Comprehensive Physiology Wiley Online Library

Adaptive Immunity and Metabolic Health: Harmony Becomes Dissonant in Obesity and Aging

Full Article on Wiley Online Library



ABSTRACT

Adipose tissue (AT) is the primary energy reservoir organ, and thereby plays a critical role in energy homeostasis and regulation of metabolism. AT expands in response to chronic overnutrition or aging and becomes a major source of inflammation that has marked influence on systemic metabolism. The chronic, sterile inflammation that occurs in the AT during the development of obesity or in aging contributes to onset of devastating diseases such as insulin resistance, diabetes, and cardiovascular pathologies. Numerous studies have shown that inflammation in the visceral AT of humans and animals is a critical trigger for the development of metabolic syndrome. This work underscores the well‐supported conclusion that the inflammatory immune response and metabolic pathways in the AT are tightly interwoven by multiple layers of relatively conserved mechanisms. During the development of diet‐induced obesity or age‐associated adiposity, cells of the innate and the adaptive immune systems infiltrate and proliferate in the AT. Macrophages, which dominate AT‐associated immune cells in mouse models of obesity, but are less dominant in obese people, have been studied extensively. However, cells of the adaptive immune system, including T cells and B cells, contribute significantly to AT inflammation, perhaps more in humans than in mice. Lymphocytes regulate recruitment of innate immune cells into AT, and produce cytokines that influence the helpful‐to‐harmful inflammatory balance that, in turn, regulates organismal metabolism. This review describes inflammation, or more precisely, metabolic inflammation (metaflammation) with an eye toward the AT and the roles lymphocytes play in regulation of systemic metabolism during obesity and aging. © 2017 American Physiological Society. Compr Physiol 7:1307‐1337, 2017.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1. Obese AT is a major source of inflammation and metabolic dysregulation. Chronic over nutrition causes the AT to undergo remodeling and expansion to store excess lipids and to protect against obesity‐associated metabolic dysregulation. When AT is overwhelmed due to pathological and excessive accumulation of lipids, it results in chronic inflammation and metabolic pathology. Pathologically obese AT is characterized by: (A) chronic inflammation, as evidenced by an increased number and frequency of immune cells from both the innate and the adaptive systems that results in an elevation of proinflammatory cytokines and an imbalance between a pro‐ and anti‐inflammatory responses, favoring a more proinflammatory environment; (B) Insulin resistance, resulting in decreased glucose intake and insulin sensitivity, and increased peripheral insulin resistance that sets the stage for development of T2D; (C) Adipocyte dysfunction, resulting in an increase in oxidative stress, promoting free radicle‐mediated damage of cellular proteins and organelles, causing ER stress/mitochondrial dysfunction, eventually leading to adipocyte necrosis and fibrosis; (D) Metabolic syndrome, characterized by hypertension, hypercholesterolemia with low HDL and high LDL and triglycerides. Apart from the immune cells that are shown in the image, several other immune cell types, such as neutrophils, NK cells, iNKT cells infiltrate the obese and inflamed AT.
Figure 2. Figure 2. Effect of physiological hyperglycemia on cytokine production by T cells stimulated in the context of PBMCs. PBMCs from 11 subjects (6 healthy, 2 pre‐T2D, 3 T2D) were stimulated with αCD3/αCD28 for 68 h in low glucose (100 mg/dL) or high glucose (200 mg/dL). High glucose modestly but significantly increased IL‐17A (***P< 0.0001) and IFNγ (13 %, P = 0.02) secretion by stimulated PBMCs as compared to low glucose. Average among samples is indicated by bold line in each panel. Power was insufficient for group‐by‐group analysis although response within groups was especially heterogeneous for TNFα and IL‐6.
Figure 3. Figure 3. Immune cell infiltrates promote AT inflammation. The quantity and types of immune cells in AT are influenced by obesity and the associated metabolic dysregulation. Obese AT is characterized by increased numbers and (especially in mice) proportions of macrophages. Macrophages also shift to a proinflammatory phenotype, resulting in the production of cytokines such as IL‐1β, IL‐6, TNFα, and chemokines such as MCP1. Adipocytes, macrophages and other cells of the innate immune system, along with the B cells that infiltrate the obese AT, can act as antigen presenting cells to activate CD4+ and CD8+ T cells. Obese AT has increased Th17 cells, mostly notably in humans, which secrete proinflammatory cytokines such as IL‐17A/F and IL‐21. This is in contrast to lean AT that has relatively high frequencies of regulatory T cells (Tregs) that suppress immune response to maintain homeostasis. Adipocyte cytokines, or adipokines such as leptin, increase in obesity, can promote an imbalance in Th17/Treg and also Th1/Th2 responses. Obese AT has a decline in B regulatory and B1‐a B cells, which results in a decline in anti‐inflammatory cytokine such as IL‐10. An increase in the frequency of MAITs results in increased production of IL‐17A. Similarly, an increase in NK cell proliferation in obese AT promotes IFNγ production and promotes the differentiation and accumulation of inflammatory macrophages.
Figure 4. Figure 4. Aging promotes adipocyte dysfunction. Aging AT is under a state of chronic sterile inflammation, which falls broadly under the term inflammaging. Environment, genetics, and the process of aging itself regulate the development of inflammation in the adipose. Inflammaging results in infiltration of proinflammatory cells such as the cytotoxic T cells (CD8+) and macrophages, along with a decline in T regulatory cells and Th2 responses. Accumulation of toxic metabolites of free fatty acids and the accompanying oxidative stress causes a redox imbalance, resulting in the activation of inflammatory pathways such as the MAPK and IKK leading to the activation of the master inflammatory regulator NF‐κB. The diverse proinflammatory environment, along with the higher proinflammatory cytokines and chemokines promote a stress response, resulting in cell cycle arrest and eventually apoptosis of the adipocyte.


Figure 1. Obese AT is a major source of inflammation and metabolic dysregulation. Chronic over nutrition causes the AT to undergo remodeling and expansion to store excess lipids and to protect against obesity‐associated metabolic dysregulation. When AT is overwhelmed due to pathological and excessive accumulation of lipids, it results in chronic inflammation and metabolic pathology. Pathologically obese AT is characterized by: (A) chronic inflammation, as evidenced by an increased number and frequency of immune cells from both the innate and the adaptive systems that results in an elevation of proinflammatory cytokines and an imbalance between a pro‐ and anti‐inflammatory responses, favoring a more proinflammatory environment; (B) Insulin resistance, resulting in decreased glucose intake and insulin sensitivity, and increased peripheral insulin resistance that sets the stage for development of T2D; (C) Adipocyte dysfunction, resulting in an increase in oxidative stress, promoting free radicle‐mediated damage of cellular proteins and organelles, causing ER stress/mitochondrial dysfunction, eventually leading to adipocyte necrosis and fibrosis; (D) Metabolic syndrome, characterized by hypertension, hypercholesterolemia with low HDL and high LDL and triglycerides. Apart from the immune cells that are shown in the image, several other immune cell types, such as neutrophils, NK cells, iNKT cells infiltrate the obese and inflamed AT.


Figure 2. Effect of physiological hyperglycemia on cytokine production by T cells stimulated in the context of PBMCs. PBMCs from 11 subjects (6 healthy, 2 pre‐T2D, 3 T2D) were stimulated with αCD3/αCD28 for 68 h in low glucose (100 mg/dL) or high glucose (200 mg/dL). High glucose modestly but significantly increased IL‐17A (***P< 0.0001) and IFNγ (13 %, P = 0.02) secretion by stimulated PBMCs as compared to low glucose. Average among samples is indicated by bold line in each panel. Power was insufficient for group‐by‐group analysis although response within groups was especially heterogeneous for TNFα and IL‐6.


Figure 3. Immune cell infiltrates promote AT inflammation. The quantity and types of immune cells in AT are influenced by obesity and the associated metabolic dysregulation. Obese AT is characterized by increased numbers and (especially in mice) proportions of macrophages. Macrophages also shift to a proinflammatory phenotype, resulting in the production of cytokines such as IL‐1β, IL‐6, TNFα, and chemokines such as MCP1. Adipocytes, macrophages and other cells of the innate immune system, along with the B cells that infiltrate the obese AT, can act as antigen presenting cells to activate CD4+ and CD8+ T cells. Obese AT has increased Th17 cells, mostly notably in humans, which secrete proinflammatory cytokines such as IL‐17A/F and IL‐21. This is in contrast to lean AT that has relatively high frequencies of regulatory T cells (Tregs) that suppress immune response to maintain homeostasis. Adipocyte cytokines, or adipokines such as leptin, increase in obesity, can promote an imbalance in Th17/Treg and also Th1/Th2 responses. Obese AT has a decline in B regulatory and B1‐a B cells, which results in a decline in anti‐inflammatory cytokine such as IL‐10. An increase in the frequency of MAITs results in increased production of IL‐17A. Similarly, an increase in NK cell proliferation in obese AT promotes IFNγ production and promotes the differentiation and accumulation of inflammatory macrophages.


Figure 4. Aging promotes adipocyte dysfunction. Aging AT is under a state of chronic sterile inflammation, which falls broadly under the term inflammaging. Environment, genetics, and the process of aging itself regulate the development of inflammation in the adipose. Inflammaging results in infiltration of proinflammatory cells such as the cytotoxic T cells (CD8+) and macrophages, along with a decline in T regulatory cells and Th2 responses. Accumulation of toxic metabolites of free fatty acids and the accompanying oxidative stress causes a redox imbalance, resulting in the activation of inflammatory pathways such as the MAPK and IKK leading to the activation of the master inflammatory regulator NF‐κB. The diverse proinflammatory environment, along with the higher proinflammatory cytokines and chemokines promote a stress response, resulting in cell cycle arrest and eventually apoptosis of the adipocyte.
References
 1.Acedo SC, Gotardo EM, Lacerda JM, de Oliveira CC, de Oliveira CP, Gambero A. Perinodal adipose tissue and mesenteric lymph node activation during reactivated TNBS‐colitis in rats. Dig Dis Sci 56: 2545‐2552, 2011.
 2.Agrawal S, Gollapudi S, Su H, Gupta S. Leptin activates human B cells to secrete TNF‐alpha, IL‐6, and IL‐10 via JAK2/STAT3 and p38MAPK/ERK1/2 signaling pathway. J Clin Immunol 31: 472‐478, 2011.
 3.Ahmed M, Gaffen SL. IL‐17 in obesity and adipogenesis. Cytokine Growth Factor Rev 21: 449‐453, 2010.
 4.Akira S, Takeda K. Toll‐like receptor signalling. Nat Rev Immunol 4: 499‐511, 2004.
 5.Alvarez‐Rodriguez L, Lopez‐Hoyos M, Munoz‐Cacho P, Martinez‐Taboada VM. Aging is associated with circulating cytokine dysregulation. Cell Immunol 273: 124‐132, 2012.
 6.Anderson EK, Gutierrez DA, Kennedy A, Hasty AH. Weight cycling increases T‐cell accumulation in adipose tissue and impairs systemic glucose tolerance. Diabetes 62: 3180‐3188, 2013.
 7.Anderson‐Baucum EK, Major AS, Hasty AH. A possible secondary immune response in adipose tissue during weight cycling: The ups and downs of yo‐yo dieting. Adipocyte 3: 141‐145, 2014.
 8.Apovian CM, Bigornia S, Mott M, Meyers MR, Ulloor J, Gagua M, McDonnell M, Hess D, Joseph L, Gokce N. Adipose macrophage infiltration is associated with insulin resistance and vascular endothelial dysfunction in obese subjects. Arterioscler Thromb Vasc Biol 28: 1654‐1659, 2008.
 9.Apovian CM, Istfan NW. Obesity: Guidelines, best practices, new research. Endocrinol Metab Clin North Am 45: xvii‐xviii, 2016.
 10.Badawi A, Klip A, Haddad P, Cole DE, Bailo BG, El‐Sohemy A, Karmali M. Type 2 diabetes mellitus and inflammation: Prospects for biomarkers of risk and nutritional intervention. Diabetes Metab Syndr Obes 3: 173‐186, 2010.
 11.Balagopal P, Graham TE, Kahn BB, Altomare A, Funanage V, George D. Reduction of elevated serum retinol binding protein in obese children by lifestyle intervention: Association with subclinical inflammation. J Clin Endocrinol Metab 92: 1971‐1974, 2007.
 12.Bapat SP, Myoung SJ, Fang S, Liu S, Zhang Y, Cheng A, Zhou C, Liang Y, LeBlanc M, Liddle C, Atkins AR, Yu RT, Downes M, Evans RM, Zheng Y. Depletion of fat‐resident Treg cells prevents age‐associated insulin resistance. Nature 528: 137‐141, 2015.
 13.Barbosa‐da‐Silva S, Fraulob‐Aquino JC, Lopes JR, Mandarim‐de‐Lacerda CA, Aguila MB. Weight cycling enhances adipose tissue inflammatory responses in male mice. PLoS One 7: e39837, 2012.
 14.Bartness TJ, Song CK. Brain‐adipose tissue neural crosstalk. Physiol Behav 91: 343‐351, 2007.
 15.Batterham RL, Cummings DE. Mechanisms of diabetes improvement following bariatric/metabolic surgery. Diabetes Care 39: 893‐901, 2016.
 16.Baylis D, Bartlett DB, Patel HP, Roberts HC. Understanding how we age: Insights into inflammaging. Longev Healthspan 2: 8, 2013.
 17.Beelen RH. Role of omental milky spots in the local immune response. Lancet 339: 689, 1992.
 18.Benezech C, Luu NT, Walker JA, Kruglov AA, Loo Y, Nakamura K, Zhang Y, Nayar S, Jones LH, Flores‐Langarica A, McIntosh A, Marshall J, Barone F, Besra G, Miles K, Allen JE, Gray M, Kollias G, Cunningham AF, Withers DR, Toellner KM, Jones ND, Veldhoen M, Nedospasov SA, McKenzie AN, Caamano JH. Inflammation‐induced formation of fat‐associated lymphoid clusters. Nat Immunol 16: 819‐828, 2015.
 19.Berberich S, Dahne S, Schippers A, Peters T, Muller W, Kremmer E, Forster R, Pabst O. Differential molecular and anatomical basis for B cell migration into the peritoneal cavity and omental milky spots. J Immunol 180: 2196‐2203, 2008.
 20.Berry DC, Stenesen D, Zeve D, Graff JM. The developmental origins of adipose tissue. Development 140: 3939‐3949, 2013.
 21.Bertola A, Ciucci T, Rousseau D, Bourlier V, Duffaut C, Bonnafous S, Blin‐Wakkach C, Anty R, Iannelli A, Gugenheim J, Tran A, Bouloumie A, Gual P, Wakkach A. Identification of adipose tissue dendritic cells correlated with obesity‐associated insulin‐resistance and inducing Th17 responses in mice and patients. Diabetes 61: 2238‐2247, 2012.
 22.Blackman MA, Woodland DL. The narrowing of the CD8 T cell repertoire in old age. Curr Opin Immunol 23: 537‐542, 2011.
 23.Bluher M. The distinction of metabolically ‘healthy’ from ‘unhealthy’ obese individuals. Curr Opin Lipidol 21: 38‐43, 2010.
 24.Brestoff JR, Kim BS, Saenz SA, Stine RR, Monticelli LA, Sonnenberg GF, Thome JJ, Farber DL, Lutfy K, Seale P, Artis D. Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature 519: 242‐246, 2015.
 25.Burrill JS, Long EK, Reilly B, Deng Y, Armitage IM, Scherer PE, Bernlohr DA. Inflammation and ER stress regulate branched‐chain amino acid uptake and metabolism in adipocytes. Mol Endocrinol 29: 411‐420, 2015.
 26.Busse S, Steiner J, Micheel J, Dobrowolny H, Mawrin C, Krause TJ, Adamaszek M, Bogerts B, Bommhardt U, Hartig R, Busse M. Age‐related increase of VGF‐expression in T lymphocytes. Aging (Albany NY) 6: 440‐453, 2014.
 27.Carlow DA, Gold MR, Ziltener HJ. Lymphocytes in the peritoneum home to the omentum and are activated by resident dendritic cells. J Immunol 183: 1155‐1165, 2009.
 28.Carolan E, Tobin LM, Mangan BA, Corrigan M, Gaoatswe G, Byrne G, Geoghegan J, Cody D, O'Connell J, Winter DC, Doherty DG, Lynch L, O'Shea D, Hogan AE. Altered distribution and increased IL‐17 production by mucosal‐associated invariant T cells in adult and childhood obesity. J Immunol 194: 5775‐5780, 2015.
 29.Cefalu WT, Rubino F, Cummings DE. Metabolic surgery for type 2 diabetes: Changing the landscape of diabetes care. Diabetes Care 39: 857‐860, 2016.
 30.Cheng X, Folco EJ, Shimizu K, Libby P. Adiponectin induces pro‐inflammatory programs in human macrophages and CD4+ T cells. J Biol Chem 287: 36896‐36904, 2012.
 31.Chikka MR, McCabe DD, Tyra HM, Rutkowski DT. C/EBP homologous protein (CHOP) contributes to suppression of metabolic genes during endoplasmic reticulum stress in the liver. J Biol Chem 288: 4405‐4415, 2013.
 32.Chimen M, McGettrick HM, Apta B, Kuravi SJ, Yates CM, Kennedy A, Odedra A, Alassiri M, Harrison M, Martin A, Barone F, Nayar S, Hitchcock JR, Cunningham AF, Raza K, Filer A, Copland DA, Dick AD, Robinson J, Kalia N, Walker LS, Buckley CD, Nash GB, Narendran P, Rainger GE. Homeostatic regulation of T cell trafficking by a B cell‐derived peptide is impaired in autoimmune and chronic inflammatory disease. Nat Med 21: 467‐475, 2015.
 33.Chiu BC, Martin BE, Stolberg VR, Chensue SW. Cutting edge: Central memory CD8 T cells in aged mice are virtual memory cells. J Immunol 191: 5793‐5796, 2013.
 34.Chng MH, Alonso MN, Barnes SE, Nguyen KD, Engleman EG. Adaptive immunity and antigen‐specific activation in obesity‐associated insulin resistance. Mediators Inflamm 2015: 593075, 2015.
 35.Cho KW, Morris DL, DelProposto JL, Geletka L, Zamarron B, Martinez‐Santibanez G, Meyer KA, Singer K, O'Rourke RW, Lumeng CN. An MHC II‐dependent activation loop between adipose tissue macrophages and CD4+ T cells controls obesity‐induced inflammation. Cell Rep 9: 605‐617, 2014.
 36.Choe SS, Huh JY, Hwang IJ, Kim JI, Kim JB. Adipose tissue remodeling: Its role in energy metabolism and metabolic disorders. Front Endocrinol (Lausanne) 7: 30, 2016.
 37.Chuang JC, Yu CL, Wang SR. Modulation of human lymphocyte proliferation by amino acids. Clin Exp Immunol 81: 173‐176, 1990.
 38.Cicin‐Sain L, Messaoudi I, Park B, Currier N, Planer S, Fischer M, Tackitt S, Nikolich‐Zugich D, Legasse A, Axthelm MK, Picker LJ, Mori M, Nikolich‐Zugich J. Dramatic increase in naive T cell turnover is linked to loss of naive T cells from old primates. Proc Natl Acad Sci U S A 104: 19960‐19965, 2007.
 39.Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, Wang S, Fortier M, Greenberg AS, Obin MS. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 46: 2347‐2355, 2005.
 40.Cipolletta D. Adipose tissue‐resident regulatory T cells: Phenotypic specialization, functions and therapeutic potential. Immunology 142: 517‐525, 2014.
 41.Cipolletta D, Feuerer M, Li A, Kamei N, Lee J, Shoelson SE, Benoist C, Mathis D. PPAR‐gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 486: 549‐553, 2012.
 42.Conroy MJ, Galvin KC, Kavanagh ME, Mongan AM, Doyle SL, Gilmartin N, O'Farrelly C, Reynolds JV, Lysaght J. CCR1 antagonism attenuates T cell trafficking to omentum and liver in obesity‐associated cancer. Immunol Cell Biol 94: 531‐537, 2016.
 43.Coppack SW. Pro‐inflammatory cytokines and adipose tissue. Proc Nutr Soc 60: 349‐356, 2001.
 44.Cunningham AF, Flores‐Langarica A, Bobat S, Dominguez Medina CC, Cook CN, Ross EA, Lopez‐Macias C, Henderson IR. B1b cells recognize protective antigens after natural infection and vaccination. Front Immunol 5: 535, 2014.
 45.Curat CA, 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 53: 1285‐1292, 2004.
 46.Dagarag M, Evazyan T, Rao N, Effros RB. Genetic manipulation of telomerase in HIV‐specific CD8+ T cells: Enhanced antiviral functions accompany the increased proliferative potential and telomere length stabilization. J Immunol 173: 6303‐6311, 2004.
 47.Dardenne M, Savino W, Gastinel LN, Nabarra B, Bach JF. Thymic dysfunction in the mutant diabetic (db/db) mouse. J Immunol 130: 1195‐1199, 1983.
 48.Davis KE, Neinast D, Sun K, Skiles M, Bills D, Zehr A, Zeve D, Hahner D, Cox W, Gent M, Xu Y, Wang V, Khan A, Clegg DJ. The sexually dimorphic role of adipose and adipocyte estrogen receptors in modulating adipose tissue expansion, inflammation, and fibrosis. Mol Metab 2: 227‐242, 2013.
 49.de FS, Mozaffarian D. The perfect storm: Obesity, adipocyte dysfunction, and metabolic consequences. Clin Chem 54: 945‐955, 2008.
 50.De PG, Zamboni M, Pannacciulli N, Turcato E, Giorgino F, Armellini F, Logoluso F, Sciaraffia M, Bosello O, Giorgino R. Divergent effects of short‐term, very‐low‐calorie diet on insulin‐like growth factor‐I and insulin‐like growth factor binding protein‐3 serum concentrations in premenopausal women with obesity. Obes Res 6: 408‐415, 1998.
 51.DeFuria J, Belkina AC, Jagannathan‐Bogdan M, Snyder‐Cappione J, Carr JD, Nersesova YR, Markham D, Strissel KJ, Watkins AA, Zhu M, Allen J, Bouchard J, Toraldo G, Jasuja R, Obin MS, McDonnell ME, Apovian C, Denis GV, Nikolajczyk BS. 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 110: 5133‐5138, 2013.
 52.Deiuliis J, Shah Z, Shah N, Needleman B, Mikami D, Narula V, Perry K, Hazey J, Kampfrath T, Kollengode M, Sun Q, Satoskar AR, Lumeng C, Moffatt‐Bruce S, Rajagopalan S. Visceral adipose inflammation in obesity is associated with critical alterations in tregulatory cell numbers. PLoS One 6: e16376, 2011.
 53.Deng T, Lyon CJ, Minze LJ, Lin J, Zou J, Liu JZ, Ren Y, Yin Z, Hamilton DJ, Reardon PR, Sherman V, Wang HY, Phillips KJ, Webb P, Wong ST, Wang RF, Hsueh WA. Class II major histocompatibility complex plays an essential role in obesity‐induced adipose inflammation. Cell Metab 17: 411‐422, 2013.
 54.Dock JN, Effros RB. Role of CD8 T cell replicative senescence in human aging and in HIV‐mediated immunosenescence. Aging Dis 2: 382‐397, 2011.
 55.Driskell RR, Jahoda CA, Chuong CM, Watt FM and Horsley V. Defining dermal adipose tissue. Exp Dermatol 23: 629‐631, 2014.
 56.Duan B, Morel L. Role of B‐1a cells in autoimmunity. Autoimmun Rev 5: 403‐408, 2006.
 57.Duffaut C, Galitzky J, Lafontan M, Bouloumie A. Unexpected trafficking of immune cells within the adipose tissue during the onset of obesity. Biochem Biophys Res Commun 384: 482‐485, 2009.
 58.Dux K, Rouse RV, Kyewski B. Composition of the lymphoid cell populations from omental milky spots during the immune response in #c57BL/Ka mice. Eur J Immunol 16: 1029‐1032, 1986.
 59.Eller K, Kirsch A, Wolf AM, Sopper S, Tagwerker A, Stanzl U, Wolf D, Patsch W, Rosenkranz AR, Eller P. Potential role of regulatory T cells in reversing obesity‐linked insulin resistance and diabetic nephropathy. Diabetes 60: 2954‐2962, 2011.
 60.Esposito R, Betuel H, Manzo M, Cirillo D, Pluvio M, Fredel A, Lanzetti N, Perna N, Giordano C. The effect of branch chain amino acids on the proliferation of normal and uremic cells. Kidney Int Suppl 17: S98‐S99, 1985.
 61.Exley MA, Hand L, O'Shea D, Lynch L. Interplay between the immune system and adipose tissue in obesity. J Endocrinol 223: R41‐R48, 2014.
 62.Fabbrini E, Cella M, McCartney SA, Fuchs A, Abumrad NA, Pietka TA, Chen Z, Finck BN, Han DH, Magkos F, Conte C, Bradley D, Fraterrigo G, Eagon JC, Patterson BW, Colonna M, Klein S. Association between specific adipose tissue CD4+ T‐cell populations and insulin resistance in obese individuals. Gastroenterology 145: 366‐374, 2013.
 63.Fain JN. Release of inflammatory mediators by human adipose tissue is enhanced in obesity and primarily by the nonfat cells: A review. Mediators Inflamm 2010: 513948, 2010.
 64.Fantuzzi G. Adipose tissue, adipokines, and inflammation. J Allergy Clin Immunol 115: 911‐919, 2005.
 65.Farooqi IS, Matarese G, Lord GM, Keogh JM, Lawrence E, Agwu C, Sanna V, Jebb SA, Perna F, Fontana S, Lechler RI, DePaoli AM, O'Rahilly S. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest 110: 1093‐1103, 2002.
 66.Ferrante AW, Jr. The immune cells in adipose tissue. Diabetes Obes Metab 15(Suppl 3): 34‐38, 2013.
 67.Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A, Lee J, Goldfine AB, 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 15: 930‐939, 2009.
 68.Fischer K, Ruiz HH, Jhun K, Finan B, Oberlin DJ, van dH, V, Kalinovich AV, Petrovic N, Wolf Y, Clemmensen C, Shin AC, Divanovic S, Brombacher F, Glasmacher E, Keipert S, Jastroch M, Nagler J, Schramm KW, Medrikova D, Collden G, Woods SC, Herzig S, Homann D, Jung S, Nedergaard J, Cannon B, Tschop MH, Muller TD, Buettner C. Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis. Nat Med 23: 623‐630, 2017.
 69.Foster MT, Pagliassotti MJ. Metabolic alterations following visceral fat removal and expansion: Beyond anatomic location. Adipocyte 1: 192‐199, 2012.
 70.Fried SK, Bunkin DA, Greenberg AS. Omental and subcutaneous adipose tissues of obese subjects release interleukin‐6: Depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab 83: 847‐850, 1998.
 71.Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 114: 1752‐1761, 2004.
 72.Gaiva MH, Couto RC, Oyama LM, Couto GE, Silveira VL, Riberio EB, Nascimento CM. Polyunsaturated fatty acid‐rich diets: Effect on adipose tissue metabolism in rats. Br J Nutr 86: 371‐377, 2001.
 73.Gambacciani M, Ciaponi M, Cappagli B, Piaggesi L, De SL, Orlandi R, Genazzani AR. Body weight, body fat distribution, and hormonal replacement therapy in early postmenopausal women. J Clin Endocrinol Metab 82: 414‐417, 1997.
 74.Ghigliotti G, Barisione C, Garibaldi S, Fabbi P, Brunelli C, Spallarossa P, Altieri P, Rosa G, Spinella G, Palombo D, Arsenescu R, Arsenescu V. Adipose tissue immune response: Novel triggers and consequences for chronic inflammatory conditions. Inflammation 37: 1337‐1353, 2014.
 75.Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ, Konkel JE, Ramos HL, Wei L, Davidson TS, Bouladoux N, Grainger JR, Chen Q, Kanno Y, Watford WT, Sun HW, Eberl G, Shevach EM, Belkaid Y, Cua DJ, Chen W, O'Shea JJ. Generation of pathogenic T(H)17 cells in the absence of TGF‐beta signalling. Nature 467: 967‐971, 2010.
 76.Giralt M, Villarroya F. White, brown, beige/brite: Different adipose cells for different functions? Endocrinology 154: 2992‐3000, 2013.
 77.Goldfine AB, Fonseca V, Jablonski KA, Pyle L, Staten MA, Shoelson SE. The effects of salsalate on glycemic control in patients with type 2 diabetes: A randomized trial. Ann Intern Med 152: 346‐357, 2010.
 78.Goronzy JJ, Lee WW, Weyand CM. Aging and T‐cell diversity. Exp Gerontol 42: 400‐406, 2007.
 79.Green CR, Wallace M, Divakaruni AS, Phillips SA, Murphy AN, Ciaraldi TP, Metallo CM. Branched‐chain amino acid catabolism fuels adipocyte differentiation and lipogenesis. Nat Chem Biol 12: 15‐21, 2016.
 80.Green DR, Galluzzi L, Kroemer G. Mitochondria and the autophagy‐inflammation‐cell death axis in organismal aging. Science 333: 1109‐1112, 2011.
 81.Greenberg AS, Obin MS. Obesity and the role of adipose tissue in inflammation and metabolism. Am J Clin Nutr 83: 461S‐465S, 2006.
 82.Griffin DO, Holodick NE, Rothstein TL. Human B1 cells in umbilical cord and adult peripheral blood express the novel phenotype CD20+ CD27+ CD43+ CD70‐. J Exp Med 208: 67‐80, 2011.
 83.Guerra C, Navarro P, Valverde AM, Arribas M, Bruning J, Kozak LP, Kahn CR, Benito M. Brown adipose tissue‐specific insulin receptor knockout shows diabetic phenotype without insulin resistance. J Clin Invest 108: 1205‐1213, 2001.
 84.Gupta RK, Mepani RJ, Kleiner S, Lo JC, Khandekar MJ, Cohen P, Frontini A, Bhowmick DC, Ye L, Cinti S, Spiegelman BM. Zfp423 expression identifies committed preadipocytes and localizes to adipose endothelial and perivascular cells. Cell Metab 15: 230‐239, 2012.
 85.Gupta S, Agrawal S, Gollapudi S. Increased activation and cytokine secretion in B cells stimulated with leptin in aged humans. Immun Ageing 10: 3, 2013.
 86.Guzik TJ, Marvar PJ, Czesnikiewicz‐Guzik M, Korbut R. Perivascular adipose tissue as a messenger of the brain‐vessel axis: role in vascular inflammation and dysfunction. J Physiol Pharmacol 58: 591‐610, 2007.
 87.Ha SA, Tsuji M, Suzuki K, Meek B, Yasuda N, Kaisho T, Fagarasan S. Regulation of B1 cell migration by signals through Toll‐like receptors. J Exp Med 203: 2541‐2550, 2006.
 88.Hafida S, Mirshahi T, Nikolajczyk BS. The impact of bariatric surgery on inflammation: quenching the fire of obesity? Curr Opin Endocrinol Diabetes Obes 23: 373‐378, 2016.
 89.Ham M, Lee JW, Choi AH, Jang H, Choi G, Park J, Kozuka C, Sears DD, Masuzaki H, Kim JB. Macrophage glucose‐6‐phosphate dehydrogenase stimulates proinflammatory responses with oxidative stress. Mol Cell Biol 33: 2425‐2435, 2013.
 90.Han CY, Subramanian S, Chan CK, Omer M, Chiba T, Wight TN, Chait A. Adipocyte‐derived serum amyloid A3 and hyaluronan play a role in monocyte recruitment and adhesion. Diabetes 56: 2260‐2273, 2007.
 91.Han JM, Wu D, Denroche HC, Yao Y, Verchere CB, Levings MK. 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, 2015.
 92.Hardy R, Hayakawa K. Generation of Ly‐1 B cells from developmentally distinct precursors. Enrichment by stromal‐cell culture or cell sorting. Ann N Y Acad Sci 651: 99‐111, 1992.
 93.Harvey NL. The link between lymphatic function and adipose biology. Ann N Y Acad Sci 1131: 82‐88, 2008.
 94.Hausman GJ, Barb CR, Dean RG. Gene expression profiling in developing pig adipose tissue: non‐secreted regulatory proteins. Animal 5: 1071‐1081, 2011.
 95.Herman MA, She P, Peroni OD, Lynch CJ, Kahn BB. Adipose tissue branched chain amino acid (BCAA) metabolism modulates circulating BCAA levels. J Biol Chem 285: 11348‐11356, 2010.
 96.Herrero L, Shapiro H, Nayer A, Lee J, Shoelson SE. Inflammation and adipose tissue macrophages in lipodystrophic mice. Proc Natl Acad Sci U S A 107: 240‐245, 2010.
 97.Hodge DL, Reynolds D, Cerban FM, Correa SG, Baez NS, Young HA, Rodriguez‐Galan MC. MCP‐1/CCR2 interactions direct migration of peripheral B and T lymphocytes to the thymus during acute infectious/inflammatory processes. Eur J Immunol 42: 2644‐2654, 2012.
 98.Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor‐alpha: Direct role in obesity‐linked insulin resistance. Science 259: 87‐91, 1993.
 99.Howcroft TK, Campisi J, Louis GB, Smith MT, Wise B, Wyss‐Coray T, Augustine AD, McElhaney JE, Kohanski R, Sierra F. The role of inflammation in age‐related disease. Aging (Albany NY) 5: 84‐93, 2013.
 100.Hua Z, Gross AJ, Lamagna C, Ramos‐Hernandez N, Scapini P, Ji M, Shao H, Lowell CA, Hou B, DeFranco AL. Requirement for MyD88 signaling in B cells and dendritic cells for germinal center anti‐nuclear antibody production in Lyn‐deficient mice. J Immunol 192: 875‐885, 2014.
 101.Hua Z, Hou B. TLR signaling in B‐cell development and activation. Cell Mol Immunol 10: 103‐106, 2013.
 102.Hubbard RE, Lang IA, Llewellyn DJ, Rockwood K. Frailty, body mass index, and abdominal obesity in older people. J Gerontol A Biol Sci Med Sci 65: 377‐381, 2010.
 103.Hube F, Hauner H. The role of TNF‐alpha in human adipose tissue: Prevention of weight gain at the expense of insulin resistance? Horm Metab Res 31: 626‐631, 1999.
 104.Huber J, Loffler M, Bilban M, Reimers M, Kadl A, Todoric J, Zeyda M, Geyeregger R, Schreiner M, Weichhart T, Leitinger N, Waldhausl W, Stulnig TM. Prevention of high‐fat diet‐induced adipose tissue remodeling in obese diabetic mice by n‐3 polyunsaturated fatty acids. Int J Obes (Lond) 31: 1004‐1013, 2007.
 105.Huh JY, Park YJ, Ham M, Kim JB. Crosstalk between adipocytes and immune cells in adipose tissue inflammation and metabolic dysregulation in obesity. Mol Cells 37: 365‐371, 2014.
 106.Hunter CA, Jones SA. IL‐6 as a keystone cytokine in health and disease. Nat Immunol 16: 448‐457, 2015.
 107.Idoate F, Cadore EL, Casas‐Herrero A, Zambom‐Ferraresi F, Marcellan T, Ruiz de GA, Rodriguez‐Manas L, Bastarrika G, Marques MC, Martinez‐Velilla N, Vicente‐Campos D, Izquierdo M. Adipose tissue compartments, muscle mass, muscle fat infiltration, and coronary calcium in institutionalized frail nonagenarians. Eur Radiol 25: 2163‐2175, 2015.
 108.Ip B, Cilfone NA, Belkina AC, DeFuria J, Jagannathan‐Bogdan M, Zhu M, Kuchibhatla R, McDonnell ME, Xiao Q, Kepler TB, Apovian CM, Lauffenburger DA, Nikolajczyk BS. Th17 cytokines differentiate obesity from obesity‐associated type 2 diabetes and promote TNFalpha production. Obesity (Silver Spring) 24: 102‐112, 2016.
 109.Ip BC, Hogan AE, Nikolajczyk BS. Lymphocyte roles in metabolic dysfunction: of men and mice. Trends Endocrinol Metab 26: 91‐100, 2015.
 110.Jagannathan M, McDonnell M, Liang Y, Hasturk H, Hetzel J, Rubin D, Kantarci A, Van Dyke TE, Ganley‐Leal LM, Nikolajczyk BS. Toll‐like receptors regulate B cell cytokine production in patients with diabetes. Diabetologia 53: 1461‐1471, 2010.
 111.Jagannathan‐Bogdan M, McDonnell ME, Shin H, Rehman Q, Hasturk H, Apovian CM, Nikolajczyk BS. Elevated proinflammatory cytokine production by a skewed T cell compartment requires monocytes and promotes inflammation in type 2 diabetes. J Immunol 186: 1162‐1172, 2011.
 112.Jennbacken K, Stahlman S, Grahnemo L, Wiklund O, Fogelstrand L. Glucose impairs B‐1 cell function in diabetes. Clin Exp Immunol 174: 129‐138, 2013.
 113.Ji Y, Sun S, Xu A, Bhargava P, Yang L, Lam KS, Gao B, Lee CH, Kersten S, Qi L. Activation of natural killer T cells promotes M2 Macrophage polarization in adipose tissue and improves systemic glucose tolerance via interleukin‐4 (IL‐4)/STAT6 protein signaling axis in obesity. J Biol Chem 287: 13561‐13571, 2012.
 114.Jo J, Gavrilova O, Pack S, Jou W, Mullen S, Sumner AE, Cushman SW, Periwal V. Hypertrophy and/or hyperplasia: Dynamics of adipose tissue growth. PLoS Comput Biol 5: e1000324, 2009.
 115.Jowitt LM, Lu LW, Rush EC. Migrant Asian Indians in New Zealand; prediction of metabolic syndrome using body weights and measures. Asia Pac J Clin Nutr 23: 385‐393, 2014.
 116.Justesen J, Stenderup K, Ebbesen EN, Mosekilde L, Steiniche T, Kassem M. Adipocyte tissue volume in bone marrow is increased with aging and in patients with osteoporosis. Biogerontology 2: 165‐171, 2001.
 117.Kahn SE, Zinman B, Haffner SM, O'Neill MC, Kravitz BG, Yu D, Freed MI, Herman WH, Holman RR, Jones NP, Lachin JM, Viberti GC. Obesity is a major determinant of the association of C‐reactive protein levels and the metabolic syndrome in type 2 diabetes. Diabetes 55: 2357‐2364, 2006.
 118.Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, Kasuga M. MCP‐1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 116: 1494‐1505, 2006.
 119.Kappes A, Loffler G. Influences of ionomycin, dibutyryl‐cycloAMP and tumour necrosis factor‐alpha on intracellular amount and secretion of apM1 in differentiating primary human preadipocytes. Horm Metab Res 32: 548‐554, 2000.
 120.Kelada S, Sethupathy P, Okoye IS, Kistasis E, Czieso S, White SD, Chou D, Martens C, Ricklefs SM, Virtaneva K, Sturdevant DE, Porcella SF, Belkaid Y, Wynn TA, Wilson MS. miR‐182 and miR‐10a are key regulators of Treg specialisation and stability during Schistosome and Leishmania‐associated inflammation. PLoS Pathog 9: e1003451, 2013.
 121.Kim EY, Kim WK, Oh KJ, Han BS, Lee SC, Bae KH. Recent advances in proteomic studies of adipose tissues and adipocytes. Int J Mol Sci 16: 4581‐4599, 2015.
 122.Kintscher U, Hartge M, Hess K, Foryst‐Ludwig A, Clemenz M, Wabitsch M, Fischer‐Posovszky P, Barth TF, Dragun D, Skurk T, Hauner H, Bluher M, Unger T, Wolf AM, Knippschild U, Hombach V, Marx N. T‐lymphocyte infiltration in visceral adipose tissue: A primary event in adipose tissue inflammation and the development of obesity‐mediated insulin resistance. Arterioscler Thromb Vasc Biol 28: 1304‐1310, 2008.
 123.Kolodin D, van PN, Li C, Magnuson AM, Cipolletta D, Miller CM, Wagers A, Germain RN, Benoist C, Mathis D. Antigen‐ and cytokine‐driven accumulation of regulatory T cells in visceral adipose tissue of lean mice. Cell Metab 21: 543‐557, 2015.
 124.Kondo M, Wagers AJ, Manz MG, Prohaska SS, Scherer DC, Beilhack GF, Shizuru JA, Weissman IL. Biology of hematopoietic stem cells and progenitors: Implications for clinical application. Annu Rev Immunol 21: 759‐806, 2003.
 125.Kotas ME, Lee HY, Gillum MP, Annicelli C, Guigni BA, Shulman GI, Medzhitov R. Impact of CD1d deficiency on metabolism. PLoS One 6: e25478, 2011.
 126.Krist LF, Eestermans IL, Steenbergen JJ, Hoefsmit EC, Cuesta MA, Meyer S, Beelen RH. Cellular composition of milky spots in the human greater omentum: An immunochemical and ultrastructural study. Anat Rec 241: 163‐174, 1995.
 127.Ku LT, Gercel‐Taylor C, Nakajima ST, Taylor DD. Alterations of T cell activation signalling and cytokine production by postmenopausal estrogen levels. Immun Ageing 6: 1, 2009.
 128.Kuan EL, Ivanov S, Bridenbaugh EA, Victora G, Wang W, Childs EW, Platt AM, Jakubzick CV, Mason RJ, Gashev AA, Nussenzweig M, Swartz MA, Dustin ML, Zawieja DC, Randolph GJ. Collecting lymphatic vessel permeability facilitates adipose tissue inflammation and distribution of antigen to lymph node‐homing adipose tissue dendritic cells. J Immunol 194: 5200‐5210, 2015.
 129.Kusminski CM, Bickel PE, Scherer PE. Targeting adipose tissue in the treatment of obesity‐associated diabetes. Nat Rev Drug Discov 2016.
 130.Lackey DE, Lynch CJ, Olson KC, Mostaedi R, Ali M, Smith WH, Karpe F, Humphreys S, Bedinger DH, Dunn TN, Thomas AP, Oort PJ, Kieffer DA, Amin R, Bettaieb A, Haj FG, Permana P, Anthony TG, Adams SH. Regulation of adipose branched‐chain amino acid catabolism enzyme expression and cross‐adipose amino acid flux in human obesity. Am J Physiol Endocrinol Metab 304: E1175‐E1187, 2013.
 131.Lan X, Cheng K, Chandel N, Lederman R, Jhaveri A, Husain M, Malhotra A, Singhal PC. High glucose enhances HIV entry into T cells through upregulation of CXCR4. J Leukoc Biol 94: 769‐777, 2013.
 132.Larrouy D, Galitzky J, Lafontan M. A1 adenosine receptors in the human fat cell: Tissue distribution and regulation of radioligand binding. Eur J Pharmacol 206: 139‐147, 1991.
 133.Leavy O. T cell responses: Metabolic pathways take sides. Nat Rev Immunol 16: 276‐277, 2016.
 134.Lebovitz HE, Banerji MA. Point: Visceral adiposity is causally related to insulin resistance. Diabetes Care 28: 2322‐2325, 2005.
 135.Lee MW, Odegaard JI, Mukundan L, Qiu Y, Molofsky AB, Nussbaum JC, Yun K, Locksley RM, Chawla A. Activated type 2 innate lymphoid cells regulate beige fat biogenesis. Cell 160: 74‐87, 2015.
 136.Lee Y, Awasthi A, Yosef N, Quintana FJ, Xiao S, Peters A, Wu C, Kleinewietfeld M, Kunder S, Hafler DA, Sobel RA, Regev A, Kuchroo VK. Induction and molecular signature of pathogenic TH17 cells. Nat Immunol 13: 991‐999, 2012.
 137.Lee YS, Li P, Huh JY, Hwang IJ, Lu M, Kim JI, Ham M, Talukdar S, Chen A, Lu WJ, Bandyopadhyay GK, Schwendener R, Olefsky J, Kim JB. Inflammation is necessary for long‐term but not short‐term high‐fat diet‐induced insulin resistance. Diabetes 60: 2474‐2483, 2011.
 138.Lefterova MI, Zhang Y, Steger DJ, Schupp M, Schug J, Cristancho A, Feng D, Zhuo D, Stoeckert CJ, Jr. Liu XS and Lazar MA. PPARgamma and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome‐wide scale. Genes Dev 22: 2941‐2952, 2008.
 139.Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA. CTLA‐4 is a second receptor for the B cell activation antigen B7. J Exp Med 174: 561‐569, 1991.
 140.Liu J, Divoux A, Sun J, Zhang J, Clement K, Glickman JN, Sukhova GK, Wolters PJ, Du J, Gorgun CZ, Doria A, Libby P, Blumberg RS, Kahn BB, Hotamisligil GS, Shi GP. Genetic deficiency and pharmacological stabilization of mast cells reduce diet‐induced obesity and diabetes in mice. Nat Med 15: 940‐945, 2009.
 141.Liu LF, Craig CM, Tolentino LL, Choi O, Morton J, Rivas H, Cushman SW, Engleman EG, McLaughlin T. Adipose tissue macrophages impair preadipocyte differentiation in humans. PLoS One 12: e0170728, 2017.
 142.Lo KA, Sun L. Turning WAT into BAT: A review on regulators controlling the browning of white adipocytes. Biosci Rep 33: 2013.
 143.Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, Lechler RI. Leptin modulates the T‐cell immune response and reverses starvation‐induced immunosuppression. Nature 394: 897‐901, 1998.
 144.Lumeng CN, Deyoung SM, Bodzin JL, Saltiel AR. Increased inflammatory properties of adipose tissue macrophages recruited during diet‐induced obesity. Diabetes 56: 16‐23, 2007.
 145.Lumeng CN, Liu J, Geletka L, Delaney C, Delproposto J, Desai A, Oatmen K, Martinez‐Santibanez G, Julius A, Garg S, Yung RL. Aging is associated with an increase in T cells and inflammatory macrophages in visceral adipose tissue. J Immunol 187: 6208‐6216, 2011.
 146.Luzina IG, Todd NW, Nacu N, Lockatell V, Choi J, Hummers LK, Atamas SP. Regulation of pulmonary inflammation and fibrosis through expression of integrins alphaVbeta3 and alphaVbeta5 on pulmonary T lymphocytes. Arthritis Rheum 60: 1530‐1539, 2009.
 147.Lynch CJ, Adams SH. Branched‐chain amino acids in metabolic signalling and insulin resistance. Nat Rev Endocrinol 10: 723‐736, 2014.
 148.Lynch L. Adipose invariant natural killer T cells. Immunology 142: 337‐346, 2014.
 149.Lynch L, Michelet X, Zhang S, Brennan PJ, Moseman A, Lester C, Besra G, Vomhof‐Dekrey EE, Tighe M, Koay HF, Godfrey DI, Leadbetter EA, Sant'Angelo DB, von AU, Brenner MB. Regulatory iNKT cells lack expression of the transcription factor PLZF and control the homeostasis of T(reg) cells and macrophages in adipose tissue. Nat Immunol 16: 85‐95, 2015.
 150.Lynch L, Nowak M, Varghese B, Clark J, Hogan AE, Toxavidis V, Balk SP, O'Shea D, O'Farrelly C, Exley MA. Adipose tissue invariant NKT cells protect against diet‐induced obesity and metabolic disorder through regulatory cytokine production. Immunity 37: 574‐587, 2012.
 151.Lyons CL, Kennedy EB, Roche HM. Metabolic inflammation‐differential modulation by dietary constituents. Nutrients 8: 2016.
 152.Magalhaes I, Pingris K, Poitou C, Bessoles S, Venteclef N, Kiaf B, Beaudoin L, Da SJ, Allatif O, Rossjohn J, Kjer‐Nielsen L, McCluskey J, Ledoux S, Genser L, Torcivia A, Soudais C, Lantz O, Boitard C, Aron‐Wisnewsky J, Larger E, Clement K, Lehuen A. Mucosal‐associated invariant T cell alterations in obese and type 2 diabetic patients. J Clin Invest 125: 1752‐1762, 2015.
 153.Makki K, Froguel P, Wolowczuk I. Adipose tissue in obesity‐related inflammation and insulin resistance: Cells, cytokines, and chemokines. ISRN Inflamm 2013: 139239, 2013.
 154.Martin CK, Bhapkar M, Pittas AG, Pieper CF, Das SK, Williamson DA, Scott T, Redman LM, Stein R, Gilhooly CH, Stewart T, Robinson L, Roberts SB. Effect of calorie restriction on mood, quality of life, sleep, and sexual function in healthy nonobese adults: The CALERIE 2 randomized clinical trial. JAMA Intern Med 176: 743‐752, 2016.
 155.Masaki T, Chiba S, Tatsukawa H, Yasuda T, Noguchi H, Seike M, Yoshimatsu H. Adiponectin protects LPS‐induced liver injury through modulation of TNF‐alpha in KK‐Ay obese mice. Hepatology 40: 177‐184, 2004.
 156.Matsushita K. Mesenchymal stem cells and metabolic syndrome: Current understanding and potential clinical implications. Stem Cells Int 2016: 2892840, 2016.
 157.Mattacks CA, Sadler D, Pond CM. The cellular structure and lipid/protein composition of adipose tissue surrounding chronically stimulated lymph nodes in rats. J Anat 202: 551‐561, 2003.
 158.Matter CM, Handschin C. RANTES (regulated on activation, normal T cell expressed and secreted), inflammation, obesity, and the metabolic syndrome. Circulation 115: 946‐948, 2007.
 159.Matthews VB, Allen TL, Risis S, Chan MH, Henstridge DC, Watson N, Zaffino LA, Babb JR, Boon J, Meikle PJ, Jowett JB, Watt MJ, Jansson JO, Bruce CR, Febbraio MA. Interleukin‐6‐deficient mice develop hepatic inflammation and systemic insulin resistance. Diabetologia 53: 2431‐2441, 2010.
 160.McDonnell ME, Ganley‐Leal LM, Mehta A, Bigornia SJ, Mott M, Rehman Q, Farb MG, Hess DT, Joseph L, Gokce N, Apovian CM. B lymphocytes in human subcutaneous adipose crown‐like structures. Obesity (Silver Spring) 20: 1372‐1378, 2012.
 161.McLaughlin T, Liu LF, Lamendola C, Shen L, Morton J, Rivas H, Winer D, Tolentino L, Choi O, Zhang H, Hui Yen CM, Engleman E. T‐cell profile in adipose tissue is associated with insulin resistance and systemic inflammation in humans. Arterioscler Thromb Vasc Biol 34: 2637‐2643, 2014.
 162.Medrikova D, Sijmonsma TP, Sowodniok K, Richards DM, Delacher M, Sticht C, Gretz N, Schafmeier T, Feuerer M, Herzig S. Brown adipose tissue harbors a distinct sub‐population of regulatory T cells. PLoS One 10: e0118534, 2015.
 163.Miljkovic I, Cauley JA, Petit MA, Ensrud KE, Strotmeyer E, Sheu Y, Gordon CL, Goodpaster BH, Bunker CH, Patrick AL, Wheeler VW, Kuller LH, Faulkner KA, Zmuda JM. Greater adipose tissue infiltration in skeletal muscle among older men of African ancestry. J Clin Endocrinol Metab 94: 2735‐2742, 2009.
 164.Minor RK, Allard JS, Younts CM, Ward TM, de CR. Dietary interventions to extend life span and health span based on calorie restriction. J Gerontol A Biol Sci Med Sci 65: 695‐703, 2010.
 165.Mittendorfer B. Origins of metabolic complications in obesity: Adipose tissue and free fatty acid trafficking. Curr Opin Clin Nutr Metab Care 14: 535‐541, 2011.
 166.Mo R, Chen J, Han Y, Bueno‐Cannizares C, Misek DE, Lescure PA, Hanash S, Yung RL. T cell chemokine receptor expression in aging. J Immunol 170: 895‐904, 2003.
 167.Molofsky AB, Nussbaum JC, Liang HE, Van Dyken SJ, Cheng LE, Mohapatra A, Chawla A, Locksley RM. Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J Exp Med 210: 535‐549, 2013.
 168.Montaldo E, Vacca P, Vitale C, Moretta F, Locatelli F, Mingari MC, Moretta L. Human innate lymphoid cells. Immunol Lett 179: 2‐8, 2016.
 169.Moraes‐Vieira PM, Castoldi A, Aryal P, Wellenstein K, Peroni OD, Kahn BB. Antigen presentation and T‐cell activation are critical for RBP4‐induced insulin resistance. Diabetes 65: 1317‐1327, 2016.
 170.Morris DL, Oatmen KE, Mergian TA, Cho KW, DelProposto JL, Singer K, Evans‐Molina C, O'Rourke RW, Lumeng CN. CD40 promotes MHC class II expression on adipose tissue macrophages and regulates adipose tissue CD4+ T cells with obesity. J Leukoc Biol 99: 1107‐1119, 2016.
 171.Mraz M, Haluzik M. The role of adipose tissue immune cells in obesity and low‐grade inflammation. J Endocrinol 222: R113‐R127, 2014.
 172.Nagelkerken L, Hertogh‐Huijbregts A, Dobber R, Drager A. Age‐related changes in lymphokine production related to a decreased number of CD45RBhi CD4+ T cells. Eur J Immunol 21: 273‐281, 1991.
 173.Naylor K, Li G, Vallejo AN, Lee WW, Koetz K, Bryl E, Witkowski J, Fulbright J, Weyand CM, Goronzy JJ. The influence of age on T cell generation and TCR diversity. J Immunol 174: 7446‐7452, 2005.
 174.Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF, Haqq AM, Shah SH, Arlotto M, Slentz CA, Rochon J, Gallup D, Ilkayeva O, Wenner BR, Yancy WS, Jr, Eisenson H, Musante G, Surwit RS, Millington DS, Butler MD, Svetkey LP. A branched‐chain amino acid‐related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab 9: 311‐326, 2009.
 175.Nijhuis J, Rensen SS, Slaats Y, van Dielen FM, Buurman WA, Greve JW. Neutrophil activation in morbid obesity, chronic activation of acute inflammation. Obesity (Silver Spring) 17: 2014‐2018, 2009.
 176.Nikolajczyk BS. B cells as under‐appreciated mediators of non‐auto‐immune inflammatory disease. Cytokine 50: 234‐242, 2010.
 177.Nikolajczyk BS, Jagannathan‐Bogdan M, Denis GV. The outliers become a stampede as immunometabolism reaches a tipping point. Immunol Rev 249: 253‐275, 2012.
 178.Nikolich‐Zugich J. Aging of the T cell compartment in mice and humans: From no naive expectations to foggy memories. J Immunol 193: 2622‐2629, 2014.
 179.Nikolich‐Zugich J, Slifka MK, Messaoudi I. The many important facets of T‐cell repertoire diversity. Nat Rev Immunol 4: 123‐132, 2004.
 180.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 15: 914‐920, 2009.
 181.Nishimura S, Manabe I, Takaki S, Nagasaki M, Otsu M, Yamashita H, Sugita J, Yoshimura K, Eto K, Komuro I, Kadowaki T, Nagai R. Adipose natural regulatory B cells negatively control adipose tissue inflammation. Cell Metab 2013.
 182.Norseen J, Hosooka T, Hammarstedt A, Yore MM, Kant S, Aryal P, Kiernan UA, Phillips DA, Maruyama H, Kraus BJ, Usheva A, Davis RJ, Smith U, Kahn BB. 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 32: 2010‐2019, 2012.
 183.O'Mahony L, Holland J, Jackson J, Feighery C, Hennessy TP, Mealy K. Quantitative intracellular cytokine measurement: Age‐related changes in proinflammatory cytokine production. Clin Exp Immunol 113: 213‐219, 1998.
 184.Ofei F, Hurel S, Newkirk J, Sopwith M, Taylor R. Effects of an engineered human anti‐TNF‐alpha antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM. Diabetes 45: 881‐885, 1996.
 185.Okeke EB, Okwor I, Uzonna JE. Regulatory T cells restrain CD4+ T cells from causing unregulated immune activation and hypersensitivity to lipopolysaccharide challenge. J Immunol 193: 655‐662, 2014.
 186.Okoye IS, Czieso S, Ktistaki E, Roderick K, Coomes SM, Pelly VS, Kannan Y, Perez‐Lloret J, Zhao JL, Baltimore D, Langhorne J, Wilson MS. Transcriptomics identified a critical role for Th2 cell‐intrinsic miR‐155 in mediating allergy and antihelminth immunity. Proc Natl Acad Sci U S A 111: E3081‐E3090, 2014.
 187.Ortega Md, V, Xu X, Koska J, Francisco AM, Scalise M, Ferrante AW, Jr., Krakoff J. Macrophage content in subcutaneous adipose tissue: Associations with adiposity, age, inflammatory markers, and whole‐body insulin action in healthy Pima Indians. Diabetes 58: 385‐393, 2009.
 188.Otero M, Lago R, Gomez R, Lago F, Gomez‐Reino JJ, Gualillo O. Leptin: A metabolic hormone that functions like a proinflammatory adipokine. Drug News Perspect 19: 21‐26, 2006.
 189.Pacifico L, Di RL, Anania C, Osborn JF, Ippoliti F, Schiavo E, Chiesa C. Increased T‐helper interferon‐gamma‐secreting cells in obese children. Eur J Endocrinol 154: 691‐697, 2006.
 190.Palmer AK, Kirkland JL. Aging and adipose tissue: Potential interventions for diabetes and regenerative medicine. Exp Gerontol 2016.
 191.Palmer G, Aurrand‐Lions M, Contassot E, Talabot‐Ayer D, Ducrest‐Gay D, Vesin C, Chobaz‐Peclat V, Busso N, Gabay C. Indirect effects of leptin receptor deficiency on lymphocyte populations and immune response in db/db mice. J Immunol 177: 2899‐2907, 2006.
 192.Park SE, Park CY, Choi JM, Chang E, Rhee EJ, Lee WY, Oh KW, Park SW, Kang ES, Lee HC, Cha BS. Depot‐specific changes in fat metabolism with aging in a type 2 diabetic animal model. PLoS One 11: e0148141, 2016.
 193.Paz‐Filho G, Esposito K, Hurwitz B, Sharma A, Dong C, Andreev V, Delibasi T, Erol H, Ayala A, Wong ML, Licinio J. Changes in insulin sensitivity during leptin replacement therapy in leptin‐deficient patients. Am J Physiol Endocrinol Metab 295: E1401‐E1408, 2008.
 194.Paz‐Filho G, Mastronardi C, Delibasi T, Wong ML, Licinio J. Congenital leptin deficiency: Diagnosis and effects of leptin replacement therapy. Arq Bras Endocrinol Metabol 54: 690‐697, 2010.
 195.Pennock ND, White JT, Cross EW, Cheney EE, Tamburini BA, Kedl RM. T cell responses: Naive to memory and everything in between. Adv Physiol Educ 37: 273‐283, 2013.
 196.Pereira S, Teixeira L, Aguilar E, Oliveira M, Savassi‐Rocha A, Pelaez JN, Capettini L, Diniz MT, Ferreira A, Alvarez‐Leite J. Modulation of adipose tissue inflammation by FOXP3+ Treg cells, IL‐10, and TGF‐beta in metabolically healthy class III obese individuals. Nutrition 30: 784‐790, 2014.
 197.Perez LM, Pareja‐Galeano H, Sanchis‐Gomar F, Emanuele E, Lucia A, Galvez BG. ‘Adipaging’: Ageing and obesity share biological hallmarks related to a dysfunctional adipose tissue. J Physiol 594: 3187‐3207, 2016.
 198.Poggi M, Engel D, Christ A, Beckers L, Wijnands E, Boon L, Driessen A, Cleutjens J, Weber C, Gerdes N, Lutgens E. CD40L deficiency ameliorates adipose tissue inflammation and metabolic manifestations of obesity in mice. Arterioscler Thromb Vasc Biol 31: 2251‐2260, 2011.
 199.Polotsky HN, Polotsky AJ. Metabolic implications of menopause. Semin Reprod Med 28: 426‐434, 2010.
 200.Pond CM. Paracrine relationships between adipose and lymphoid tissues: Implications for the mechanism of HIV‐associated adipose redistribution syndrome. Trends Immunol 24: 13‐18, 2003.
 201.Pond CM, Mattacks CA. The source of fatty acids incorporated into proliferating lymphoid cells in immune‐stimulated lymph nodes. Br J Nutr 89: 375‐383, 2003.
 202.Priceman SJ, Kujawski M, Shen S, Cherryholmes GA, Lee H, Zhang C, Kruper L, Mortimer J, Jove R, Riggs AD, Yu H. 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, 2013.
 203.Priddle JD, Mattacks CA, Sadler DA, MacQueen HA, Pond CM. Changes in lymphokine receptor expression and fatty acid composition of phospholipids and triacylglycerols in rat adipocytes associated with lymph nodes following a transient immune challenge. Cell Biol Int 27: 23‐29, 2003.
 204.Qiu Y, Nguyen KD, Odegaard JI, Cui X, Tian X, Locksley RM, Palmiter RD, Chawla A. Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell 157: 1292‐1308, 2014.
 205.Ramesh R, Kozhaya L, McKevitt K, Djuretic IM, Carlson TJ, Quintero MA, McCauley JL, Abreu MT, Unutmaz D, Sundrud MS. Pro‐inflammatory human Th17 cells selectively express P‐glycoprotein and are refractory to glucocorticoids. J Exp Med 211: 89‐104, 2014.
 206.Rao RR, Long JZ, White JP, Svensson KJ, Lou J, Lokurkar I, Jedrychowski MP, Ruas JL, Wrann CD, Lo JC, Camera DM, Lachey J, Gygi S, Seehra J, Hawley JA, Spiegelman BM. Meteorin‐like is a hormone that regulates immune‐adipose interactions to increase beige fat thermogenesis. Cell 157: 1279‐1291, 2014.
 207.Rausch ME, Weisberg S, Vardhana P, Tortoriello DV. Obesity in #c57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T‐cell infiltration. Int J Obes (Lond) 32: 451‐463, 2008.
 208.Raval FM, Nikolajczyk BS. The bidirectional relationship between metabolism and immune responses. Discoveries (Craiova) 1: e6, 2013.
 209.Rebuffe‐Scrive M, Lundholm K, Bjorntorp P. Glucocorticoid hormone binding to human adipose tissue. Eur J Clin Invest 15: 267‐271, 1985.
 210.Reddy NL, Tan BK, Barber TM, Randeva HS. Brown adipose tissue: Endocrine determinants of function and therapeutic manipulation as a novel treatment strategy for obesity. BMC Obes 1: 13, 2014.
 211.Reis BS, Lee K, Fanok MH, Mascaraque C, Amoury M, Cohn LB, Rogoz A, Dallner OS, Moraes‐Vieira PM, Domingos AI, Mucida D. Leptin receptor signaling in T cells is required for Th17 differentiation. J Immunol 194: 5253‐5260, 2015.
 212.Ridker PM, Howard CP, Walter V, Everett B, Libby P, Hensen J, Thuren T. Effects of interleukin‐1beta inhibition with canakinumab on hemoglobin A1c, lipids, C‐reactive protein, interleukin‐6, and fibrinogen: A phase IIb randomized, placebo‐controlled trial. Circulation 126: 2739‐2748, 2012.
 213.Rocha VZ, Folco EJ, Sukhova G, Shimizu K, Gotsman I, Vernon AH, Libby P. Interferon‐gamma, a Th1 cytokine, regulates fat inflammation: A role for adaptive immunity in obesity. Circ Res 103: 467‐476, 2008.
 214.Rodeheffer MS, Birsoy K, Friedman JM. Identification of white adipocyte progenitor cells in vivo. Cell 135: 240‐249, 2008.
 215.Rogers NH, Perfield JW, Strissel KJ, Obin MS, Greenberg AS. Reduced energy expenditure and increased inflammation are early events in the development of ovariectomy‐induced obesity. Endocrinology 150: 2161‐2168, 2009.
 216.Rosen CJ, Ackert‐Bicknell C, Rodriguez JP, Pino AM. Marrow fat and the bone microenvironment: Developmental, functional, and pathological implications. Crit Rev Eukaryot Gene Expr 19: 109‐124, 2009.
 217.Rubino F, Nathan DM, Eckel RH, Schauer PR, Alberti KG, Zimmet PZ, Del PS, Ji L, Sadikot SM, Herman WH, Amiel SA, Kaplan LM, Taroncher‐Oldenburg G, Cummings DE. Metabolic surgery in the treatment algorithm for type 2 diabetes: A joint statement by International Diabetes Organizations. Diabetes Care 39: 861‐877, 2016.
 218.Rudd BD, Venturi V, Li G, Samadder P, Ertelt JM, Way SS, Davenport MP, Nikolich‐Zugich J. Nonrandom attrition of the naive CD8+ T‐cell pool with aging governed by T‐cell receptor:pMHC interactions. Proc Natl Acad Sci U S A 108: 13694‐13699, 2011.
 219.Sacks H, Symonds ME. Anatomical locations of human brown adipose tissue: Functional relevance and implications in obesity and type 2 diabetes. Diabetes 62: 1783‐1790, 2013.
 220.Sadler D, Mattacks CA, Pond CM. Changes in adipocytes and dendritic cells in lymph node containing adipose depots during and after many weeks of mild inflammation. J Anat 207: 769‐781, 2005.
 221.Sanchez‐Gurmaches J, Guertin DA. Adipocyte lineages: Tracing back the origins of fat. Biochim Biophys Acta 1842: 340‐351, 2014.
 222.Satoh M, Hoshino M, Fujita K, Iizuka M, Fujii S, Clingan CS, Van KL, Iwabuchi K. Adipocyte‐specific CD1d‐deficiency mitigates diet‐induced obesity and insulin resistance in mice. Sci Rep 6: 28473, 2016.
 223.Scheja L, Heese B, Zitzer H, Michael MD, Siesky AM, Pospisil H, Beisiegel U, Seedorf K. Acute‐phase serum amyloid A as a marker of insulin resistance in mice. Exp Diabetes Res 2008: 230837, 2008.
 224.Serhan CN, Yacoubian S, Yang R. Anti‐inflammatory and proresolving lipid mediators. Annu Rev Pathol 3: 279‐312, 2008.
 225.Shanmugam N, Reddy MA, Guha M, Natarajan R. High glucose‐induced expression of proinflammatory cytokine and chemokine genes in monocytic cells. Diabetes 52: 1256‐1264, 2003.
 226.Shapiro H, Pecht T, Shaco‐Levy R, Harman‐Boehm I, Kirshtein B, Kuperman Y, Chen A, Bluher M, Shai I, Rudich A. Adipose tissue foam cells are present in human obesity. J Clin Endocrinol Metab 98: 1173‐1181, 2013.
 227.Shen L, Chng MH, Alonso MN, Yuan R, Winer DA, Engleman EG. B‐1a lymphocytes attenuate insulin resistance. Diabetes 64: 593‐603, 2015.
 228.Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid‐induced insulin resistance. J Clin Invest 116: 3015‐3025, 2006.
 229.Shi H, Tzameli I, Bjorbaek C, Flier JS. Suppressor of cytokine signaling 3 is a physiological regulator of adipocyte insulin signaling. J Biol Chem 279: 34733‐34740, 2004.
 230.Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, Chi H. HIF1alpha‐dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 208: 1367‐1376, 2011.
 231.Shimomura Y, Tamura T, Suzuki M. Less body fat accumulation in rats fed a safflower oil diet than in rats fed a beef tallow diet. J Nutr 120: 1291‐1296, 1990.
 232.Singh T, Newman AB. Inflammatory markers in population studies of aging. Ageing Res Rev 10: 319‐329, 2011.
 233.Skaper SD, Molden DP, Seegmiller JE. Maple syrup urine disease: Branched‐chain amino acid concentrations and metabolism in cultured human lymphoblasts. Biochem Genet 14: 527‐539, 1976.
 234.Snyder‐Cappione JE, Nikolajczyk BS. When diet and exercise are not enough, think immunomodulation. Mol Aspects Med 34: 30‐38, 2013.
 235.Solvason N, Kearney JF. The human fetal omentum: A site of B cell generation. J Exp Med 175: 397‐404, 1992.
 236.Starr ME, Hu Y, Stromberg AJ, Carmical JR, Wood TG, Evers BM, Saito H. Gene expression profile of mouse white adipose tissue during inflammatory stress: Age‐dependent upregulation of major procoagulant factors. Aging Cell 12: 194‐206, 2013.
 237.Strissel KJ, Denis GV, Nikolajczyk BS. Immune regulators of inflammation in obesity‐associated type 2 diabetes and coronary artery disease. Curr Opin Endocrinol Diabetes Obes 21: 330‐338, 2014.
 238.Strissel KJ, Stancheva Z, Miyoshi H, Perfield JW, DeFuria J, Jick Z, Greenberg AS, Obin MS. Adipocyte death, adipose tissue remodeling, and obesity complications. Diabetes 56: 2910‐2918, 2007.
 239.Sun K, Kusminski CM, Scherer PE. Adipose tissue remodeling and obesity. J Clin Invest 121: 2094‐2101, 2011.
 240.Talukdar S, Oh DY, Bandyopadhyay G, Li D, Xu J, McNelis J, Lu M, Li P, Yan Q, Zhu Y, Ofrecio J, Lin M, Brenner MB, Olefsky JM. Neutrophils mediate insulin resistance in mice fed a high‐fat diet through secreted elastase. Nat Med 18: 1407‐1412, 2012.
 241.Tang W, Zeve D, Suh JM, Bosnakovski D, Kyba M, Hammer RE, Tallquist MD, Graff JM. White fat progenitor cells reside in the adipose vasculature. Science 322: 583‐586, 2008.
 242.Tilg H, Moschen AR. Adipocytokines: Mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 6: 772‐783, 2006.
 243.Tilg H, Moschen AR. Inflammatory mechanisms in the regulation of insulin resistance. Mol Med 14: 222‐231, 2008.
 244.Tilg H, Moschen AR. Role of adiponectin and PBEF/visfatin as regulators of inflammation: Involvement in obesity‐associated diseases. Clin Sci (Lond) 114: 275‐288, 2008.
 245.Todoric J, Loffler M, Huber J, Bilban M, Reimers M, Kadl A, Zeyda M, Waldhausl W, Stulnig TM. Adipose tissue inflammation induced by high‐fat diet in obese diabetic mice is prevented by n‐3 polyunsaturated fatty acids. Diabetologia 49: 2109‐2119, 2006.
 246.Tran TT, Yamamoto Y, Gesta S, Kahn CR. Beneficial effects of subcutaneous fat transplantation on metabolism. Cell Metab 7: 410‐420, 2008.
 247.Tsuboyama‐Kasaoka N, Takahashi M, Kim H, Ezaki O. Up‐regulation of liver uncoupling protein‐2 mRNA by either fish oil feeding or fibrate administration in mice. Biochem Biophys Res Commun 257: 879‐885, 1999.
 248.Ueno K, Anzai T, Jinzaki M, Yamada M, Jo Y, Maekawa Y, Kawamura A, Yoshikawa T, Tanami Y, Sato K, Kuribayashi S, Ogawa S. Increased epicardial fat volume quantified by 64‐multidetector computed tomography is associated with coronary atherosclerosis and totally occlusive lesions. Circ J 73: 1927‐1933, 2009.
 249.Valmori D, Raffin C, Raimbaud I, Ayyoub M. Human RORgammat+ TH17 cells preferentially differentiate from naive FOXP3+Treg in the presence of lineage‐specific polarizing factors. Proc Natl Acad Sci U S A 107: 19402‐19407, 2010.
 250.Van VE, Van Rijthoven EA, Kamperdijk EW, Beelen RH. Omental milky spots in the local immune response in the peritoneal cavity of rats. Anat Rec 244: 235‐245, 1996.
 251.Vieira Potter VJ, Strissel KJ, Xie C, Chang E, Bennett G, DeFuria J, Obin MS, Greenberg AS. Adipose tissue inflammation and reduced insulin sensitivity in ovariectomized mice occurs in the absence of increased adiposity. Endocrinology 153: 4266‐4277, 2012.
 252.Villaret A, Galitzky J, Decaunes P, Esteve D, Marques MA, Sengenes C, Chiotasso P, Tchkonia T, Lafontan M, Kirkland JL, Bouloumie A. Adipose tissue endothelial cells from obese human subjects: Differences among depots in angiogenic, metabolic, and inflammatory gene expression and cellular senescence. Diabetes 59: 2755‐2763, 2010.
 253.Vo H, Chiu J, Allaimo D, Mao C, Wang Y, Gong Y, Ow H, Porter T, Zhong X. High fat diet deviates PtC‐specific B1 B cell phagocytosis in obese mice. Immun Inflamm Dis 2: 254‐261, 2014.
 254.Wagner NM, Brandhorst G, Czepluch F, Lankeit M, Eberle C, Herzberg S, Faustin V, Riggert J, Oellerich M, Hasenfuss G, Konstantinides S, Schafer K. Circulating regulatory T cells are reduced in obesity and may identify subjects at increased metabolic and cardiovascular risk. Obesity (Silver Spring) 21: 461‐468, 2013.
 255.Waithe WI, Dauphinais C, Hathaway P, Hirschhorn K. Protein synthesis in stimulated lymphocytes. II. Amino acid requirements. Cell Immunol 17: 323‐334, 1975.
 256.Waring ME, Eaton CB, Lasater TM, Lapane KL. Incident diabetes in relation to weight patterns during middle age. Am J Epidemiol 171: 550‐556, 2010.
 257.Wascher TC, Lindeman JH, Sourij H, Kooistra T, Pacini G, Roden M. Chronic TNF‐alpha neutralization does not improve insulin resistance or endothelial function in “healthy” men with metabolic syndrome. Mol Med 17: 189‐193, 2011.
 258.Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW, Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112: 1796‐1808, 2003.
 259.Wensveen FM, Jelencic V, Valentic S, Sestan M, Wensveen TT, Theurich S, Glasner A, Mendrila D, Stimac D, Wunderlich FT, Bruning JC, Mandelboim O, Polic B. NK cells link obesity‐induced adipose stress to inflammation and insulin resistance. Nat Immunol 16: 376‐385, 2015.
 260.White JT, Cross EW, Burchill MA, Danhorn T, McCarter MD, Rosen HR, O'Connor B, Kedl RM. Virtual memory T cells develop and mediate bystander protective immunity in an IL‐15‐dependent manner. Nat Commun 7: 11291, 2016.
 261.Wilk S, Scheibenbogen C, Bauer S, Jenke A, Rother M, Guerreiro M, Kudernatsch R, Goerner N, Poller W, Elligsen‐Merkel D, Utku N, Magrane J, Volk HD, Skurk C. Adiponectin is a negative regulator of antigen‐activated T cells. Eur J Immunol 41: 2323‐2332, 2011.
 262.Winer DA, Winer S, Shen L, Wadia PP, Yantha J, Paltser G, Tsui H, Wu P, Davidson MG, Alonso MN, Leong HX, Glassford A, Caimol M, Kenkel JA, Tedder TF, McLaughlin T, Miklos DB, Dosch HM, Engleman EG. B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat Med 17: 610‐617, 2011.
 263.Winer S, Chan Y, Paltser G, Truong D, Tsui H, Bahrami J, Dorfman R, Wang Y, Zielenski J, Mastronardi F, Maezawa Y, Drucker DJ, Engleman E, Winer D, Dosch HM. Normalization of obesity‐associated insulin resistance through immunotherapy. Nat Med 15: 921‐929, 2009.
 264.Winer S, Paltser G, Chan Y, Tsui H, Engleman E, Winer D, Dosch HM. Obesity predisposes to Th17 bias. Eur J Immunol 39: 2629‐2635, 2009.
 265.Wisse BE. The inflammatory syndrome: The role of adipose tissue cytokines in metabolic disorders linked to obesity. J Am Soc Nephrol 15: 2792‐2800, 2004.
 266.Wolf AM, Wolf D, Rumpold H, Enrich B, Tilg H. Adiponectin induces the anti‐inflammatory cytokines IL‐10 and IL‐1RA in human leukocytes. Biochem Biophys Res Commun 323: 630‐635, 2004.
 267.Wolf D, Jehle F, Ortiz RA, Dufner B, Hoppe N, Colberg C, Lozhkin A, Bassler N, Rupprecht B, Wiedemann A, Hilgendorf I, Stachon P, Willecke F, Febbraio M, von Zur MC, Binder CJ, Bode C, Zirlik A, Peter K. CD40L deficiency attenuates diet‐induced adipose tissue inflammation by impairing immune cell accumulation and production of pathogenic IgG‐antibodies. PLoS One 7: e33026, 2012.
 268.Wu D, Molofsky AB, Liang HE, Ricardo‐Gonzalez RR, Jouihan HA, Bando JK, Chawla A, Locksley RM. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332: 243‐247, 2011.
 269.Wu D, Ren Z, Pae M, Guo W, Cui X, Merrill AH, Meydani SN. Aging up‐regulates expression of inflammatory mediators in mouse adipose tissue. J Immunol 179: 4829‐4839, 2007.
 270.Wu H, Ghosh S, Perrard XD, Feng L, Garcia GE, Perrard JL, Sweeney JF, Peterson LE, Chan L, Smith CW, Ballantyne CM. T‐cell accumulation and regulated on activation, normal T cell expressed and secreted upregulation in adipose tissue in obesity. Circulation 115: 1029‐1038, 2007.
 271.Wu L, Parekh VV, Gabriel CL, Bracy DP, Marks‐Shulman PA, Tamboli RA, Kim S, Mendez‐Fernandez YV, Besra GS, Lomenick JP, Williams B, Wasserman DH, Van KL. Activation of invariant natural killer T cells by lipid excess promotes tissue inflammation, insulin resistance, and hepatic steatosis in obese mice. Proc Natl Acad Sci U S A 109: E1143‐E1152, 2012.
 272.Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity‐related insulin resistance. J Clin Invest 112: 1821‐1830, 2003.
 273.Xu L, Kitade H, Ni Y, Ota T. Roles of chemokines and chemokine receptors in obesity‐associated insulin resistance and nonalcoholic fatty liver disease. Biomolecules 5: 1563‐1579, 2015.
 274.Xue J, Kass DJ, Bon J, Vuga L, Tan J, Csizmadia E, Otterbein L, Soejima M, Levesque MC, Gibson KF, Kaminski N, Pilewski JM, Donahoe M, Sciurba FC, Duncan SR. Plasma B lymphocyte stimulator and B cell differentiation in idiopathic pulmonary fibrosis patients. J Immunol 191: 2089‐2095, 2013.
 275.Yang H, Youm YH, Vandanmagsar B, Ravussin A, Gimble JM, Greenway F, Stephens JM, Mynatt RL, Dixit VD. Obesity increases the production of proinflammatory mediators from adipose tissue T cells and compromises TCR repertoire diversity: Implications for systemic inflammation and insulin resistance. J Immunol 185: 1836‐1845, 2010.
 276.Yang H, Youm YH, Vandanmagsar B, Rood J, Kumar KG, Butler AA, Dixit VD. Obesity accelerates thymic aging. Blood 114: 3803‐3812, 2009.
 277.Yeop HC, Kargi AY, Omer M, Chan CK, Wabitsch M, O'Brien KD, Wight TN, Chait A. Differential effect of saturated and unsaturated free fatty acids on the generation of monocyte adhesion and chemotactic factors by adipocytes: dissociation of adipocyte hypertrophy from inflammation. Diabetes 59: 386‐396, 2010.
 278.Yi Z, Stunz LL, Bishop GA. CD40‐mediated maintenance of immune homeostasis in the adipose tissue microenvironment. Diabetes 63: 2751‐2760, 2014.
 279.Ying W, Wollam J, Ofrecio JM, Bandyopadhyay G, El OD, Lee YS, Oh DY, Li P, Osborn O, Olefsky JM. Adipose tissue B2 cells promote insulin resistance through leukotriene LTB4/LTB4R1 signaling. J Clin Invest 127: 1019‐1030, 2017.
 280.Youm YH, Yang H, Sun Y, Smith RG, Manley NR, Vandanmagsar B, Dixit VD. Deficient ghrelin receptor‐mediated signaling compromises thymic stromal cell microenvironment by accelerating thymic adiposity. J Biol Chem 284: 7068‐7077, 2009.
 281.Zeng M, Liang Y, Li H, Wang M, Wang B, Chen X, Zhou N, Cao D, Wu J. Plasma metabolic fingerprinting of childhood obesity by GC/MS in conjunction with multivariate statistical analysis. J Pharm Biomed Anal 52: 265‐272, 2010.
 282.Zeyda M, Huber J, Prager G, Stulnig TM. Inflammation correlates with markers of T‐cell subsets including regulatory T cells in adipose tissue from obese patients. Obesity (Silver Spring) 19: 743‐748, 2011.
 283.Zhu M, Belkina AC, DeFuria J, Carr JD, Van Dyke TE, Gyurko R, Nikolajczyk BS. B cells promote obesity‐associated periodontitis and oral pathogen‐associated inflammation. J Leukoc Biol 96: 349‐357, 2014.
 284.Zuniga LA, Shen WJ, Joyce‐Shaikh B, Pyatnova EA, Richards AG, Thom C, Andrade SM, Cua DJ, Kraemer FB, Butcher EC. IL‐17 regulates adipogenesis, glucose homeostasis, and obesity. J Immunol 185: 6947‐6959, 2010.

Teaching Material

L. P. Bharath, B. C. Ip, B. S. Nikolajczyk. Adaptive Immunity and Metabolic Health: Harmony Becomes Dissonant in Obesity and Aging. Compr Physiol 7: 2017, 1307-1337.

Didactic Synopsis

The information in this article will help teach the following important points

  • Adipose tissue (AT) is both an immunological and metabolic organ, in addition to its well-known role as a storage organ.
  • Safe storage of lipids in AT is important to prevent free fatty acid-mediated immunological and metabolic dysregulation.
  • Lymphocytes (T and B cells among others) contribute significantly to the development of obesity- and aging-associated immune and metabolic dysregulation.
  • Obesity causes an imbalance in T cells and T cell responses in the AT causing increased Th1s and Th17s compared to Treg and Th2 responses.
  • Nutrients in general and fatty acids in particular (saturated vs. unsaturated fatty acids) can skew the AT immune responses, either to a pro- or anti-inflammatory phenotype.
  • “Inflammaging” and effects of menopause may in part account for age-associated metabolic declines and confound the associated shift in AT distribution in the elderly.
  • This review will provide an overview of the crosstalk between the adaptive immune system and metabolism in the context of obesity and aging.

Didactic Legends

The figures–in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. This figure illustrates the pathological changes that occur in the adipose tissue (AT) during the development of obesity

Teaching points:

  • The obese AT has increased presence of immune system cells that contrasts with lean AT.
  • The cells that infiltrate the AT and are shown in the figure include the T and B cells from the lymphoid lineage and the macrophages from the myeloid lineage.
  • Brief descriptions of the lineages of the immune cells, can be introduced here.
  • Apart from the cells mentioned in the image, there are other cells such as the neutrophils, NK cells, iNKT cells and dendritic cells that have altered frequencies and impact inflammation in obese AT.
  • Consequences of pro-inflammatory immune cell infiltration include elevated cytokines and a balance shift in Th1/Th2 responses and Th17/Treg ratio.
  • The subsets of T cells and the T cell responses can be introduced here.
  • Obese AT is also characterized by decreased glucose uptake and insulin sensitivity. Impaired insulin sensitivity eventually leads to the development of diabetes.
  • Pathological accumulation of lipids in the AT promotes oxidant stress, causing high intracellular levels of superoxide and hydrogen peroxide that can damage proteins by interfering with post-translational modifications. Increased oxidant stress can also affect organelles such as the endoplasmic reticulum and the mitochondria, causing a stress response, eventually leading to adipocyte necrosis and fibrosis of the AT.
  • AT dysfunction promotes hypercholesterolemia with high LDL and triglycerides and low levels of HDL, which will support the development of metabolic syndrome.

Figure 2.This figure illustrates the production of cytokines by PBMCs in response to treatment with normal and physiologically high levels of glucose.

Teaching points:

  • Elevated levels of glucose may result in increased production of pro inflammatory cytokines.
  • Pro-inflammatory cytokines are those that promote inflammation. Some examples of pro-inflammatory cytokines are IL-17A, IFNγ and TNFa.
  • Anti-inflammatory cytokines are opposing in action to the pro-inflammatory cytokines and they can ameliorate or prevent inflammation. Some examples of anti-inflammatory cytokines are IL-4, IL-10 and IL-13.
  • Some cytokines are pleiotrophic meaning they can be either pro- or anti-inflammatory and can play different roles in different cell types or under different stimulus. An example of a pleiotrophic cytokine is IL-6
  • High blood glucose concentrations have been shown to increase T cell chemokine expression and also alter the ability of B cells to produce antibodies.
  • When PBMCs were treated with physiologically high levels of glucose and stimulated with T cell-targeted stimuli, an increase in production of T cell cytokines IL-17A and IFN γ was observed in comparison to low glucose conditions.
  • No increase in classical diabetogenic cytokines such TNFα and IL-6 was observed in T cell-stimulated PBMCs from T2D versus the ND subjects.
  • A stimulus from excess glucose alone in the circulation can promote inflammation.

Figure 3. This figure illustrates the immunological events that occur within an obese AT

Teaching points:

  • An obese AT is a ripe environment for infiltration of proinflammatory cells.
  • Multiple types of adaptive immune cells (T cells, B cells, iNKTs etc.) and cells of the innate immune system, such as macrophages, increase in the obese AT. Since this review is on adaptive immune system, the cells of the innate immune system are not addressed in detail.
  • The AT adipocytes, B cells and macrophages can present antigens to the T cells and activate both CD4+ and CD8+ T cells. The MHC II (HLA for human) houses antigenic peptides in a groove that physically interacts with T cell receptors on the CD4+ T cells and the MHC I/peptide combiantion interacts with the receptors on the CD8+ T cells. These interactions lead to activation of T cells.
  • The activated T cells and macrophages produce cytokines that are either pro-inflammatory, anti-inflammatory or plieotropic,depending on the stimulus. In obese AT, the stimulus is pro-inflammatory and hence cytokines, such as the IL-6, IL-1b, TNFα and chemokines such as MCP1 are produced. The B cells produce the antibodies in response to antigens, the identity of which is currently unknown.
  • Th17 pro-inflammatory response also occur in the obese AT in people (but significantly less so in mice), resulting in the production of cytokines such as IL-17A/F, IL-21 and IL-22.
  • The pro-inflammatory responses, including inflammation from Th17s, are checked by Tregs (also known as suppressor T cells).
  • In obese AT, a decline in Tregs occur, resulting in exaggerated inflammatory responses. The presence of adipokines such as leptin downregulates Tregs and supports pro-inflammatory Th1s, thereby contributing to development of inflammation.

Figure 4. This figure illustrates that the aging AT is under a chronic inflammatory stimulus, which would eventually result in the development of adipocyte dysfunction.

Teaching points:

  • Inflammaging occurs systemically and in the AT due to environmental factors such as nutrient excess, exposure to environmental pollutants, and genetics of the individual. Aging-associated changes also occur at the cellular and molecular levels.
  • The primary changes that occur in aging ATare activation of inflammation, accumulation of toxic lipid metabolites, activation of pro-inflammatory pathways along with the development of oxidant stress.
  • The organelles in the aging AT such as the endoplasmic reticulum and mitochondria undergo a stress response due to accumulation of oxidants such as superoxide and hydrogen peroxide.
  • The dysfunctional adipocyte undergoes cell cycle arrest and eventually necrosis.


Related Articles:

Diabetes and Obesity
Immunity and Inflammation

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Leena P. Bharath, Blanche C. Ip, Barbara S. Nikolajczyk. Adaptive Immunity and Metabolic Health: Harmony Becomes Dissonant in Obesity and Aging. Compr Physiol 2017, 7: 1307-1337. doi: 10.1002/cphy.c160042