8):866-876.

[268] Bultman SJ. A reversible epigenetic link between obesity and cancer risk. Trends Endocrinol Metab. 2018;29(8):529-531.

[269] Li R, Grimm SA, Mav D, et al. Transcriptome and DNA methylome analysis in a mouse model of diet-induced obesity predicts increased risk of colorectal cancer. Cell Rep. 2018;22(3):624-637.

[270] Talukdar FR, Marcillo DIE, Laskar RS, et al. Bariatric surgery-induced weight loss and associated genome-wide DNA-methylation alterations in obese individuals. Clin Epigenet. 2022;14(1):176.

[271] Zhang LH, Wang J, Tan BH, Yin YB, Kang YM. The association of lncRNA and mRNA changes in adipose tissue with improved insulin resistance in type 2 obese diabetes mellitus rats after Roux-en-Y gastric bypass. Dis Markers. 2022;2022:8902916.

[272] Aminian A, Wilson R, Al-Kurd A, et al. Association of bariatric surgery with cancer risk and mortality in adults with obesity. JAMA. 2022;327(24):2423-2433.

[273] Breininger SP, Sabater L, Malcomson FC, Afshar S, Mann J, Mathers JC. Obesity and Roux-en-Y gastric bypass drive changes in miR-31 and miR-215 expression in the human rectal mucosa. Int J Obes (Lond). 2021;46(2):333-341.

[274] Blum A, Yehuda H, Geron N, Meerson A. Elevated levels of miR-122 in serum may contribute to improved endothelial function and lower oncologic risk following bariatric surgery. Isr Med Assoc J. 2017;19(10):620-624.

[275] Fang Z, Fan M, Yuan D, et al. Downregulation of hepatic lncRNA Gm19619 improves gluconeogenesis and lipogenesis following vertical sleeve gastrectomy in mice. Commun Biol. 2023;6(1):105.

[276] Wei W, Wang X, Wei Y, et al. lncRNA TUG1 protects intestinal epithelial cells from damage induced by high glucose and high fat via AMPK/SIRT1. Mol Med Rep. 2022;25(4):139.

[277] Hosseini H, Teimouri M, Shabani M, et al. Resveratrol alleviates non-alcoholic fatty liver disease through epigenetic modification of the Nrf2 signaling pathway. Int J Biochem Cell Biol. 2020;119:105667.

[278] Liu DB, Wong CC, Fu L, et al. Squalene epoxidase drives NAFLD-induced hepatocellular carcinoma and is a pharmaceutical target. Sci Transl Med. 2018;10(437):eaap9840.

[279] Yan F, Shen N, Pang JX, et al. Fatty acid-binding protein FABP4 mechanistically links obesity with aggressive AML by enhancing aberrant DNA methylation in AML cells. Leukemia. 2017;31(6):1434-1442.

[280] Andrade FO, Nguyen NM, Warri A, Hilakivi-Clarke L. Reversal of increased mammary tumorigenesis by valproic acid and hydralazine in offspring of dams fed high fat diet during pregnancy. Sci Rep. 2019;9(1):20271.

[281] Suárez R, Chapela SP, Álvarez-Córdova L, et al. Epigenetics in obesity and diabetes mellitus: new insights. Nutrients. 2023;15(4):811.

[282] Ringel AE, Drijvers JM, Baker GJ, et al. Obesity shapes metabolism in the tumor microenvironment to suppress anti-tumor immunity. Cell. 2020;183(7):1848-1866. e26.

[283] Sanchez-Pino MD, Gilmore LA, Ochoa AC, Brown JC. Obesity-associated myeloid immunosuppressive cells, key players in cancer risk and response to immunotherapy. Obesity (Silver Spring). 2021;29(6):944-953.

[284] Xiong Z, Li X, Yang L, et al. Integrative analysis of gene expression and DNA methylation depicting the impact of obesity on breast cancer. Front Cell Dev Biol. 2022;10:818082.

[285] Woodall MJ, Neumann S, Campbell K, Pattison ST, Young SL. The effects of obesity on anti-cancer immunity and cancer immunotherapy. Cancers (Basel). 2020;12(5):1230.

[286] Sharma BR, Kanneganti TD. NLRP3 inflammasome in cancer and metabolic diseases. Nat Immunol. 2021;22(5):550-559.

[287] Zhang L, Li H, Zang Y, Wang F. NLRP3 inflammasome inactivation driven by miR‑223‑3p reduces tumor growth and increases anticancer immunity in breast cancer. Mol Med Rep. 2019;19(3):2180-2188.

[288] Chakravarti R, Lenka SK, Gautam A, et al. A review on CRISPR-mediated epigenome editing: a future directive for therapeutic management of cancer. Curr Drug Targets. 2022;23(8):836-853.

[289] Goell JH, Hilton IB. CRISPR/Cas-based epigenome editing: advances, applications, and clinical utility. Trends Biotechnol. 2021;39(7):678-691.

[290] Feinberg AP, Levchenko A. Epigenetics as a mediator of plasticity in cancer. Science. 2023;379(6632):eaaw3835.

[291] Abdulhaq H, Rossetti JM. The role of azacitidine in the treatment of myelodysplastic syndromes. Expert Opin Investig Drugs. 2007;16(12):1967-1975.

[292] Atallah E, Kantarjian H, Garcia-Manero G. The role of decitabine in the treatment of myelodysplastic syndromes. Expert Opin Pharmacother. 2007;8(1):65-73.

[293] Hoy SM. Tazemetostat: first approval. Drugs. 2020;80(5):513-521.

[294] Keam SJ. Valemetostat tosilate: first approval. Drugs. 2022;82(16):1621-1627.

[295] Siegel D, Hussein M, Belani C, et al. Vorinostat in solid and hematologic malignancies. J Hematol Oncol. 2009;2:31.

[296] Sawas A, Radeski D, O'Connor OA. Belinostat in patients with refractory or relapsed peripheral T-cell lymphoma: a perspective review. Ther Adv Hematol. 2015;6(4):202-208.

[297] Smolewski P, Robak T. The discovery and development of romidepsin for the treatment of T-cell lymphoma. Expert Opin Drug Discov. 2017;12(8):859-873.

[298] Shi Y, Jia B, Xu W, et al. Chidamide in relapsed or refractory peripheral T cell lymphoma: a multicenter real-world study in China. J Hematol Oncol. 2017;10(1):69.

[299] Laubach JP, Moreau P, San-Miguel JF, Richardson PG. Panobinostat for the treatment of multiple myeloma. Clin Cancer Res. 2015;21(21):4767-4773.

[300] Donker ML, Ossenkoppele GJ. Evaluating ivosidenib for the treatment of acute myeloid leukemia. Expert Opin Pharmacother. 2020;21(18):2205-2213.

[301] Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722-731.

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