Skip to main content
SpringerLink
Log in

Adipose Tissue T Regulatory Cells: Implications for Health and Disease

  • Chapter
  • First Online:
T Regulatory Cells in Human Health and Diseases

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1278))

Abstract

Obesity dramatically increases the risk of numerous conditions, including type 2 diabetes mellitus and other components of the metabolic syndrome. Pro-inflammatory changes that occur in adipose tissue are critical to the pathogenesis of these obesity-induced complications. Adipose tissue is one of the body’s largest endocrine organs, and the cells that comprise the adipose tissue immunoenvironment secrete multiple factors (including adipokines and cytokines) that impact systemic metabolism. In particular, immunosuppressive regulatory T cells (Tregs) decline in obesity, partly in response to its complex interaction with adipocytes, and this decline contributes to disruption of the typical homeostasis observed in lean adipose tissue. Although the regulation of Treg differentiation, function, and enrichment is incompletely understood, factors including various cell-surface co-stimulatory molecules, certain lipid species, and cytokines such as PPARγ, adiponectin, and leptin are important mediators. It is also clear that there may be depot-specific differences in Tregs, rendering adipose tissue Tregs distinct from lymphoid or circulating Tregs, with implications on maintenance and functionality. While most of these findings are derived from studies in murine models, comparatively little is known about the human adipose tissue Treg signature, which requires further investigation.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Alcala M, Calderon-Dominguez M, Bustos E, Ramos P, Casals N, Serra D, Viana M, Herrero L (2017) Increased inflammation, oxidative stress and mitochondrial respiration in brown adipose tissue from obese mice. Sci Rep 7:16082

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Al-Lahham SH, Peppelenbosch MP, Roelofsen H, Vonk RJ, Venema K (2010) Biological effects of propionic acid in humans; metabolism, potential applications and underlying mechanisms. Biochim Biophys Acta 1801:1175–1183

    Article  CAS  PubMed  Google Scholar 

  • Alwarawrah Y, Kiernan K, MacIver NJ (2018) Changes in nutritional status impact immune cell metabolism and function. Front Immunol 9:1055

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Baker NA, Muir LA, Washabaugh AR, Neeley CK, Chen SY, Flesher CG, Vorwald J, Finks JF, Ghaferi AA, Mulholland MW et al (2017) Diabetes-specific regulation of adipocyte metabolism by the adipose tissue extracellular matrix. J Clin Endocrinol Metab 102:1032–1043

    PubMed  PubMed Central  Google Scholar 

  • Bar-On L, Birnberg T, Kim KW, Jung S (2011) Dendritic cell-restricted CD80/86 deficiency results in peripheral regulatory T-cell reduction but is not associated with lymphocyte hyperactivation. Eur J Immunol 41:291–298

    Article  CAS  PubMed  Google Scholar 

  • Benezech C, Jackson-Jones LH (2019) ILC2 orchestration of local immune function in adipose tissue. Front Immunol 10:171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Benson MJ, Pino-Lagos K, Rosemblatt M, Noelle RJ (2007) All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J Exp Med 204:1765–1774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Biswas SK, Mantovani A (2010) Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 11:889–896

    Article  CAS  PubMed  Google Scholar 

  • Blaszczak AM, Jalilvand A, Liu J, Wright VP, Suzo A, Needleman B, Noria S, Lafuse W, Hsueh WA, Bradley D (2019a) Human visceral adipose tissue macrophages are not adequately defined by standard methods of characterization. J Diabetes Res 2019:8124563

    Article  PubMed  PubMed Central  Google Scholar 

  • Blaszczak AM, Wright VP, Anandani K, Liu J, Jalilvand A, Bergin S, Nicoloro SM, Czech MP, Lafuse W, Deng T et al (2019b) Loss of antigen presentation in adipose tissue macrophages or in adipocytes, but not both, improves glucose metabolism. J Immunol 202:2451–2459

    Article  CAS  PubMed  Google Scholar 

  • Boden G (2006) Fatty acid-induced inflammation and insulin resistance in skeletal muscle and liver. Curr Diab Rep 6:177–181

    Article  CAS  PubMed  Google Scholar 

  • Brestoff JR, Artis D (2015) Immune regulation of metabolic homeostasis in health and disease. Cell 161:146–160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brun PJ, Yang KJ, Lee SA, Yuen JJ, Blaner WS (2013) Retinoids: potent regulators of metabolism. Biofactors 39:151–163

    Article  CAS  PubMed  Google Scholar 

  • Chang AY, Dao T, Gejman RS, Jarvis CA, Scott A, Dubrovsky L, Mathias MD, Korontsvit T, Zakhaleva V, Curcio M et al (2017) A therapeutic T cell receptor mimic antibody targets tumor-associated PRAME peptide/HLA-I antigens. J Clin Invest 127:3557

    Article  PubMed  PubMed Central  Google Scholar 

  • Cheng KK, Iglesias MA, Lam KS, Wang Y, Sweeney G, Zhu W, Vanhoutte PM, Kraegen EW, Xu A (2009) APPL1 potentiates insulin-mediated inhibition of hepatic glucose production and alleviates diabetes via Akt activation in mice. Cell Metab 9:417–427

    Article  CAS  PubMed  Google Scholar 

  • Choi M, Doss HM, Kim KS (2020) Multifaceted physiological roles of adiponectin in inflammation and diseases. Int J Mol Sci 21:1219

    Article  CAS  PubMed Central  Google Scholar 

  • Cipolletta D (2014) Adipose tissue-resident regulatory T cells: phenotypic specialization, functions and therapeutic potential. Immunology 142:517–525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cipolletta D, Feuerer M, Li A, Kamei N, Lee J, Shoelson SE, Benoist C, Mathis D (2012a) PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 486:549–553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cipolletta D, Feuerer M, Li A, Kamei N, Lee J, Shoelson SE, Benoist C, Mathis D (2012b) PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue T reg cells. Nature 486:549–553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cipolletta D, Cohen P, Spiegelman BM, Benoist C, Mathis D (2015a) Appearance and disappearance of the mRNA signature characteristic of Treg cells in visceral adipose tissue: age, diet, and PPARgamma effects. Proc Natl Acad Sci U S A 112:482–487

    Article  CAS  PubMed  Google Scholar 

  • Cipolletta D, Cohen P, Spiegelman BM, Benoist C, Mathis D (2015b) Appearance and disappearance of the mRNA signature characteristic of Treg cells in visceral adipose tissue: age, diet, and PPARγ effects. Proc Natl Acad Sci 112:482–487

    Article  CAS  PubMed  Google Scholar 

  • Crewe C, Joffin N, Rutkowski JM, Kim M, Zhang F, Towler DA, Gordillo R, Scherer PE (2018) An endothelial-to-adipocyte extracellular vesicle Axis governed by metabolic state. Cell 175(695–708):e613

    Google Scholar 

  • Dastych M, Dastych M Jr, Novotna H, Cihalova J (2008) Lactulose/mannitol test and specificity, sensitivity, and area under curve of intestinal permeability parameters in patients with liver cirrhosis and Crohn’s disease. Dig Dis Sci 53:2789–2792

    Article  CAS  PubMed  Google Scholar 

  • De Rosa V, Procaccini C, Cali G, Pirozzi G, Fontana S, Zappacosta S, La Cava A, Matarese G (2007) A key role of leptin in the control of regulatory T cell proliferation. Immunity 26:241–255

    Article  PubMed  CAS  Google Scholar 

  • DeFronzo RA (2004) Pathogenesis of type 2 diabetes mellitus. Med Clin North Am 88:787–835, ix

    Article  CAS  PubMed  Google Scholar 

  • DeFronzo RA, Jacot E, Jequier E, Maeder E, Wahren J, Felber JP (1981) The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes 30:1000–1007

    Article  CAS  PubMed  Google Scholar 

  • Deng T, Lyon CJ, Minze LJ, Lin J, Zou J, Liu JZ, Ren Y, Yin Z, Hamilton DJ, Reardon PR et al (2013) Class II major histocompatibility complex plays an essential role in obesity-induced adipose inflammation. Cell Metab 17:411–422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Deng T, Liu J, Deng Y, Minze L, Xiao X, Wright V, Yu R, Li XC, Blaszczak A, Bergin S et al (2017) Adipocyte adaptive immunity mediates diet-induced adipose inflammation and insulin resistance by decreasing adipose Treg cells. Nat Commun 8:15725

    Article  CAS  PubMed Central  Google Scholar 

  • Deshmukh AS, Peijs L, Beaudry JL, Jespersen NZ, Nielsen CH, Ma T, Brunner AD, Larsen TJ, Bayarri-Olmos R, Prabhakar BS et al (2019) Proteomics-based comparative mapping of the secretomes of human Brown and White adipocytes reveals EPDR1 as a novel Batokine. Cell Metab 30:963–975.e967

    Article  CAS  PubMed  Google Scholar 

  • DiSpirito JR, Zemmour D, Ramanan D, Cho J, Zilionis R, Klein AM, Benoist C, Mathis D (2018) Molecular diversification of regulatory T cells in nonlymphoid tissues. Sci Immunol 3:eaat5861

    Article  PubMed  PubMed Central  Google Scholar 

  • El Karim IA, Linden GJ, Irwin CR, Lundy FT (2009) Neuropeptides regulate expression of angiogenic growth factors in human dental pulp fibroblasts. J Endod 35:829–833

    Article  PubMed  Google Scholar 

  • Ferrannini E, Barrett EJ, Bevilacqua S, DeFronzo RA (1983) Effect of fatty acids on glucose production and utilization in man. J Clin Invest 72:1737–1747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A, Lee J, Goldfine AB, Benoist C, Shoelson S (2009) Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 15:930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fitzgibbons TP, Kogan S, Aouadi M, Hendricks GM, Straubhaar J, Czech MP (2011) Similarity of mouse perivascular and brown adipose tissues and their resistance to diet-induced inflammation. Am J Physiol Heart Circ Physiol 301:H1425–H1437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Flaherty SE III, Grijalva A, Xu X, Ables E, Nomani A, Ferrante AW Jr (2019) A lipase-independent pathway of lipid release and immune modulation by adipocytes. Science 363:989–993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Freigang S, Ampenberger F, Weiss A, Kanneganti TD, Iwakura Y, Hersberger M, Kopf M (2013) Fatty acid-induced mitochondrial uncoupling elicits inflammasome-independent IL-1alpha and sterile vascular inflammation in atherosclerosis. Nat Immunol 14:1045–1053

    Article  CAS  PubMed  Google Scholar 

  • Frias AB, Hyzny EJ, Buechel HM, Beppu LY, Xie B, Jurczak MJ, D’Cruz LM (2019) The transcriptional regulator Id2 is critical for adipose-resident regulatory T cell differentiation, survival, and function. J Immunol 203:658–664

    Article  CAS  PubMed  Google Scholar 

  • Fujisaka S, Usui I, Bukhari A, Ikutani M, Oya T, Kanatani Y, Tsuneyama K, Nagai Y, Takatsu K, Urakaze M et al (2009) Regulatory mechanisms for adipose tissue M1 and M2 macrophages in diet-induced obese mice. Diabetes 58:2574–2582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gainsford T, Willson TA, Metcalf D, Handman E, McFarlane C, Ng A, Nicola NA, Alexander WS, Hilton DJ (1996) Leptin can induce proliferation, differentiation, and functional activation of hemopoietic cells. Proc Natl Acad Sci U S A 93:14564–14568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gesta S, Tseng YH, Kahn CR (2007) Developmental origin of fat: tracking obesity to its source. Cell 131:242–256

    Article  CAS  PubMed  Google Scholar 

  • Gyllenhammer LE, Lam J, Alderete TL, Allayee H, Akbari O, Katkhouda N, Goran MI (2016) Lower omental T-regulatory cell count is associated with higher fasting glucose and lower beta-cell function in adults with obesity. Obesity (Silver Spring) 24:1274–1282

    Article  CAS  Google Scholar 

  • Hams E, Locksley RM, McKenzie AN, Fallon PG (2013) Cutting edge: IL-25 elicits innate lymphoid type 2 and type II NKT cells that regulate obesity in mice. J Immunol 191:5349–5353

    Article  CAS  PubMed  Google Scholar 

  • Han JM, Wu D, Denroche HC, Yao Y, Verchere CB, Levings MK (2015) IL-33 reverses an obesity-induced deficit in visceral adipose tissue ST2+ T regulatory cells and ameliorates adipose tissue inflammation and insulin resistance. J Immunol 194:4777–4783

    Article  CAS  PubMed  Google Scholar 

  • Heilbronn LK, Campbell LV (2008) Adipose tissue macrophages, low grade inflammation and insulin resistance in human obesity. Curr Pharm Des 14:1225–1230

    Article  CAS  PubMed  Google Scholar 

  • Hevener AL, Olefsky JM, Reichart D, Nguyen MT, Bandyopadyhay G, Leung HY, Watt MJ, Benner C, Febbraio MA, Nguyen AK et al (2007) Macrophage PPAR gamma is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones. J Clin Invest 117:1658–1669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Holland WL, Bikman BT, Wang LP, Yuguang G, Sargent KM, Bulchand S, Knotts TA, Shui G, Clegg DJ, Wenk MR et al (2011) Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice. J Clin Invest 121:1858–1870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259:87–91

    Article  CAS  PubMed  Google Scholar 

  • Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM (1995) Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest 95:2409–2415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang Q, Niu Z, Tan J, Yang J, Liu Y, Ma H, Lee VW, Sun S, Song X, Guo M et al (2015) IL-25 elicits innate lymphoid cells and multipotent progenitor type 2 cells that reduce renal ischemic/reperfusion injury. J Am Soc Nephrol 26(9):2199–2211

    Google Scholar 

  • Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, Taskinen MR, Groop L (2001) Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 24:683–689

    Article  CAS  PubMed  Google Scholar 

  • Jackaman C, Radley-Crabb HG, Soffe Z, Shavlakadze T, Grounds MD, Nelson DJ (2013) Targeting macrophages rescues age-related immune deficiencies in C57 BL/6J geriatric mice. Aging Cell 12:345–357

    Article  CAS  PubMed  Google Scholar 

  • Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K et al (2006) MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 116:1494–1505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kelley DE, Mokan M, Simoneau JA, Mandarino LJ (1993) Interaction between glucose and free fatty acid metabolism in human skeletal muscle. J Clin Invest 92:91–98

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kelly J, Khan AA, Yin J, Ferguson TA, Apte RS (2007) Senescence regulates macrophage activation and angiogenic fate at sites of tissue injury in mice. J Clin Invest 117:3421–3426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khan T, Muise ES, Iyengar P, Wang ZV, Chandalia M, Abate N, Zhang BB, Bonaldo P, Chua S, Scherer PE (2009) Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Mol Cell Biol 29:1575–1591

    Article  CAS  PubMed  Google Scholar 

  • Kita S, Maeda N, Shimomura I (2019) Interorgan communication by exosomes, adipose tissue, and adiponectin in metabolic syndrome. J Clin Invest 129:4041–4049

    Article  PubMed  PubMed Central  Google Scholar 

  • Kohlgruber AC, Gal-Oz ST, LaMarche NM, Shimazaki M, Duquette D, Koay HF, Nguyen HN, Mina AI, Paras T, Tavakkoli A et al (2018) Gammadelta T cells producing interleukin-17A regulate adipose regulatory T cell homeostasis and thermogenesis. Nat Immunol 19:464–474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kolodin D, van Panhuys N, Li C, Magnuson AM, Cipolletta D, Miller CM, Wagers A, Germain RN, Benoist C, Mathis D (2015) Antigen-and cytokine-driven accumulation of regulatory T cells in visceral adipose tissue of lean mice. Cell Metab 21:543–557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kong X, Yao T, Zhou P, Kazak L, Tenen D, Lyubetskaya A, Dawes BA, Tsai L, Kahn BB, Spiegelman BM et al (2018) Brown adipose tissue controls skeletal muscle function via the secretion of myostatin. Cell Metab 28:631–643.e633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • La Cava A (2017) Leptin in inflammation and autoimmunity. Cytokine 98:51–58

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lam QL, Liu S, Cao X, Lu L (2006) Involvement of leptin signaling in the survival and maturation of bone marrow-derived dendritic cells. Eur J Immunol 36:3118–3130

    Article  CAS  PubMed  Google Scholar 

  • Large V, Reynisdottir S, Langin D, Fredby K, Klannemark M, Holm C, Arner P (1999) Decreased expression and function of adipocyte hormone-sensitive lipase in subcutaneous fat cells of obese subjects. J Lipid Res 40:2059–2066

    Article  CAS  PubMed  Google Scholar 

  • Lee MW, Odegaard JI, Mukundan L, Qiu Y, Molofsky AB, Nussbaum JC, Yun K, Locksley RM, Chawla A (2015) Activated type 2 innate lymphoid cells regulate beige fat biogenesis. Cell 160:74–87

    Article  CAS  PubMed  Google Scholar 

  • Li C, DiSpirito JR, Zemmour D, Spallanzani RG, Kuswanto W, Benoist C, Mathis D (2018) TCR transgenic mice reveal stepwise, multi-site acquisition of the distinctive fat-Treg phenotype. Cell 174:285–299.e212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu R, Nikolajczyk BS (2019) Tissue immune cells fuel obesity-associated inflammation in adipose tissue and beyond. Front Immunol 10:1587

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Loffreda S, Yang SQ, Lin HZ, Karp CL, Brengman ML, Wang DJ, Klein AS, Bulkley GB, Bao C, Noble PW et al (1998) Leptin regulates proinflammatory immune responses. FASEB J 12:57–65

    Article  CAS  PubMed  Google Scholar 

  • Lu L, Ma J, Li Z, Lan Q, Chen M, Liu Y, Xia Z, Wang J, Han Y, Shi W et al (2011) All-trans retinoic acid promotes TGF-beta-induced Tregs via histone modification but not DNA demethylation on Foxp3 gene locus. PLoS One 6:e24590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu L, Lan Q, Li Z, Zhou X, Gu J, Li Q, Wang J, Chen M, Liu Y, Shen Y et al (2014) Critical role of all-trans retinoic acid in stabilizing human natural regulatory T cells under inflammatory conditions. Proc Natl Acad Sci U S A 111:E3432–E3440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lucca LE, Dominguez-Villar M (2020) Modulation of regulatory T cell function and stability by co-inhibitory receptors. Nat Rev Immunol 20:680

    Article  CAS  PubMed  Google Scholar 

  • Lumeng CN, Bodzin JL, Saltiel AR (2007a) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117:175–184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lumeng CN, Deyoung SM, Bodzin JL, Saltiel AR (2007b) Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes 56:16–23

    Article  CAS  PubMed  Google Scholar 

  • Luo Y, Liu M (2016) Adiponectin: a versatile player of innate immunity. J Mol Cell Biol 8:120–128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • MacDougald OA, Burant CF (2007) The rapidly expanding family of adipokines. Cell Metab 6:159–161

    Article  CAS  PubMed  Google Scholar 

  • Maeda Y, Nishikawa H, Sugiyama D, Ha D, Hamaguchi M, Saito T, Nishioka M, Wing JB, Adeegbe D, Katayama I et al (2014) Detection of self-reactive CD8(+) T cells with an anergic phenotype in healthy individuals. Science 346:1536–1540

    Article  CAS  PubMed  Google Scholar 

  • Mancuso P, McNish RW, Peters-Golden M, Brock TG (2001) Evaluation of phagocytosis and arachidonate metabolism by alveolar macrophages and recruited neutrophils from F344xBN rats of different ages. Mech Ageing Dev 122:1899–1913

    Article  CAS  PubMed  Google Scholar 

  • van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, Schrauwen P, Teule GJ (2009) Cold-activated brown adipose tissue in healthy men. N Engl J Med 360:1500–1508

    Article  PubMed  Google Scholar 

  • McLaughlin T, Liu LF, Lamendola C, Shen L, Morton J, Rivas H, Winer D, Tolentino L, Choi O, Zhang H et al (2014) T-cell profile in adipose tissue is associated with insulin resistance and systemic inflammation in humans. Arterioscler Thromb Vasc Biol 34:2637–2643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miller GD (2010) Improved nutrient intake in older obese adults undergoing a structured diet and exercise intentional weight loss program. J Nutr Health Aging 14:461–466

    Article  CAS  PubMed  Google Scholar 

  • Molofsky AB, Nussbaum JC, Liang HE, Van Dyken SJ, Cheng LE, Mohapatra A, Chawla A, Locksley RM (2013) Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J Exp Med 210:535–549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Molofsky AB, Savage AK, Locksley RM (2015) Interleukin-33 in tissue homeostasis, injury, and inflammation. Immunity 42:1005–1019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moon HS, Dalamaga M, Kim SY, Polyzos SA, Hamnvik OP, Magkos F, Paruthi J, Mantzoros CS (2013) Leptin’s role in lipodystrophic and nonlipodystrophic insulin-resistant and diabetic individuals. Endocr Rev 34:377–412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Muller S, Kulenkampff E, Wolfrum C (2016) Adipose tissue stem cells. Handb Exp Pharmacol 233:251–263

    Article  CAS  PubMed  Google Scholar 

  • Murai M, Turovskaya O, Kim G, Madan R, Karp CL, Cheroutre H, Kronenberg M (2009) Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nat Immunol 10:1178–1184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Myers MG Jr (2004) Leptin receptor signaling and the regulation of mammalian physiology. Recent Prog Horm Res 59:287–304

    Article  CAS  PubMed  Google Scholar 

  • Naylor C, Petri WA Jr (2016) Leptin regulation of immune responses. Trends Mol Med 22:88–98

    Article  CAS  PubMed  Google Scholar 

  • Nussbaum JC, Van Dyken SJ, von Moltke J, Cheng LE, Mohapatra A, Molofsky AB, Thornton EE, Krummel MF, Chawla A, Liang HE et al (2013) Type 2 innate lymphoid cells control eosinophil homeostasis. Nature 502:245–248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ogden CL, Carroll MD, Kit BK, Flegal KM (2014) Prevalence of childhood and adult obesity in the United States, 2011-2012. JAMA 311:806–814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Onodera T, Fukuhara A, Jang MH, Shin J, Aoi K, Kikuta J, Otsuki M, Ishii M, Shimomura I (2015) Adipose tissue macrophages induce PPARgamma-high FOXP3(+) regulatory T cells. Sci Rep 5:16801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Osborn O, Olefsky JM (2012) The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med 18:363–374

    Article  CAS  PubMed  Google Scholar 

  • Ottonello L, Gnerre P, Bertolotto M, Mancini M, Dapino P, Russo R, Garibotto G, Barreca T, Dallegri F (2004) Leptin as a uremic toxin interferes with neutrophil chemotaxis. J Am Soc Nephrol 15:2366–2372

    Article  CAS  PubMed  Google Scholar 

  • Pan Y, Hui X, Hoo RLC, Ye D, Chan CYC, Feng T, Wang Y, Lam KSL, Xu A (2019) Adipocyte-secreted exosomal microRNA-34a inhibits M2 macrophage polarization to promote obesity-induced adipose inflammation. J Clin Invest 129:834–849

    Article  PubMed  PubMed Central  Google Scholar 

  • Perez-Perez A, Vilarino-Garcia T, Fernandez-Riejos P, Martin-Gonzalez J, Segura-Egea JJ, Sanchez-Margalet V (2017) Role of leptin as a link between metabolism and the immune system. Cytokine Growth Factor Rev 35:71–84

    Article  CAS  PubMed  Google Scholar 

  • Priceman SJ, Kujawski M, Shen S, Cherryholmes GA, Lee H, Zhang C, Kruper L, Mortimer J, Jove R, Riggs AD et al (2013) Regulation of adipose tissue T cell subsets by Stat3 is crucial for diet-induced obesity and insulin resistance. Proc Natl Acad Sci U S A 110:13079–13084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Quesada-Lopez T, Cereijo R, Turatsinze JV, Planavila A, Cairo M, Gavalda-Navarro A, Peyrou M, Moure R, Iglesias R, Giralt M et al (2016) The lipid sensor GPR120 promotes brown fat activation and FGF21 release from adipocytes. Nat Commun 7:13479

    Article  PubMed  PubMed Central  Google Scholar 

  • Ramalingam R, Larmonier CB, Thurston RD, Midura-Kiela MT, Zheng SG, Ghishan FK, Kiela PR (2012) Dendritic cell-specific disruption of TGF-beta receptor II leads to altered regulatory T cell phenotype and spontaneous multiorgan autoimmunity. J Immunol 189:3878–3893

    Article  CAS  PubMed  Google Scholar 

  • Reynisdottir S, Ellerfeldt K, Wahrenberg H, Lithell H, Arner P (1994) Multiple lipolysis defects in the insulin resistance (metabolic) syndrome. J Clin Invest 93:2590–2599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ricardo-Gonzalez RR, Red Eagle A, Odegaard JI, Jouihan H, Morel CR, Heredia JE, Mukundan L, Wu D, Locksley RM, Chawla A (2010) IL-4/STAT6 immune axis regulates peripheral nutrient metabolism and insulin sensitivity. Proc Natl Acad Sci U S A 107:22617–22622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rotter V, Nagaev I, Smith U (2003) 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 278:45777–45784

    Article  CAS  PubMed  Google Scholar 

  • Sabio G, Das M, Mora A, Zhang Z, Jun JY, Ko HJ, Barrett T, Kim JK, Davis RJ (2008) A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science 322:1539–1543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K, Yoneshiro T, Nio-Kobayashi J, Iwanaga T, Miyagawa M, Kameya T, Nakada K et al (2009) High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 58:1526–1531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A, Bluestone JA (2000) B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12:431–440

    Article  CAS  PubMed  Google Scholar 

  • Samms RJ, Smith DP, Cheng CC, Antonellis PP, Perfield JW 2nd, Kharitonenkov A, Gimeno RE, Adams AC (2015) Discrete aspects of FGF21 in vivo pharmacology do not require UCP1. Cell Rep 11:991–999

    Article  CAS  PubMed  Google Scholar 

  • Sano H, Kane S, Sano E, Miinea CP, Asara JM, Lane WS, Garner CW, Lienhard GE (2003) Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation. J Biol Chem 278:14599–14602

    Article  CAS  PubMed  Google Scholar 

  • Scheele C, Wolfrum C (2020) Brown adipose crosstalk in tissue plasticity and human metabolism. Endocr Rev 41:53

    Article  Google Scholar 

  • Scheja L, Heeren J (2019) The endocrine function of adipose tissues in health and cardiometabolic disease. Nat Rev Endocrinol 15:507–524

    Article  CAS  PubMed  Google Scholar 

  • Schwartz MA, Schaller MD, Ginsberg MH (1995) Integrins: emerging paradigms of signal transduction. Annu Rev Cell Dev Biol 11:549–599

    Article  CAS  PubMed  Google Scholar 

  • Shulman GI (2000) Cellular mechanisms of insulin resistance. J Clin Invest 106:171–176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sokolowska E, Blachnio-Zabielska A (2019) The role of ceramides in insulin resistance. Front Endocrinol 10:577

    Article  Google Scholar 

  • Spallanzani RG, Zemmour D, Xiao T, Jayewickreme T, Li C, Bryce PJ, Benoist C, Mathis D (2019) Distinct immunocyte-promoting and adipocyte-generating stromal components coordinate adipose tissue immune and metabolic tenors. Sci immunol 4:eaaw3658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stanford KI, Lynes MD, Takahashi H, Baer LA, Arts PJ, May FJ, Lehnig AC, Middelbeek RJW, Richard JJ, So K et al (2018) 12,13-diHOME: an exercise-induced lipokine that increases skeletal muscle fatty acid uptake. Cell Metab 27:1357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Steculorum SM, Ruud J, Karakasilioti I, Backes H, Engstrom Ruud L, Timper K, Hess ME, Tsaousidou E, Mauer J, Vogt MC et al (2016) AgRP neurons control systemic insulin sensitivity via myostatin expression in Brown adipose tissue. Cell 165:125–138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sullivan JM, Höllbacher B, Campbell DJ (2019) Cutting edge: dynamic expression of Id3 defines the stepwise differentiation of tissue-resident regulatory T cells. J Immunol 202:31–36

    Article  CAS  PubMed  Google Scholar 

  • Tam CS, Viardot A, Clement K, Tordjman J, Tonks K, Greenfield JR, Campbell LV, Samocha-Bonet D, Heilbronn LK (2010) Short-term overfeeding may induce peripheral insulin resistance without altering subcutaneous adipose tissue macrophages in humans. Diabetes 59:2164–2170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tchkonia T, Thomou T, Zhu Y, Karagiannides I, Pothoulakis C, Jensen MD, Kirkland JL (2013) Mechanisms and metabolic implications of regional differences among fat depots. Cell Metab 17:644–656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thomou T, Mori MA, Dreyfuss JM, Konishi M, Sakaguchi M, Wolfrum C, Rao TN, Winnay JN, Garcia-Martin R, Grinspoon SK et al (2017) Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature 542:450–455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Varga T, Czimmerer Z, Nagy L (2011) PPARs are a unique set of fatty acid regulated transcription factors controlling both lipid metabolism and inflammation. Biochim Biophys Acta 1812:1007–1022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vasanthakumar A, Moro K, Xin A, Liao Y, Gloury R, Kawamoto S, Fagarasan S, Mielke LA, Afshar-Sterle S, Masters SL (2015) The transcriptional regulators IRF4, BATF and IL-33 orchestrate development and maintenance of adipose tissue–resident regulatory T cells. Nat Immunol 16:276

    Article  CAS  PubMed  Google Scholar 

  • Veniant MM, Sivits G, Helmering J, Komorowski R, Lee J, Fan W, Moyer C, Lloyd DJ (2015) Pharmacologic effects of FGF21 are independent of the “Browning” of white adipose tissue. Cell Metab 21:731–738

    Article  CAS  PubMed  Google Scholar 

  • Vijay J et al (2020) Single-cell analysis of human adipose tissue identifies depot- and disease-specific cell types. Nat Metab 2:97–109

    Article  PubMed  Google Scholar 

  • Wang R, Yang F, Qing L, Huang R, Liu Q, Li X (2019) Decreased serum neuregulin 4 levels associated with non-alcoholic fatty liver disease in children with obesity. Clin Obes 9:e12289

    Article  PubMed  Google Scholar 

  • Wei J, Duramad O, Perng OA, Reiner SL, Liu YJ, Qin FX (2007) Antagonistic nature of T helper 1/2 developmental programs in opposing peripheral induction of Foxp3+ regulatory T cells. Proc Natl Acad Sci U S A 104:18169–18174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796–1808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weisberg SP, Hunter D, Huber R, Lemieux J, Slaymaker S, Vaddi K, Charo I, Leibel RL, Ferrante AW Jr (2006) CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest 116:115–124

    Article  CAS  PubMed  Google Scholar 

  • Wentworth JM, Naselli G, Brown WA, Doyle L, Phipson B, Smyth GK, Wabitsch M, O’Brien PE, Harrison LC (2010) Pro-inflammatory CD11c+ CD206+ adipose tissue macrophages are associated with insulin resistance in human obesity. Diabetes 59:1648–1656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Winer S, Chan Y, Paltser G, Truong D, Tsui H, Bahrami J, Dorfman R, Wang Y, Zielenski J, Mastronardi F et al (2009) Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med 15:921–929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wolf AM, Wolf D, Rumpold H, Enrich B, Tilg H (2004) Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1RA in human leukocytes. Biochem Biophys Res Commun 323:630–635

    Article  CAS  PubMed  Google Scholar 

  • Wu D, Han JM, Yu X, Lam AJ, Hoeppli RE, Pesenacker AM, Huang Q, Chen V, Speake C, Yorke E (2019) Characterization of regulatory T cells in obese omental adipose tissue in humans. Eur J Immunol 49:336–347

    Article  CAS  PubMed  Google Scholar 

  • Xu K, Geczy CL (2000) IFN-gamma and TNF regulate macrophage expression of the chemotactic S100 protein S100A8. J Immunol 164:4916–4923

    Article  CAS  PubMed  Google Scholar 

  • Xuan D, Han Q, Tu Q, Zhang L, Yu L, Murry D, Tu T, Tang Y, Lian JB, Stein GS et al (2016) Epigenetic modulation in periodontitis: interaction of adiponectin and JMJD3-IRF4 Axis in macrophages. J Cell Physiol 231:1090–1096

    Article  CAS  PubMed  Google Scholar 

  • Yamaguchi T, Kishi A, Osaki M, Morikawa H, Prieto-Martin P, Wing K, Saito T, Sakaguchi S (2013) Construction of self-recognizing regulatory T cells from conventional T cells by controlling CTLA-4 and IL-2 expression. Proc Natl Acad Sci U S A 110:E2116–E2125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang B-H, Wang K, Wan S, Liang Y, Yuan X, Dong Y, Cho S, Xu W, Jepsen K, Feng G-S (2019) TCF1 and LEF1 control Treg competitive survival and Tfr development to prevent autoimmune diseases. Cell Rep 27:3629–3645.e3626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yore MM, Syed I, Moraes-Vieira PM, Zhang T, Herman MA, Homan EA, Patel RT, Lee J, Chen S, Peroni OD et al (2014) Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell 159:318–332

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu QN, Guo YB, Li X, Li CL, Tan WP, Fan XL, Qin ZL, Chen D, Wen WP, Zheng SG et al (2018) ILC2 frequency and activity are inhibited by glucocorticoid treatment via STAT pathway in patients with asthma. Allergy 73:1860–1870

    Article  CAS  PubMed  Google Scholar 

  • Zarkesh-Esfahani H, Pockley G, Metcalfe RA, Bidlingmaier M, Wu Z, Ajami A, Weetman AP, Strasburger CJ, Ross RJ (2001) High-dose leptin activates human leukocytes via receptor expression on monocytes. J Immunol 167:4593–4599

    Article  CAS  PubMed  Google Scholar 

  • Zeyda M, Farmer D, Todoric J, Aszmann O, Speiser M, Györi G, Zlabinger G, Stulnig T (2007) Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production. Int J Obes 31:1420–1428

    Article  CAS  Google Scholar 

  • Zheng SG, Gray JD, Ohtsuka K, Yamagiwa S, Horwitz DA (2002) Generation ex vivo of TGF-beta-producing regulatory T cells from CD4+CD25- precursors. J Immunol 169:4183–4189

    Article  CAS  PubMed  Google Scholar 

  • Zheng SG, Wang JH, Gray JD, Soucier H, Horwitz DA (2004) Natural and induced CD4+CD25+ cells educate CD4+CD25- cells to develop suppressive activity: the role of IL-2, TGF-beta, and IL-10. J Immunol 172:5213–5221

    Article  CAS  PubMed  Google Scholar 

  • Zheng SG, Wang JH, Stohl W, Kim KS, Gray JD, Horwitz DA (2006) TGF-beta requires CTLA-4 early after T cell activation to induce FoxP3 and generate adaptive CD4+CD25+ regulatory cells. J Immunol 176:3321–3329

    Article  CAS  PubMed  Google Scholar 

  • Zhong J, Rao X, Braunstein Z, Taylor A, Narula V, Hazey J, Mikami D, Needleman B, Rutsky J, Sun Q et al (2014) T-cell costimulation protects obesity-induced adipose inflammation and insulin resistance. Diabetes 63:1289–1302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou Y, Salker MS, Walker B, Munzer P, Borst O, Gawaz M, Gulbins E, Singh Y, Lang F (2016) Acid sphingomyelinase (ASM) is a negative regulator of regulatory T cell (Treg) development. Cell Physiol Biochem 39:985–995

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA

    David Bradley, Dharti Shantaram, Alan Smith & Willa A. Hsueh

Authors
  1. David Bradley
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dharti Shantaram
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alan Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Willa A. Hsueh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David Bradley .

Editor information

Editors and Affiliations

  1. Department of Internal Medicine, Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH, USA

    Song-Guo Zheng

Ethics declarations

None

Rights and permissions

Reprints and permissions

Copyright information

© 2021 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Bradley, D., Shantaram, D., Smith, A., Hsueh, W.A. (2021). Adipose Tissue T Regulatory Cells: Implications for Health and Disease. In: Zheng, SG. (eds) T Regulatory Cells in Human Health and Diseases. Advances in Experimental Medicine and Biology, vol 1278. Springer, Singapore. https://doi.org/10.1007/978-981-15-6407-9_8

Download citation

Publish with us

Policies and ethics

Search

Navigation