Advertisement

Regulation of white adipogenesis and its relation to ectopic fat accumulation and cardiovascular risk

  • Birgit Gustafson
    Affiliations
    The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
    Search for articles by this author
  • Ulf Smith
    Correspondence
    Corresponding author. The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital, Blå Stråket 5, SE413 45 Gothenburg, Sweden.
    Affiliations
    The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
    Search for articles by this author

      Highlights

      • A comprehensive summary of adipogenesis, ectopic fat accumulation and consequences.
      • The role of inflammation in the adipose tissue, cross-talk with inflammatory cells.
      • Overview of vasocrine signalling and the role of perivascular adipose tissue.

      Abstract

      The subcutaneous adipose tissue (SAT) is the largest and least harmful adipose depot to store excess lipids. However, SAT has a limited ability to expand and recruit new cells. When the SAT adipose cells become expanded (hypertrophic obesity), this leads to a dysregulated and dysfunctional SAT and the accumulation of ectopic fat in many depots. Increased hepatic and visceral fat are well-known ectopic fat depots and reflect the inability of SAT to accommodate excess fat. Ectopic fat also leads to paracrine and endocrine effects and promotes the metabolic profile of the Metabolic Syndrome. In addition, ectopic fat accumulation in and around the heart and vessels are considered to be active and cross talk with the tissues, thereby enhancing several aspects associated with the risk of developing cardiovascular disease and atherosclerosis.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Yudkin J.S.
        Insulin resistance and the metabolic syndrome–or the pitfalls of epidemiology.
        Diabetologia. 2007; 50: 1576-1586
        • Krotkiewski M.
        • Bjorntorp P.
        • Sjostrom L.
        • Smith U.
        Impact of obesity on metabolism in men and women. Importance of regional adipose tissue distribution.
        J. Clin. Invest. 1983; 72: 1150-1162
        • Despres J.P.
        Body fat distribution and risk of cardiovascular disease: an update.
        Circulation. 2012; 126: 1301-1313
        • Despres J.P.
        • Lemieux I.
        Abdominal obesity and metabolic syndrome.
        Nature. 2006; 444: 881-887
        • Anand S.S.
        • Tarnopolsky M.A.
        • Rashid S.
        • Schulze K.M.
        • Desai D.
        • Mente A.
        • Rao S.
        • Yusuf S.
        • Gerstein H.C.
        • Sharma A.M.
        Adipocyte hypertrophy, fatty liver and metabolic risk factors in South Asians: the Molecular Study of Health and Risk in Ethnic Groups (mol-SHARE).
        PLoS One. 2011; 6: e22112
        • Kishida K.
        • Funahashi T.
        • Matsuzawa Y.
        • Shimomura I.
        Visceral adiposity as a target for the management of the metabolic syndrome.
        Ann. Med. 2012; 44: 233-241
        • Primeau V.
        • Coderre L.
        • Karelis A.D.
        • Brochu M.
        • Lavoie M.E.
        • Messier V.
        • Sladek R.
        • Rabasa-Lhoret R.
        Characterizing the profile of obese patients who are metabolically healthy.
        Int. J. Obes. (Lond). 2011; 35: 971-981
        • van Vliet-Ostaptchouk J.V.
        • Nuotio M.L.
        • Slagter S.N.
        • Doiron D.
        • Fischer K.
        • Foco L.
        • Gaye A.
        • Gogele M.
        • Heier M.
        • Hiekkalinna T.
        • Joensuu A.
        • Newby C.
        • Pang C.
        • Partinen E.
        • Reischl E.
        • Schwienbacher C.
        • Tammesoo M.L.
        • Swertz M.A.
        • Burton P.
        • Ferretti V.
        • Fortier I.
        • Giepmans L.
        • Harris J.R.
        • Hillege H.L.
        • Holmen J.
        • Jula A.
        • Kootstra-Ros J.E.
        • Kvaloy K.
        • Holmen T.L.
        • Mannisto S.
        • Metspalu A.
        • Midthjell K.
        • Murtagh M.J.
        • Peters A.
        • Pramstaller P.P.
        • Saaristo T.
        • Salomaa V.
        • Stolk R.P.
        • Uusitupa M.
        • van der Harst P.
        • van der Klauw M.M.
        • Waldenberger M.
        • Perola M.
        • Wolffenbuttel B.H.
        The prevalence of metabolic syndrome and metabolically healthy obesity in Europe: a collaborative analysis of ten large cohort studies.
        BMC Endocr. Disord. 2014; 14: 9
        • Virtue S.
        • Vidal-Puig A.
        Adipose tissue expandability, lipotoxicity and the Metabolic Syndrome–an allostatic perspective.
        Biochim. Biophys. Acta. 2010; 1801: 338-349
        • Weyer C.
        • Foley J.E.
        • Bogardus C.
        • Tataranni P.A.
        • Pratley R.E.
        Enlarged subcutaneous abdominal adipocyte size, but not obesity itself, predicts type II diabetes independent of insulin resistance.
        Diabetologia. 2000; 43: 1498-1506
        • Arner P.
        • Arner E.
        • Hammarstedt A.
        • Smith U.
        Genetic predisposition for Type 2 diabetes, but not for overweight/obesity, is associated with a restricted adipogenesis.
        PLoS One. 2011; 6: e18284
        • Mittelman S.D.
        • Van Citters G.W.
        • Kirkman E.L.
        • Bergman R.N.
        Extreme insulin resistance of the central adipose depot in vivo.
        Diabetes. 2002; 51: 755-761
        • Gustafson B.
        • Hammarstedt A.
        • Hedjazifar S.
        • Smith U.
        Restricted adipogenesis in hypertrophic obesity: the role of WISP2, WNT, and BMP4.
        Diabetes. 2013; 62: 2997-3004
        • Gustafson B.
        • Smith U.
        The WNT inhibitor Dickkopf 1 and bone morphogenetic protein 4 rescue adipogenesis in hypertrophic obesity in humans.
        Diabetes. 2012; 61: 1217-1224
        • Hammarstedt A.
        • Hedjazifar S.
        • Jenndahl L.
        • Gogg S.
        • Grunberg J.
        • Gustafson B.
        • Klimcakova E.
        • Stich V.
        • Langin D.
        • Laakso M.
        • Smith U.
        WISP2 regulates preadipocyte commitment and PPARgamma activation by BMP4.
        Proc. Natl. Acad. Sci. U. S. A. 2013; 110: 2563-2568
        • Cederberg H.
        • Stancakova A.
        • Kuusisto J.
        • Laakso M.
        • Smith U.
        Family history of type 2 diabetes increases the risk of both obesity and its complications: is type 2 diabetes a disease of inappropriate lipid storage?.
        J. Intern. Med. 2015; 277: 540-551
        • InterAct C.
        • Langenberg C.
        • Sharp S.J.
        • Schulze M.B.
        • Rolandsson O.
        • Overvad K.
        • Forouhi N.G.
        • Spranger J.
        • Drogan D.
        • Huerta J.M.
        • Arriola L.
        • de Lauzon-Guillan B.
        • Tormo M.J.
        • Ardanaz E.
        • Balkau B.
        • Beulens J.W.
        • Boeing H.
        • Bueno-de-Mesquita H.B.
        • Clavel-Chapelon F.
        • Crowe F.L.
        • Franks P.W.
        • Gonzalez C.A.
        • Grioni S.
        • Halkjaer J.
        • Hallmans G.
        • Kaaks R.
        • Kerrison N.D.
        • Key T.J.
        • Khaw K.T.
        • Mattiello A.
        • Nilsson P.
        • Norat T.
        • Palla L.
        • Palli D.
        • Panico S.
        • Quiros J.R.
        • Romaguera D.
        • Romieu I.
        • Sacerdote C.
        • Sanchez M.J.
        • Slimani N.
        • Sluijs I.
        • Spijkerman A.M.
        • Teucher B.
        • Tjonneland A.
        • Tumino R.
        • van der A.D.
        • van der Schouw Y.T.
        • Feskens E.J.
        • Riboli E.
        • Wareham N.J.
        Long-term risk of incident type 2 diabetes and measures of overall and regional obesity: the EPIC-InterAct case-cohort study.
        PLoS Med. 2012; 9: e1001230
        • Neeland I.J.
        • Turer A.T.
        • Ayers C.R.
        • Powell-Wiley T.M.
        • Vega G.L.
        • Farzaneh-Far R.
        • Grundy S.M.
        • Khera A.
        • McGuire D.K.
        • de Lemos J.A.
        Dysfunctional adiposity and the risk of prediabetes and type 2 diabetes in obese adults.
        JAMA: J. Am. Med. Assoc. 2012; 308: 1150-1159
        • Despres J.P.
        Obesity and cardiovascular disease: weight loss is not the only target.
        Can. J. Cardiol. 2015; 31: 216-222
        • Estruch R.
        • Ros E.
        • Salas-Salvado J.
        • Covas M.I.
        • Corella D.
        • Aros F.
        • Gomez-Gracia E.
        • Ruiz-Gutierrez V.
        • Fiol M.
        • Lapetra J.
        • Lamuela-Raventos R.M.
        • Serra-Majem L.
        • Pinto X.
        • Basora J.
        • Munoz M.A.
        • Sorli J.V.
        • Martinez J.A.
        • Martinez-Gonzalez M.A.
        • Investigators P.S.
        Primary prevention of cardiovascular disease with a Mediterranean diet.
        N. Engl. J. Med. 2013; 368: 1279-1290
        • Broekhuizen L.N.
        • Boekholdt S.M.
        • Arsenault B.J.
        • Despres J.P.
        • Stroes E.S.
        • Kastelein J.J.
        • Khaw K.T.
        • Wareham N.J.
        Physical activity, metabolic syndrome, and coronary risk: the EPIC-Norfolk prospective population study.
        Eur. J. Cardiovasc. Prev. Rehabili.: Off. J. Eur. Soc. Cardiol. Work. Groups Epidemiol. Prev. Cardiac Rehabil. Exerc. Physiol. 2011; 18: 209-217
        • Miyazaki Y.
        • Mahankali A.
        • Matsuda M.
        • Mahankali S.
        • Hardies J.
        • Cusi K.
        • Mandarino L.J.
        • DeFronzo R.A.
        Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients.
        J. Clin. Endocrinol. Metab. 2002; 87: 2784-2791
        • Park K.W.
        • Halperin D.S.
        • Tontonoz P.
        Before they were fat: adipocyte progenitors.
        Cell. Metab. 2008; 8: 454-457
        • Gesta S.
        • Tseng Y.H.
        • Kahn C.R.
        Developmental origin of fat: tracking obesity to its source.
        Cell. 2007; 131: 242-256
        • Clark E.R.
        • Clark E.L.
        Microscopic studies of the new formation of fat.
        Am. J. Anat. 1940; 67: 255-285
        • Tang W.
        • Zeve D.
        • Suh J.M.
        • Bosnakovski D.
        • Kyba M.
        • Hammer R.E.
        • Tallquist M.D.
        • Graff J.M.
        White fat progenitor cells reside in the adipose vasculature.
        Science. 2008; 322: 583-586
        • Nishimura S.
        • Manabe I.
        • Nagasaki M.
        • Hosoya Y.
        • Yamashita H.
        • Fujita H.
        • Ohsugi M.
        • Tobe K.
        • Kadowaki T.
        • Nagai R.
        • Sugiura S.
        Adipogenesis in obesity requires close interplay between differentiating adipocytes, stromal cells, and blood vessels.
        Diabetes. 2007; 56: 1517-1526
        • Bowers R.R.
        • Kim J.W.
        • Otto T.C.
        • Lane M.D.
        Stable stem cell commitment to the adipocyte lineage by inhibition of DNA methylation: role of the BMP-4 gene.
        Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 13022-13027
        • Tseng Y.H.
        • Kokkotou E.
        • Schulz T.J.
        • Huang T.L.
        • Winnay J.N.
        • Taniguchi C.M.
        • Tran T.T.
        • Suzuki R.
        • Espinoza D.O.
        • Yamamoto Y.
        • Ahrens M.J.
        • Dudley A.T.
        • Norris A.W.
        • Kulkarni R.N.
        • Kahn C.R.
        New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure.
        Nature. 2008; 454: 1000-1004
        • Barak Y.
        • Nelson M.C.
        • Ong E.S.
        • Jones Y.Z.
        • Ruiz-Lozano P.
        • Chien K.R.
        • Koder A.
        • Evans R.M.
        PPAR gamma is required for placental, cardiac, and adipose tissue development.
        Mol. Cell. 1999; 4: 585-595
        • Savage D.B.
        • Tan G.D.
        • Acerini C.L.
        • Jebb S.A.
        • Agostini M.
        • Gurnell M.
        • Williams R.L.
        • Umpleby A.M.
        • Thomas E.L.
        • Bell J.D.
        • Dixon A.K.
        • Dunne F.
        • Boiani R.
        • Cinti S.
        • Vidal-Puig A.
        • Karpe F.
        • Chatterjee V.K.
        • O'Rahilly S.
        Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-gamma.
        Diabetes. 2003; 52: 910-917
        • Gouda H.N.
        • Sagoo G.S.
        • Harding A.H.
        • Yates J.
        • Sandhu M.S.
        • Higgins J.P.
        The association between the peroxisome proliferator-activated receptor-gamma2 (PPARG2) Pro12Ala gene variant and type 2 diabetes mellitus: a HuGE review and meta-analysis.
        Am. J. Epidemiol. 2010; 171: 645-655
        • Majithia A.R.
        • Flannick J.
        • Shahinian P.
        • Guo M.
        • Bray M.A.
        • Fontanillas P.
        • Gabriel S.B.
        • Go T.D.C.
        • Project N.J.F.A.S.
        • Rosen E.D.
        • Altshuler D.
        • Consortium, S. T. D
        • Consortium, T. D. G
        Rare variants in PPARG with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetes.
        Proc. Natl. Acad. Sci. U. S. A. 2014; 111: 13127-13132
        • Chondronikola M.
        • Volpi E.
        • Borsheim E.
        • Porter C.
        • Annamalai P.
        • Enerback S.
        • Lidell M.E.
        • Saraf M.K.
        • Labbe S.M.
        • Hurren N.M.
        • Yfanti C.
        • Chao T.
        • Andersen C.R.
        • Cesani F.
        • Hawkins H.
        • Sidossis L.S.
        Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans.
        Diabetes. 2014; 63: 4089-4099
        • Gustafson B.
        • Hammarstedt A.
        • Hedjazifar S.
        • Hoffmann J.M.
        • Svensson P.A.
        • Grimsby J.
        • Rondinone C.
        • Smith U.
        BMP4 and BMP antagonists regulate human White and beige adipogenesis.
        Diabetes. 2015; 64: 1670-1681
        • Wu J.
        • Bostrom P.
        • Sparks L.M.
        • Ye L.
        • Choi J.H.
        • Giang A.H.
        • Khandekar M.
        • Virtanen K.A.
        • Nuutila P.
        • Schaart G.
        • Huang K.
        • Tu H.
        • van Marken Lichtenbelt W.D.
        • Hoeks J.
        • Enerback S.
        • Schrauwen P.
        • Spiegelman B.M.
        Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human.
        Cell. 2012; 150: 366-376
        • Scherer P.E.
        Adipose tissue: from lipid storage compartment to endocrine organ.
        Diabetes. 2006; 55: 1537-1545
        • Gustafson B.
        • Hammarstedt A.
        • Andersson C.X.
        • Smith U.
        Inflamed adipose tissue: a culprit underlying the metabolic syndrome and atherosclerosis.
        Arterioscler. Thromb. Vasc. Biol. 2007; 27: 2276-2283
        • Compher C.
        • Badellino K.O.
        Obesity and inflammation: lessons from bariatric surgery.
        JPEN J. Parenter. Enter. Nutr. 2008; 32: 645-647
        • Isakson P.
        • Hammarstedt A.
        • Gustafson B.
        • Smith U.
        Impaired preadipocyte differentiation in human abdominal obesity: role of Wnt, tumor necrosis factor-alpha, and inflammation.
        Diabetes. 2009; 58: 1550-1557
        • Geer E.B.
        • Shen W.
        Gender differences in insulin resistance, body composition, and energy balance.
        Gend. Med. 2009; 6: 60-75
        • Bluher M.
        • Mantzoros C.S.
        From leptin to other adipokines in health and disease: facts and expectations at the beginning of the 21st century.
        Metab.: Clin. Exp. 2015; 64: 131-145
        • Deng Y.
        • Scherer P.E.
        Adipokines as novel biomarkers and regulators of the metabolic syndrome.
        Ann. N. Y. Acad. Sci. 2010; 1212: E1-E19
        • Norseen J.
        • Hosooka T.
        • Hammarstedt A.
        • Yore M.M.
        • Kant S.
        • Aryal P.
        • Kiernan U.A.
        • Phillips D.A.
        • Maruyama H.
        • Kraus B.J.
        • Usheva A.
        • Davis R.J.
        • Smith U.
        • Kahn B.B.
        Retinol-binding protein 4 inhibits insulin signaling in adipocytes by inducing proinflammatory cytokines in macrophages through a c-Jun N-terminal kinase- and toll-like receptor 4-dependent and retinol-independent mechanism.
        Mol. Cell. Biol. 2012; 32: 2010-2019
        • Yang Q.
        • Graham T.E.
        • Mody N.
        • Preitner F.
        • Peroni O.D.
        • Zabolotny J.M.
        • Kotani K.
        • Quadro L.
        • Kahn B.B.
        Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes.
        Nature. 2005; 436: 356-362
        • Graham T.E.
        • Yang Q.
        • Bluher M.
        • Hammarstedt A.
        • Ciaraldi T.P.
        • Henry R.R.
        • Wason C.J.
        • Oberbach A.
        • Jansson P.A.
        • Smith U.
        • Kahn B.B.
        Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects.
        N. Engl. J. Med. 2006; 354: 2552-2563
        • Tzou P.
        • De Gregorio E.
        • Lemaitre B.
        How Drosophila combats microbial infection: a model to study innate immunity and host-pathogen interactions.
        Curr. Opin. Microbiol. 2002; 5: 102-110
        • Charriere G.
        • Cousin B.
        • Arnaud E.
        • Andre M.
        • Bacou F.
        • Penicaud L.
        • Casteilla L.
        Preadipocyte conversion to macrophage. Evidence of plasticity.
        J. Biol. Chem. 2003; 278: 9850-9855
        • Wellen K.E.
        • Hotamisligil G.S.
        Inflammation, stress, and diabetes.
        J. Clin. Invest. 2005; 115: 1111-1119
        • Tchoukalova Y.D.
        • Sarr M.G.
        • Jensen M.D.
        Measuring committed preadipocytes in human adipose tissue from severely obese patients by using adipocyte fatty acid binding protein.
        Am. J. Physiol. Regul. Integr. Comp. Physiol. 2004; 287: R1132-R1140
        • Cancello R.
        • Henegar C.
        • Viguerie N.
        • Taleb S.
        • Poitou C.
        • Rouault C.
        • Coupaye M.
        • Pelloux V.
        • Hugol D.
        • Bouillot J.L.
        • Bouloumie A.
        • Barbatelli G.
        • Cinti S.
        • Svensson P.A.
        • Barsh G.S.
        • Zucker J.D.
        • Basdevant A.
        • Langin D.
        • Clement K.
        Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss.
        Diabetes. 2005; 54: 2277-2286
        • Weisberg S.P.
        • McCann D.
        • Desai M.
        • Rosenbaum M.
        • Leibel R.L.
        • Ferrante Jr., A.W.
        Obesity is associated with macrophage accumulation in adipose tissue.
        J. Clin. Invest. 2003; 112: 1796-1808
        • Takahashi K.
        • Mizuarai S.
        • Araki H.
        • Mashiko S.
        • Ishihara A.
        • Kanatani A.
        • Itadani H.
        • Kotani H.
        Adiposity elevates plasma MCP-1 levels leading to the increased CD11b-positive monocytes in mice.
        J. Biol. Chem. 2003; 278: 46654-46660
        • Xu H.
        • Barnes G.T.
        • Yang Q.
        • Tan G.
        • Yang D.
        • Chou C.J.
        • Sole J.
        • Nichols A.
        • Ross J.S.
        • Tartaglia L.A.
        • Chen H.
        Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.
        J. Clin. Invest. 2003; 112: 1821-1830
        • Lumeng C.N.
        • Bodzin J.L.
        • Saltiel A.R.
        Obesity induces a phenotypic switch in adipose tissue macrophage polarization.
        J. Clin. Invest. 2007; 117: 175-184
        • Curat C.A.
        • Miranville A.
        • Sengenes C.
        • Diehl M.
        • Tonus C.
        • Busse R.
        • Bouloumie A.
        From blood monocytes to adipose tissue-resident macrophages: induction of diapedesis by human mature adipocytes.
        Diabetes. 2004; 53: 1285-1292
        • Suganami T.
        • Nishida J.
        • Ogawa Y.
        A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: role of free fatty acids and tumor necrosis factor alpha.
        Arterioscler. Thromb. Vasc. Biol. 2005; 25: 2062-2068
        • Seijkens T.
        • Kusters P.
        • Chatzigeorgiou A.
        • Chavakis T.
        • Lutgens E.
        Immune cell crosstalk in obesity: a key role for costimulation?.
        Diabetes. 2014; 63: 3982-3991
        • Cinti S.
        • Mitchell G.
        • Barbatelli G.
        • Murano I.
        • Ceresi E.
        • Faloia E.
        • Wang S.
        • Fortier M.
        • Greenberg A.S.
        • Obin M.S.
        Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans.
        J. Lipid Res. 2005; 46: 2347-2355
        • Nishimura S.
        • Manabe I.
        • Nagasaki M.
        • Eto K.
        • Yamashita H.
        • Ohsugi M.
        • Otsu M.
        • Hara K.
        • Ueki K.
        • Sugiura S.
        • Yoshimura K.
        • Kadowaki T.
        • Nagai R.
        CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity.
        Nat. Med. 2009; 15: 914-920
        • Feuerer M.
        • Herrero L.
        • Cipolletta D.
        • Naaz A.
        • Wong J.
        • Nayer A.
        • Lee J.
        • Goldfine A.B.
        • Benoist C.
        • Shoelson S.
        • Mathis D.
        Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters.
        Nat. Med. 2009; 15: 930-939
        • Cipolletta D.
        • Feuerer M.
        • Li A.
        • Kamei N.
        • Lee J.
        • Shoelson S.E.
        • Benoist C.
        • Mathis D.
        PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells.
        Nature. 2012; 486: 549-553
        • DeFuria J.
        • Belkina A.C.
        • Jagannathan-Bogdan M.
        • Snyder-Cappione J.
        • Carr J.D.
        • Nersesova Y.R.
        • Markham D.
        • Strissel K.J.
        • Watkins A.A.
        • Zhu M.
        • Allen J.
        • Bouchard J.
        • Toraldo G.
        • Jasuja R.
        • Obin M.S.
        • McDonnell M.E.
        • Apovian C.
        • Denis G.V.
        • Nikolajczyk B.S.
        B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile.
        Proc. Natl. Acad. Sci. U. S. A. 2013; 110: 5133-5138
        • Lynch L.
        • Nowak M.
        • Varghese B.
        • Clark J.
        • Hogan A.E.
        • Toxavidis V.
        • Balk S.P.
        • O'Shea D.
        • O'Farrelly C.
        • Exley M.A.
        Adipose tissue invariant NKT cells protect against diet-induced obesity and metabolic disorder through regulatory cytokine production.
        Immunity. 2012; 37: 574-587
        • Khan T.
        • Muise E.S.
        • Iyengar P.
        • Wang Z.V.
        • Chandalia M.
        • Abate N.
        • Zhang B.B.
        • Bonaldo P.
        • Chua S.
        • Scherer P.E.
        Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI.
        Mol. Cell. Biol. 2009; 29: 1575-1591
        • Divoux A.
        • Tordjman J.
        • Lacasa D.
        • Veyrie N.
        • Hugol D.
        • Aissat A.
        • Basdevant A.
        • Guerre-Millo M.
        • Poitou C.
        • Zucker J.D.
        • Bedossa P.
        • Clement K.
        Fibrosis in human adipose tissue: composition, distribution, and link with lipid metabolism and fat mass loss.
        Diabetes. 2010; 59: 2817-2825
        • Henninger A.M.
        • Eliasson B.
        • Jenndahl L.E.
        • Hammarstedt A.
        Adipocyte hypertrophy, inflammation and fibrosis characterize subcutaneous adipose tissue of healthy, non-obese subjects predisposed to type 2 diabetes.
        PLOS One. 2014; 9: e105262
        • Lin J.
        • Patel S.R.
        • Cheng X.
        • Cho E.A.
        • Levitan I.
        • Ullenbruch M.
        • Phan S.H.
        • Park J.M.
        • Dressler G.R.
        Kielin/chordin-like protein, a novel enhancer of BMP signaling, attenuates renal fibrotic disease.
        Nat. Med. 2005; 11: 387-393
        • Sun K.
        • Tordjman J.
        • Clement K.
        • Scherer P.E.
        Fibrosis and adipose tissue dysfunction.
        Cell. Metab. 2013; 18: 470-477
        • Farb M.G.
        • Ganley-Leal L.
        • Mott M.
        • Liang Y.
        • Ercan B.
        • Widlansky M.E.
        • Bigornia S.J.
        • Fiscale A.J.
        • Apovian C.M.
        • Carmine B.
        • Hess D.T.
        • Vita J.A.
        • Gokce N.
        Arteriolar function in visceral adipose tissue is impaired in human obesity.
        Arterioscler. Thromb. Vasc. Biol. 2012; 32: 467-473
        • Heilbronn L.
        • Smith S.R.
        • Ravussin E.
        Failure of fat cell proliferation, mitochondrial function and fat oxidation results in ectopic fat storage, insulin resistance and type II diabetes mellitus.
        Int. J. Obes. Relat. Metab. Disord. 2004; 28: S12-S21
        • Cornier M.A.
        • Despres J.P.
        • Davis N.
        • Grossniklaus D.A.
        • Klein S.
        • Lamarche B.
        • Lopez-Jimenez F.
        • Rao G.
        • St-Onge M.P.
        • Towfighi A.
        • Poirier P.
        • American Heart Association Obesity Committee of the Council on, N.
        • Physical, A., Metabolism
        • Council on, A.
        • Thrombosis, Vascular, B.
        • Council on Cardiovascular Disease in the, Y.
        • Council on Cardiovascular, R., Intervention
        • Council on Cardiovascular Nursing, C. o. E., Prevention
        • Council on the Kidney in Cardiovascular, D. & Stroke, C
        Assessing adiposity: a scientific statement from the American Heart Association.
        Circulation. 2011; 124: 1996-2019
        • Rotter V.
        • Nagaev I.
        • Smith U.
        Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects.
        J. Biol. Chem. 2003; 278: 45777-45784
        • Bjorntorp P.
        “Portal” adipose tissue as a generator of risk factors for cardiovascular disease and diabetes.
        Arteriosclerosis. 1990; 10: 493-496
        • Jensen M.D.
        Is visceral fat involved in the pathogenesis of the metabolic syndrome? Human model.
        Obes. (Silver Spring). 2006; 14: 20S-24S
        • Graner M.
        • Siren R.
        • Nyman K.
        • Lundbom J.
        • Hakkarainen A.
        • Pentikainen M.O.
        • Lauerma K.
        • Lundbom N.
        • Adiels M.
        • Nieminen M.S.
        • Taskinen M.R.
        Cardiac steatosis associates with visceral obesity in nondiabetic obese men.
        J. Clin. Endocrinol. Metab. 2013; 98: 1189-1197
        • Kotronen A.
        • Juurinen L.
        • Hakkarainen A.
        • Westerbacka J.
        • Corner A.
        • Bergholm R.
        • Yki-Jarvinen H.
        Liver fat is increased in type 2 diabetic patients and underestimated by serum alanine aminotransferase compared with equally obese nondiabetic subjects.
        Diabetes Care. 2008; 31: 165-169
        • Adiels M.
        • Taskinen M.R.
        • Packard C.
        • Caslake M.J.
        • Soro-Paavonen A.
        • Westerbacka J.
        • Vehkavaara S.
        • Hakkinen A.
        • Olofsson S.O.
        • Yki-Jarvinen H.
        • Boren J.
        Overproduction of large VLDL particles is driven by increased liver fat content in man.
        Diabetologia. 2006; 49: 755-765
        • Fabbrini E.
        • Magkos F.
        • Mohammed B.S.
        • Pietka T.
        • Abumrad N.A.
        • Patterson B.W.
        • Okunade A.
        • Klein S.
        Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity.
        Proc. Natl. Acad. Sci. U. S. A. 2009; 106: 15430-15435
        • Cansby E.
        • Amrutkar M.
        • Manneras Holm L.
        • Nerstedt A.
        • Reyahi A.
        • Stenfeldt E.
        • Boren J.
        • Carlsson P.
        • Smith U.
        • Zierath J.R.
        • Mahlapuu M.
        Increased expression of STK25 leads to impaired glucose utilization and insulin sensitivity in mice challenged with a high-fat diet.
        FASEB J. 2013; 27: 3660-3671
        • Jacob S.
        • Machann J.
        • Rett K.
        • Brechtel K.
        • Volk A.
        • Renn W.
        • Maerker E.
        • Matthaei S.
        • Schick F.
        • Claussen C.D.
        • Haring H.U.
        Association of increased intramyocellular lipid content with insulin resistance in lean nondiabetic offspring of type 2 diabetic subjects.
        Diabetes. 1999; 48: 1113-1119
        • Coen P.M.
        • Goodpaster B.H.
        Role of intramyocellular lipids in human health.
        Trends Endocrinol. Metab.: TEM. 2012; 23: 391-398
        • Kim S.K.
        • Park S.W.
        • Hwang I.J.
        • Lee Y.K.
        • Cho Y.W.
        High fat stores in ectopic compartments in men with newly diagnosed type 2 diabetes: an anthropometric determinant of carotid atherosclerosis and insulin resistance.
        Int. J. Obes. 2010; 34: 105-110
        • Muoio D.M.
        • Neufer P.D.
        Lipid-induced mitochondrial stress and insulin action in muscle.
        Cell. Metab. 2012; 15: 595-605
        • Sacks H.S.
        • Fain J.N.
        • Holman B.
        • Cheema P.
        • Chary A.
        • Parks F.
        • Karas J.
        • Optican R.
        • Bahouth S.W.
        • Garrett E.
        • Wolf R.Y.
        • Carter R.A.
        • Robbins T.
        • Wolford D.
        • Samaha J.
        Uncoupling protein-1 and related messenger ribonucleic acids in human epicardial and other adipose tissues: epicardial fat functioning as brown fat.
        J. Clin. Endocrinol. Metab. 2009; 94: 3611-3615
        • Kremen J.
        • Dolinkova M.
        • Krajickova J.
        • Blaha J.
        • Anderlova K.
        • Lacinova Z.
        • Haluzikova D.
        • Bosanska L.
        • Vokurka M.
        • Svacina S.
        • Haluzik M.
        Increased subcutaneous and epicardial adipose tissue production of proinflammatory cytokines in cardiac surgery patients: possible role in postoperative insulin resistance.
        J. Clin. Endocrinol. Metab. 2006; 91: 4620-4627
        • Mazurek T.
        • Zhang L.
        • Zalewski A.
        • Mannion J.D.
        • Diehl J.T.
        • Arafat H.
        • Sarov-Blat L.
        • O'Brien S.
        • Keiper E.A.
        • Johnson A.G.
        • Martin J.
        • Goldstein B.J.
        • Shi Y.
        Human epicardial adipose tissue is a source of inflammatory mediators.
        Circulation. 2003; 108: 2460-2466
        • Yudkin J.S.
        • Eringa E.
        • Stehouwer C.D.
        “Vasocrine” signalling from perivascular fat: a mechanism linking insulin resistance to vascular disease.
        Lancet. 2005; 365: 1817-1820
        • Guzik T.J.
        • Mangalat D.
        • Korbut R.
        Adipocytokines - novel link between inflammation and vascular function?.
        J. Physiol. Pharmacol. : Official J. Pol. Physiol. Soc. 2006; 57: 505-528
        • Marchington J.M.
        • Pond C.M.
        Site-specific properties of pericardial and epicardial adipose tissue: the effects of insulin and high-fat feeding on lipogenesis and the incorporation of fatty acids in vitro.
        Int. J. Obes. 1990; 14: 1013-1022
        • Iacobellis G.
        • Ribaudo M.C.
        • Assael F.
        • Vecci E.
        • Tiberti C.
        • Zappaterreno A.
        • Di Mario U.
        • Leonetti F.
        Echocardiographic epicardial adipose tissue is related to anthropometric and clinical parameters of metabolic syndrome: a new indicator of cardiovascular risk.
        J. Clin. Endocrinol. Metab. 2003; 88: 5163-5168
        • Iacobellis G.
        • Corradi D.
        • Sharma A.M.
        Epicardial adipose tissue: anatomic, biomolecular and clinical relationships with the heart.
        Nat. Clin. Pract. Cardiovasc Med. 2005; 2: 536-543
        • Nyman K.
        • Graner M.
        • Pentikainen M.O.
        • Lundbom J.
        • Hakkarainen A.
        • Siren R.
        • Nieminen M.S.
        • Taskinen M.R.
        • Lundbom N.
        • Lauerma K.
        Cardiac steatosis and left ventricular function in men with metabolic syndrome.
        J. Cardiovasc. Magn. Resonance: Off. J. Soc. Cardiovasc. Magnetic Reson. 2013; 15: 103
        • Tran K.V.
        • Gealekman O.
        • Frontini A.
        • Zingaretti M.C.
        • Morroni M.
        • Giordano A.
        • Smorlesi A.
        • Perugini J.
        • De Matteis R.
        • Sbarbati A.
        • Corvera S.
        • Cinti S.
        The vascular endothelium of the adipose tissue gives rise to both white and brown fat cells.
        Cell. Metab. 2012; 15: 222-229
        • Fantuzzi G.
        • Mazzone T.
        Adipose tissue and atherosclerosis: exploring the connection.
        Arterioscler. Thromb. Vasc. Biol. 2007; 27: 996-1003
        • Montani J.P.
        • Carroll J.F.
        • Dwyer T.M.
        • Antic V.
        • Yang Z.
        • Dulloo A.G.
        Ectopic fat storage in heart, blood vessels and kidneys in the pathogenesis of cardiovascular diseases.
        Int. J. Obes. Relat. Metab. Disord. 2004; 28: S58-S65
        • McGavock J.M.
        • Lingvay I.
        • Zib I.
        • Tillery T.
        • Salas N.
        • Unger R.
        • Levine B.D.
        • Raskin P.
        • Victor R.G.
        • Szczepaniak L.S.
        Cardiac steatosis in diabetes mellitus: a 1H-magnetic resonance spectroscopy study.
        Circulation. 2007; 116: 1170-1175
        • Sun K.
        • Kusminski C.M.
        • Scherer P.E.
        Adipose tissue remodeling and obesity.
        J. Clin. Invest. 2011; 121: 2094-2101