Obesity and atherosclerosis: the exosome link

Abstract

Obesity is a global public health issue with serious health consequences and rising prevalence. It is a risk factor for a broad range of diseases, particularly atherosclerosis and cardiovascular disease. Long-term weight loss is difficult to achieve, even with diet, life-style changes and anti-obesity drugs. The causes of the association between obesity and atherosclerotic cardiovascular disease are the subject of ongoing investigation. It is known that a chronic surplus in nutritional intake results in expansion and remodeling of adipose tissue, leading to chronic inflammation. Lipid overloaded adipocytes secrete pro-inflammatory adipokines and other mediators that produce this inflammatory state that may in turn, promote atherosclerosis, which is considered an inflammatory disorder. This review discusses the potential role of exosomes from adipose tissue in accelerating atherosclerosis in the setting of obesity. Exosomes are small membrane-bound vesicles that circulate in body fluids and are important participants in intercellular communication both locally and at a distance. They can transfer their cargo of protein, DNA, RNA and microRNA between cells, thus impacting cellular function and signaling. Adipose tissue-derived exosomes may be involved in heightening of the atherogenic environment and, if so, suggests a therapeutic target for the treatment and prevention of cardiovascular complications of obesity.

Keywords

Obesity / atherosclerosis / adipocyte / macrophage / exosome

References

[1] Dalen JE,Goldberg RJ.The epidemic of the 20(th) century: coronary heart disease..Am J Med2014;127:807-2

[2] Wong ND.Epidemiological studies of CHD and the evolution of preventive cardiology..Nat Rev Cardiol2014;11:276-89

[3] Benjamin EJ,Callaway CW,Chang AR.Heart disease and stroke statistics-2018 update: a report from the American Heart Association..Circulation2018;137:e67-492

[4] Whitlock G,Sherliker P,Emberson J.Body mass index and cause-specific mortality in 900,000 adults: collaborative analyses of 57 prospective studies..Lancet2009;373:1083-96 PMCID:PMC2662372

[5] Phillips CM.Metabolically healthy obesity: personalised and public health implications..Trends Endocrinol Metabol2016;27:189-91

[6] Bradshaw PT,Stevens J.Metabolic syndrome in healthy obese, overweight, and normal weight individuals: the Atherosclerosis Risk in Communities Study..Obesity (Silver Spring)2013;21:203-9 PMCID:PMC4170589

[7] Fasshauer M.Adipokines in health and disease..Trends Pharmacol Sci2015;36:461-70

[8] Kershaw EE.Adipose tissue as an endocrine organ..J Clin Endocrinol Metab2004;89:2548-56

[9] Coelho M,Fernandes R.Biochemistry of adipose tissue: an endocrine organ..Arch Med Sci2013;9:191-200 PMCID:PMC3648822

[10] Gao X,Freeman DJ.Extracellular vesicles from adipose tissue - a potential role in obesity and type 2 diabetes?.Front Endocrinol (Lausanne)2017;8:202 PMCID:PMC5563356

[11] Vieira-Potter VJ.Inflammation and macrophage modulation in adipose tissues..Cell Microbiol2014;16:1484-92

[12] Pellegrinelli V,Vidal-Puig A.Adipose tissue plasticity: how fat depots respond differently to pathophysiological cues..Diabetologia2016;59:1075-88 PMCID:PMC4861754

[13] Hansson GK.The immune response in atherosclerosis: a double-edged sword..Nat Rev Immunol2006;6:508-19

[14] Mathieu P,Pibarot,Despres JP.Visceral obesity: the link among inflammation, hypertension, and cardiovascular disease..Hypertension2009;53:577-84

[15] Bobryshev YV.Monocyte recruitment and foam cell formation in atherosclerosis..Micron2006;37:208-22

[16] Gimbrone MA Jr.Endothelial cell dysfunction and the pathobiology of atherosclerosis..Circ Res2016;118:620-36 PMCID:PMC4762052

[17] Bhatt A.HDL cholesterol efflux capacity: cardiovascular risk factor and potential therapeutic target..Curr Atheroscler Rep2016;18:2

[18] Maguire EM,Xiao Q.Foam cell formation: a new target for fighting atherosclerosis and cardiovascular disease..Vascul Pharmacol2019;112:54-71

[19] Ley K,Hedrick CC.Monocyte and macrophage dynamics during atherogenesis..Arterioscler Thromb Vasc Biol2011;31:1506-16 PMCID:PMC3133596

[20] Feig JE,Reiser V,Statnikov A.Regression of atherosclerosis is characterized by broad changes in the plaque macrophage transcriptome..PLoS One2012;7:e39790 PMCID:PMC3384622

[21] Moore KJ,Fisher EA.Macrophages in atherosclerosis: a dynamic balance..Nat Rev Immunol2013;13:709-21 PMCID:PMC4357520

[22] Reiss AB,Merrill JT,Awadallah NW.Plasma from systemic lupus patients compromises cholesterol homeostasis: a potential mechanism linking autoimmunity to atherosclerotic cardiovascular disease..Rheumatol Int2010;30:591-8 PMCID:PMC3736583

[23] Reiss AB,Anwar K,Wirkowski PA.Enhanced CD36 scavenger receptor expression in THP-1 human monocytes in the presence of lupus plasma: linking autoimmunity and atherosclerosis..Exp Biol Med (Maywood)2009;234:354-60 PMCID:PMC4362773

[24] Reiss AB,Malhotra S,Chan ESL.Immune complexes and interferon-γ decrease cholesterol 27-hydroxylase in human arterial endothelium and macrophages..J Lipid Res2001;42:1913-22

[25] Reiss AB,Rahman MM,Hasneen K.IFN-gamma impedes reverse cholesterol transport and promotes foam cell transformation in THP-1 human monocytes/macrophages..Med Sci Monit2004;10:BR420-5

[26] Reiss AB.Effects of inflammation on cholesterol metabolism: impact on systemic lupus erythematosus..Curr Rheumatol Rep2009;11:255-60

[27] Voloshyna I,Littlefield MJ,Belostocki KB.Plasma from rheumatoid arthritis patients promotes pro-atherogenic cholesterol transport gene expression in THP-1 human macrophages..Exp Biol Med (Maywood)2013;238:1192-7 PMCID:PMC3872451

[28] Tan L,Jiang Z.Inhibition of microRNA-17-5p reduces the inflammation and lipid accumulation, and up-regulates ATP-binding cassette transporterA1 in atherosclerosis..J Pharmacol Sci2019;139:280-8

[29] Choromańska B,Choromańska K,Chabowski A.The role of CD36 receptor in the pathogenesis of atherosclerosis..Adv Clin Exp Med2017;26:717-22

[30] Reardon CA,Schoenfelt KQ,Cui C.Obesity and insulin resistance promote atherosclerosis through an IFNγ-regulated macrophage protein network..Cell Rep2018;23:3021-30 PMCID:PMC6082182

[31] Zhu Y,Wang Z,Chen Q.Research progress on the relationship between atherosclerosis and inflammation..Biomolecules2018;8:80 PMCID:PMC6163673

[32] Zhang L,Sivashanmugam P,Brian L.Expression of tumor necrosis factor receptor-1 in arterial wall cells promotes atherosclerosis..Arterioscler Thromb Vasc Biol2007;27:1087-94 PMCID:PMC2522308

[33] Howe KL.Transforming endothelial cells in atherosclerosis..Nat Metab2019;1:856-7

[34] Yu XH,Zheng XL,Tang CK.Interferon-γ in foam cell formation and progression of atherosclerosis..Clin Chim Acta2015;441:33-43

[35] Hotamisligil GS.Inflammation and metabolic disorders..Nature2006;444:860-7

[36] Hu D,Gray RS,Henderson JA.Effects of obesity and body fat distribution on lipids and lipoproteins in nondiabetic american indians: the strong heart study..Obes Res2000;8:411-21

[37] Franssen R,Stroes ES.Obesity and dyslipidemia..Med Clin North Am2011;95:893-902

[38] Jellinger PS,Smith DA,Ganda O.American Association of Clinical Endocrinologists’ Guidelines for management of dyslipidemia and prevention of atherosclerosis..Endocr Pract2012;18:1-78

[39] Rashid S.Effect of obesity on high-density lipoprotein metabolism..Obesity2007;15:2875-88

[40] Klop B,Cabezas MC.Dyslipidemia in obesity: mechanisms and potential targets..Nutrients2013;5:1218-40 PMCID:PMC3705344

[41] Grundy SM.Obesity, metabolic syndrome, and cardiovascular disease..J Clin Endocrinol Metab2004;89:2595-600

[42] Fruchart JC,Hermans MP,Brown WV.The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia..Am J Cardiol2008;102:1K-34K

[43] Kolovou GD,Cokkinos DV.Pathophysiology of dyslipidaemia in the metabolic syndrome..Postgrad Med J2005;81:358-66 PMCID:PMC1743285

[44] Athyros VG,Karagiannis A.Dyslipidaemia of obesity, metabolic syndrome and type 2 diabetes mellitus: the case for residual risk reduction after statin treatment..Open Cardiovasc Med J2011;5:24-34 PMCID:PMC3109607

[45] Ottaviani E,Franceschi C.The evolution of the adipose tissue: a neglected enigma..Gen Comp Endocrinol2011;174:1-4

[46] Després JP.Body fat distribution and risk of cardiovascular disease: an update..Circulation2012;126:1301-13

[47] Van Dam AD,Berbee JFP,Van Harmelen V.Targeting white, brown and perivascular adipose tissue in atherosclerosis development..Eur J Pharmacol2017;816:82-92

[48] Frühbeck G,Muruzabal FJ.The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation..Am J Physiol Endocrinol Metab2001;280:E827-47

[49] Ouchi N,Lugus JJ.Adipokines in inflammation and metabolic disease..Nat Rev Immunol2011;11:85-97 PMCID:PMC3518031

[50] Liberale L,Vecchiè A,Dallegri F.The role of adipocytokines in coronary atherosclerosis..Curr Atheroscler Rep2017;19:10

[51] Blüher M.Adipose tissue dysfunction in obesity..Exp Clin Endocrinol Diabetes2009;117:241-50

[52] Ohman MK,Obimba CI,Warnock M.Visceral adipose tissue inflammation accelerates atherosclerosis in apolipoprotein E-deficient mice..Circulation2008;117:798-805 PMCID:PMC4007137

[53] Pollack RM,LeRoith D.Anti-inflammatory agents in the treatment of diabetes and its vascular complications..Diabetes Care2016;39:S244-52

[54] O’Donoghue ML,White HD,Tarka E.Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial..JAMA2014;312:1006-15

[55] Reiss AB,Siegart NM,Kasselman LJ.Exosomes in cholesterol metabolism and atherosclerosis..Cardiovasc Hematol Disord Drug Targets2017;17:185-94

[56] Hoeke G,Boon MR,Berbée JF.Role of Brown fat in lipoprotein metabolism and atherosclerosis..Circ Res2016;118:173-82

[57] Xiong W,Villacorta L,Garciabarrio MT.Brown adipocyte-specific PPARγ (peroxisome proliferator-activated receptor γ) deletion impairs perivascular adipose tissue development and enhances atherosclerosis in mice..Arterioscler Thromb Vasc Biol2018;38:1738-47 PMCID:PMC6202167

[58] Nedergaard J,Cannon B.Unexpected evidence for active brown adipose tissue in adult humans..Am J Physiol Endocrinol Metab2007;293:E444-52

[59] Cypess AM,Williams G,Rodman D.Identification and importance of brown adipose tissue in adult humans..N Engl J Med2009;360:1509-17 PMCID:PMC2859951

[60] Bartelt A,Reimer R,Ittrich H.Brown adipose tissue activity controls triglyceride clearance..Nat Med2011;17:200-5

[61] Liu X,Zhu X,Li L.Brown adipose tissue transplantation improves whole-body energy metabolism..Cell Res2013;23:851-4 PMCID:PMC3674396

[62] Geerling JJ,van der Zon GC,van den Hoek AM.Metformin lowers plasma triglycerides by promoting VLDL-triglyceride clearance by brown adipose tissue in mice..Diabetes2014;63:880-91

[63] Tanyanskiy DA,Maltseva SV.Immunohistochemical analysis of adiponectin in atherosclerotic lesions of human aorta..ARYA Atheroscler2019;15:179-84 PMCID:PMC6884728

[64] Achari AE.Adiponectin, a therapeutic target for obesity, diabetes, and endothelial dysfunction..Int J Mol Sci2017;18:1321 PMCID:PMC5486142

[65] Magni P,Ruscica M,Ferrario S.Free and bound plasma leptin in normal weight and obese men and women: relationship with body composition, resting energy expenditure, insulin-sensitivity, lipid profile and macronutrient preference..Clin Endocrinol (Oxf)2005;62:189-96

[66] Hartwig S,Göddeke S,Kotzka J.Exosomal proteins constitute an essential part of the human adipose tissue secretome..Biochim Biophys Acta Proteins Proteom2019;1867:140172

[67] Phoonsawat W,Tsuruta T.Adiponectin is partially associated with exosomes in mouse serum..Biochem Biophys Res Commun2014;448:261-6

[68] Lee JE,Lee IK.Proteomic analysis of extracellular vesicles released by adipocytes of otsuka long-evans tokushima fatty (OLETF) rats..Protein J2015;34:220-35

[69] Raposo G.Extracellular vesicles: exosomes, microvesicles, and friends..J Cell Biol2013;200:373-83 PMCID:PMC3575529

[70] Shah R,Freedman JE.Circulating extracellular vesicles in human disease..N Engl J Med2018;379:2180-1

[71] Haraszti RA,Sapp E,Shaffer SA.High-resolution proteomic and lipidomic analysis of exosomes and microvesicles from different cell sources..J Extracell Vesicles2016;5:32570 PMCID:PMC5116062

[72] Trajkovic K,Chiantia S,Wenzel D.Ceramide triggers budding of exosome vesicles into multivesicular endosomes..Science2008;319:1244-7

[73] Skotland T,Sandvig K.Exosomal lipid composition and the role of ether lipids and phosphoinositides in exosome biology..J Lipid Res2019;60:9-18 PMCID:PMC6314266

[74] Yoon Y,Gho Y.Extracellular vesicles as emerging intercellular communicasomes..BMB Rep2014;47:531-9 PMCID:PMC4261509

[75] O’Brien J,Zayed Y.Overview of microRNA biogenesis, mechanisms of actions, and circulation..Front Endocrinol2018;9:402 PMCID:PMC6085463

[76] Dini L,Carata E,Vergallo C.Microvesicles and exosomes in metabolic diseases and inflammation..Cytokine Growth Factor Rev2020;51:27-39

[77] Colombo M,Théry C.Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles..Annu Rev Cell Dev Biol2014;30:255-89

[78] Chen Y,Hanssen MJ,Pan R.Exosomal microRNA miR-92a concentration in serum reflects human brown fat activity..Nat Commun2016;27;7:11420 PMCID:PMC4853423

[79] Thomou T,Dreyfuss JM,Sakaguchi M.Adipose-derived circulating miRNAs regulate gene expression in other tissues..Nature2017;542:450-5 PMCID:PMC5330251

[80] Ortega FJ,Mercader JM,Fuentes-Batllevell N.Inflammation triggers specific microRNA profiles in human adipocytes and macrophages and in their supernatants..Clin Epigenetics2015;7:49 PMCID:PMC4413548

[81] Ortega FJ,Moreno-Navarrete JM,Puigdecanet E.Surgery-induced weight loss is associated with the downregulation of genes targeted by microRNAs in adipose tissue..J Clin Endocrinol Metab2015;100:E1467-76

[82] Ferrante SC,Pillai DK,Wang Z.Adipocyte-derived exosomal miRNAs: a novel mechanism for obesity-related disease..Pediatr Res2015;77:447-54 PMCID:PMC4346410

[83] Chartoumpekis DV,Ziros PG,Psyrogiannis AI.Differential expression of microRNAs in adipose tissue after long-term high-fat diet-induced obesity in mice..PLoS One2012;7:e34872 PMCID:PMC3319598

[84] Chang W.Exosomes and their noncoding RNA cargo are emerging as new modulators for diabetes mellitus..Cells2019;8:E853 PMCID:PMC6721737

[85] Mori MA,Boucher J,Lallukka S.Altered miRNA processing disrupts brown/white adipocyte determination and associates with lipodystrophy..J Clin Invest2014;124:3339-51 PMCID:PMC4109560

[86] Ying W,Bandyopadhyay G,Birmingham A.Adipose tissue macrophage-derived exosomal miRNAs can modulate in vivo and in vitro insulin sensitivity..Cell2017;171:372-84.e12

[87] Chen Y.Brown fat-derived exosomes: small vesicles with big impact..Cell Metab2017;425:759-60

[88] Fisher FM,Douris N,Mepani RJ.FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis..Genes Dev2012;26:271-81 PMCID:PMC3278894

[89] Kokkinos J,Rye KA.The role of fibroblast growth factor 21 in atherosclerosis..Atherosclerosis2017;257:259-65

[90] Deng ZB,Hardy RW,Liu C.Adipose tissue exosome-like vesicles mediate activation of macrophage-induced insulin resistance..Diabetes2009;58:2498-505 PMCID:PMC2768161

[91] Curtiss LK.Emerging role of toll-like receptors in atherosclerosis..J Lipid Res2009;50:S340-5 PMCID:PMC2674724

[92] Xie Z,Liu X,Sun C.Adipose-derived exosomes exert proatherogenic effects by regulating macrophage foam cell formation and polarization..J Am Heart Assoc2018;7:e007442 PMCID:PMC5866320

[93] Voloshyna I.The ABC transporters in lipid flux and atherosclerosis..Prog Lipid Res2011;50:213-24

[94] Barberio MD,Playford MP,Renna HA.Cholesterol efflux alterations in adolescent obesity: role of adipose-derived extracellular vesical microRNAs..J Transl Med2019;17:232 PMCID:PMC6647309

[95] Crewe C,Rutkowski JM,Zhang F.An endothelial-to-adipocyte extracellular vesicle axis governed by metabolic state..Cell2018;175:695-708 PMCID:PMC6195477

[96] Zhao Q,Liu B,Li Y.Exosomes derived from mangiferin-stimulated perivascular adipose tissue ameliorate endothelial dysfunction..Mol Med Rep2019;19:4797-805 PMCID:PMC6522825

[97] Kita S,Shimomura I.Interorgan communication by exosomes, adipose tissue, and adiponectin in metabolic syndrome..J Clin Invest2019;129:4041-9 PMCID:PMC6763291

[98] Summerhill V.Pericytes in atherosclerosis..Adv Exp Med Biol2019;1147:279-97

[99] Orekhov AN,Chistiakov DA.The complexity of cell composition of the intima of large arteries: focus on pericyte-like cells..Cardiovasc Res2014;103:438-51

[100] Liu C,Liu BH,Shan K.Targeting pericyte-endothelial cell crosstalk by circular RNA-cPWWP2A inhibition aggravates diabetes-induced microvascular dysfunction..Proc Natl Acad Sci U S A2019;116:7455-64 PMCID:PMC6462073

[101] Pan Y,Hoo RLC,Chan CYC.Adipocyte-secreted exosomal microRNA-34a inhibits M2 macrophage polarization to promote obesity-induced adipose inflammation..J Clin Invest2019;129:834-49 PMCID:PMC6355214

[102] Ogawa R,Sato M,Sugimura K.Adipocyte-derived microvesicles contain RNA that is transported into macrophages and might be secreted into blood circulation..Biochem Biophys Res Commun2010;398:723-9

[103] Eguchi A,Armando AM,Katebian R.Circulating adipocyte-derived extracellular vesicles are novel markers of metabolic stress..J Mol Med (Berl)2016;94:1241-53 PMCID:PMC5071132

[104] Kobayashi Y,Tempaku M,Togashi K.Circulating extracellular vesicles are associated with lipid and insulin metabolism..Am J Physiol Endocrinol Metab2018;315:E574-82

[105] Hubal MJ,Ferrante SC,Suh JH.Circulating adipocyte-derived exosomal MicroRNAs associated with decreased insulin resistance after gastric bypass..Obesity (Silver Spring)2017;25:102-10 PMCID:PMC5182153

[106] Zhao H,Pan Z,Li Z.Exosomes from adipose-derived stem cells attenuate adipose inflammation and obesity through polarizing M2 macrophages and beiging in white adipose tissue..Diabetes2018;67:235-47

[107] Chistiakov DA,Khotina VA,Orekhov AN.Immune-inflammatory responses in atherosclerosis: the role of myeloid cells..J Clin Med2019;8:1798 PMCID:PMC6912749

[108] Lu Z,Yu P,Wang Y.Inhibition of miR-29b suppresses MAPK signaling pathway through targeting SPRY1 in atherosclerosis..Vascul Pharmacol2018;102:29-36