Abstract
Intracellular changes in immune cells lead to metabolic dysfunction, which is termed immunometabolism. Chronic inflammation is a hallmark of aging; this phenomenon is described as inflamm-aging. Immunometabolism and inflamm-aging are closely linked to obesity, insulin resistance, type 2 diabetes (T2D), cardiovascular diseases, and cancers, which consequently reduce life span and health span of the elderly. Ghrelin is an orexigenic hormone that regulates appetite and food intake. Ghrelin’s functions are mediated through its receptor, growth hormone secretagogue receptor (GHS-R). Ghrelin and GHS-R have important roles in age-associated obesity, insulin resistance, and T2D. In this chapter, we have discussed the roles of ghrelin signaling in diet-induced obesity and normal aging as it relates to energy metabolism and inflammation in key metabolic tissues and organs. The new findings reveal that ghrelin signaling is an important regulatory mechanism for immunometabolism and inflamm-aging. Ghrelin signaling offers an exciting novel therapeutic strategy for treatment of obesity and insulin resistance of the elderly.
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References
Health UDo, Services H (2010) Multiple chronic conditions—a strategic framework: optimum health and quality of life for individuals with multiple chronic conditions. US Department of Health and Human Services 2, Washington, DC
Gerteis J, Izrael D, Deitz D, LeRoy L, Ricciardi R, Miller T, Basu J (2014) Multiple chronic conditions chartbook. Agency for Healthcare Research and Quality, Rockville
Kabakov E, Norymberg C, Osher E, Koffler M, Tordjman K, Greenman Y, Stern N (2006) Prevalence of hypertension in type 2 diabetes mellitus: impact of the tightening definition of high blood pressure and association with confounding risk factors. J Cardiometab Syndr 1(2):95–101
Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, White A, Cushman WC, White W, Sica D (2008) Resistant hypertension: diagnosis, evaluation, and treatment. Circulation 117(25):e510–e526
Rimm EB, Stampfer MJ, Giovannucci E, Ascherio A, Spiegelman D, Colditz GA, Willett WC (1995) Body size and fat distribution as predictors of coronary heart disease among middle-aged and older US men. Am J Epidemiol 141(12):1117–1127
Weiss CO, Boyd CM, Yu Q, Wolff JL, Leff B (2007) Patterns of prevalent major chronic disease among older adults in the United States. JAMA 298(10):1158–1162
López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153(6):1194–1217
Kaeberlein M, Rabinovitch PS, Martin GM (2015) Healthy aging: the ultimate preventative medicine. Science 350(6265):1191–1193
Pradhan G, Samson SL, Sun Y (2013) Ghrelin: much more than a hunger hormone. Curr Opin Clin Nutr Metab Care 16(6):619
Murphy SL, Xu J, Kochanek KD (2012) Deaths: preliminary data for 2010. National vital statistics reports: from the Centers for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System 60 (4):1–52
Ward BW, Schiller JS, Goodman RA (2014) Peer reviewed: multiple chronic conditions among us adults: a 2012 update. Prev Chronic Dis 11
Ogden CL, Carroll MD, Fryar CD, Flegal KM (2015) Prevalence of obesity among adults and youth: United States, 2011–2014. US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics
Wang YC, McPherson K, Marsh T, Gortmaker SL, Brown M (2011) Health and economic burden of the projected obesity trends in the USA and the UK. Lancet 378(9793):815–825
Organization WH (2015) Obesity and overweight. Fact sheet No 311.2015. Ref Type: Online Source
Guo S (2014) Insulin signaling, resistance, and metabolic syndrome: insights from mouse models into disease mechanisms. J Endocrinol 220(2):T1–T23
Abbasi F, Brown BW, Lamendola C, McLaughlin T, Reaven GM (2002) Relationship between obesity, insulin resistance, and coronary heart disease risk. J Am Coll Cardiol 40(5):937–943
McArdle MA, Finucane OM, Connaughton RM, McMorrow AM, Roche HM (2013) Mechanisms of obesity-induced inflammation and insulin resistance: insights into the emerging role of nutritional strategies. Front Endocrinol 4
Gregoire FM, Smas CM, Sul HS (1998) Understanding adipocyte differentiation. Physiol Rev 78(3):783–809
Greenberg AS, Obin MS (2006) Obesity and the role of adipose tissue in inflammation and metabolism. Am J Clin Nutr 83(2):461S–465S
Lin L, Lee JH, Bongmba OY, Ma X, Zhu X, Sheikh-Hamad D, Sun Y (2014) The suppression of ghrelin signaling mitigates age-associated thermogenic impairment. Aging (Albany NY) 6(12):1019
Cannon B, Nedergaard J (2011) Nonshivering thermogenesis and its adequate measurement in metabolic studies. J Exp Biol 214(2):242–253
Boden G (2008) Obesity and free fatty acids. Endocrinol Metab Clin N Am 37(3):635–646
Zhang HH, Halbleib M, Ahmad F, Manganiello VC, Greenberg AS (2002) Tumor necrosis factor-α stimulates lipolysis in differentiated human adipocytes through activation of extracellular signal-related kinase and elevation of intracellular cAMP. Diabetes 51(10):2929–2935
Souza SC, Palmer HJ, Kang YH, Yamamoto MT, Muliro KV, Eric Paulson K, Greenberg AS (2003) TNF-α induction of lipolysis is mediated through activation of the extracellular signal related kinase pathway in 3T3-L1 adipocytes. J Cell Biochem 89(6):1077–1086
Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259(5091):87–91
Klover PJ, Zimmers TA, Koniaris LG, Mooney RA (2003) Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. Diabetes 52(11):2784–2789
Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM (2001) C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 286(3):327–334
Ridker PM, Rifai N, Stampfer MJ, Hennekens CH (2000) Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 101(15):1767–1772
van der Heijden RA, Sheedfar F, Morrison MC, Hommelberg PP, Kor D, Kloosterhuis NJ, Gruben N, Youssef SA, de Bruin A, Hofker MH (2015) High-fat diet induced obesity primes inflammation in adipose tissue prior to liver in C57BL/6j mice. Aging (Albany NY) 7(4):256
Dong X, Park S, Lin X, Copps K, Yi X, White MF (2006) Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth. J Clin Investig 116(1):101
Copps K, White M (2012) Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia 55(10):2565–2582
Lam TK, Yoshii H, Haber CA, Bogdanovic E, Lam L, Fantus IG, Giacca A (2002) Free fatty acid-induced hepatic insulin resistance: a potential role for protein kinase C-δ. Am J Physiol Endocrinol Metab 283(4):E682–E691
Samuel VT, Liu Z-X, Qu X, Elder BD, Bilz S, Befroy D, Romanelli AJ, Shulman GI (2004) Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem 279(31):32345–32353
Paredes-Turrubiarte G, González-Chávez A, Pérez-Tamayo R, Salazar-Vázquez BY, Hernández VS, Garibay-Nieto N, Fragoso JM, Escobedo G (2016) Severity of non-alcoholic fatty liver disease is associated with high systemic levels of tumor necrosis factor alpha and low serum interleukin 10 in morbidly obese patients. Clin Exp Med 16(2):193–202
Czaja AJ (2014) Hepatic inflammation and progressive liver fibrosis in chronic liver disease. World J Gastroenterol: WJG 20(10):2515
Nieto-Vazquez I, Fernández-Veledo S, de Alvaro C, Lorenzo M (2008) Dual role of interleukin-6 in regulating insulin sensitivity in murine skeletal muscle. Diabetes 57(12):3211–3221
DeFronzo RA, Tripathy D (2009) Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care 32(suppl 2):S157–S163
Boden G (2006) Fatty acid—induced inflammation and insulin resistance in skeletal muscle and liver. Curr Diab Rep 6(3):177–181
Torres S, De Sanctis J, de Briceno L, Hernandez N, Finol H (2004) Inflammation and nitric oxide production in skeletal muscle of type 2 diabetic patients. J Endocrinol 181(3):419–427
Hong E-G, Ko HJ, Cho Y-R, Kim H-J, Ma Z, Tim YY, Friedline RH, Kurt-Jones E, Finberg R, Fischer MA (2009) Interleukin-10 prevents diet-induced insulin resistance by attenuating macrophage and cytokine response in skeletal muscle. Diabetes 58(11):2525–2535
Fujiwara N, Kobayashi K (2005) Macrophages in inflammation. Curr Drug Targets Inflamm Allergy 4(3):281–286
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 Investig 112(12):1796
Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K-i, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K (2006) MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Investig 116(6):1494
Lumeng CN, DeYoung SM, Bodzin JL, Saltiel AR (2007) Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes 56(1):16–23
Castoldi A, Naffah de Souza C, Câmara NOS, Moraes-Vieira PM (2016) The macrophage switch in obesity development. Front Immunol 6:637
Liu Y-C, Zou X-B, Chai Y-F, Yao Y-M (2014) Macrophage polarization in inflammatory diseases. Int J Biol Sci 10(5):520
Chinetti-Gbaguidi G, Staels B (2011) Macrophage polarization in metabolic disorders: functions and regulation. Curr Opin Lipidol 22(5):365
Xu X, Grijalva A, Skowronski A, van Eijk M, Serlie MJ, Ferrante AW (2013) Obesity activates a program of lysosomal-dependent lipid metabolism in adipose tissue macrophages independently of classic activation. Cell Metab 18(6):816–830
Boden G, Chen X, Ruiz J, White JV, Rossetti L (1994) Mechanisms of fatty acid-induced inhibition of glucose uptake. J Clin Investig 93(6):2438
Nguyen MA, Favelyukis S, Nguyen A-K, Reichart D, Scott PA, Jenn A, Liu-Bryan R, Glass CK, Neels JG, Olefsky JM (2007) A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways. J Biol Chem 282(48):35279–35292
Juhas U, Ryba-Stanisławowska M, Szargiej P, Myśliwska J (2015) Different pathways of macrophage activation and polarization. Adv Hyg Exp Med/Postepy Higieny i Medycyny Doswiadczalnej 69:496–502
Wang N, Liang H, Zen K (2014) Molecular mechanisms that influence the macrophage m1–m2 polarization balance. Front Immunol 5
Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS (2006) TLR4 links innate immunity and fatty acid–induced insulin resistance. J Clin Investig 116(11):3015
Orr JS, Puglisi MJ, Ellacott KL, Lumeng CN, Wasserman DH, Hasty AH (2012) Toll-like receptor 4 deficiency promotes the alternative activation of adipose tissue macrophages. Diabetes 61(11):2718–2727
Claeys S, De Belder T, Holtappels G, Gevaert P, Verhasselt B, Van Cauwenberge P, Bachert C (2003) Human β-defensins and toll-like receptors in the upper airway. Allergy 58(8):748–753
Renshaw M, Rockwell J, Engleman C, Gewirtz A, Katz J, Sambhara S (2002) Cutting edge: impaired Toll-like receptor expression and function in aging. J Immunol 169(9):4697–4701
Olah ME, Caldwell CC (2003) Adenosine receptors and mammalian toll-like receptors: synergism in macrophages. Mol Interv 3(7):370
Linehan E, Dombrowski Y, Snoddy R, Fallon PG, Kissenpfennig A, Fitzgerald DC (2014) Aging impairs peritoneal but not bone marrow-derived macrophage phagocytosis. Aging Cell 13(4):699–708
Wong CK, Smith CA, Sakamoto K, Kaminski N, Koff JL, Goldstein DR (2017) Aging impairs alveolar macrophage phagocytosis and increases influenza-induced mortality in mice. J Immunol 199(3):1060–1068
Nathan CF (1987) Secretory products of macrophages. J Clin Investig 79(2):319
Boehmer ED, Goral J, Faunce DE, Kovacs EJ (2004) Age-dependent decrease in Toll-like receptor 4-mediated proinflammatory cytokine production and mitogen-activated protein kinase expression. J Leukoc Biol 75(2):342–349
Chelvarajan RL, Collins SM, Van Willigen JM, Bondada S (2005) The unresponsiveness of aged mice to polysaccharide antigens is a result of a defect in macrophage function. J Leukoc Biol 77(4):503–512
Roubenoff R, Harris TB, Abad LW, Wilson PW, Dallal GE, Dinarello CA (1998) Monocyte cytokine production in an elderly population: effect of age and inflammation. J Gerontol Ser A Biol Med Sci 53(1):M20–M26
Van Duin D, Mohanty S, Thomas V, Ginter S, Montgomery RR, Fikrig E, Allore HG, Medzhitov R, Shaw AC (2007) Age-associated defect in human TLR-1/2 function. J Immunol 178(2):970–975
Gibon E, Loi F, Córdova LA, Pajarinen J, Lin T, Lu L, Nabeshima A, Yao Z, Goodman SB (2016) Aging affects bone marrow macrophage polarization: relevance to bone healing. Regen Eng Translat Med 2(2):98–104
Ponnappan S, Ponnappan U (2011) Aging and immune function: molecular mechanisms to interventions. Antioxid Redox Signal 14(8):1551–1585
Franceschi C, Campisi J (2014) Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci 69(Suppl_1):S4–S9
Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G (2000) Inflamm-aging: an evolutionary perspective on immunosenescence. Ann N Y Acad Sci 908(1):244–254
Bruunsgaard H, Andersen-Ranberg K, vB Hjelmborg J, Pedersen BK, Jeune B (2003) Elevated levels of tumor necrosis factor alpha and mortality in centenarians. Am J Med 115(4):278–283
Ershler WB, Keller ET (2000) Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu Rev Med 51(1):245–270
O’mahony L, Holland J, Jackson J, Feighery C, Hennessy T, Mealy K (1998) Quantitative intracellular cytokine measurement: age-related changes in proinflammatory cytokine production. Clin Exp Immunol 113(2):213
Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, Purnell JQ (2002) Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 346(21):1623–1630
Landi F, Calvani R, Tosato M, Martone AM, Ortolani E, Savera G, Sisto A, Marzetti E (2016) Anorexia of aging: risk factors, consequences, and potential treatments. Nutrients 8(2):69
Sun Y, Garcia JM, Smith RG (2007) Ghrelin and growth hormone secretagogue receptor expression in mice during aging. Endocrinology 148(3):1323–1329
Lin L, Saha PK, Ma X, Henshaw IO, Shao L, Chang BH, Buras ED, Tong Q, Chan L, McGuinness OP (2011) Ablation of ghrelin receptor reduces adiposity and improves insulin sensitivity during aging by regulating fat metabolism in white and brown adipose tissues. Aging Cell 10(6):996–1010
Lin L, Lee JH, Buras ED, Yu K, Wang R, Smith CW, Wu H, Sheikh-Hamad D, Sun Y (2016) Ghrelin receptor regulates adipose tissue inflammation in aging. Aging (Albany NY) 8(1):178
Pfannenberg C, Werner MK, Ripkens S, Stef I, Deckert A, Schmadl M, Reimold M, Häring H-U, Claussen CD, Stefan N (2010) Impact of age on the relationships of brown adipose tissue with sex and adiposity in humans. Diabetes 59(7):1789–1793
Hassouna R, Zizzari P, Tolle V (2010) The ghrelin/obestatin balance in the physiological and pathological control of growth hormone secretion, body composition and food intake. J Neuroendocrinol 22(7):793–804
Archer SL (2013) Mitochondrial dynamics—mitochondrial fission and fusion in human diseases. N Engl J Med 369(23):2236–2251
Ma X, Lin L, Yue J, Pradhan G, Qin G, Minze L, Wu H, Sheikh-Hamad D, Smith CW, Sun Y (2013) Ghrelin receptor regulates HFCS-induced adipose inflammation and insulin resistance. Nutr Diabetes 3(12):e99
Chabot F, Caron A, Laplante M, St-Pierre DH (2014) Interrelationships between ghrelin, insulin and glucose homeostasis: physiological relevance. World J Diabetes 5(3):328
Guillory B, Ja C, Patel S, Luo J, Splenser A, Mody A, Ding M, Baghaie S, Anderson B, Iankova B (2017) Deletion of ghrelin prevents aging-associated obesity and muscle dysfunction without affecting longevity. Aging Cell 16:859
Cappellari GG, Zanetti M, Semolic A, Vinci P, Ruozi G, Falcione A, Filigheddu N, Guarnieri G, Graziani A, Giacca M (2016) Unacylated ghrelin reduces skeletal muscle reactive oxygen species generation and inflammation and prevents high-fat diet induced hyperglycemia and whole-body insulin resistance in rodents. Diabetes:db151019
Wu C-S, Bongmba OY, Yue J, Lee JH, Lin L, Saito K, Pradhan G, Li D-P, Pan H-L, Xu A (2017) Suppression of GHS-R in AgRP neurons mitigates diet-induced obesity by activating thermogenesis. Int J Mol Sci 18(4):832
Lee JH, Lin L, Xu P, Saito K, Wei Q, Meadows AG, Bongmba OY, Pradhan G, Zheng H, Xu Y (2016) Neuronal deletion of ghrelin receptor almost completely prevents diet-induced obesity. Diabetes:db151587
Varela L, Horvath TL (2012) Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis. EMBO Rep 13(12):1079–1086
Coll AP, Farooqi IS, O’Rahilly S (2007) The hormonal control of food intake. Cell 129(2):251–262
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Fang, C., Xu, H., Guo, S., Mertens-Talcott, S.U., Sun, Y. (2018). Ghrelin Signaling in Immunometabolism and Inflamm-Aging. In: Wu, Q., Zheng, R. (eds) Neural Regulation of Metabolism. Advances in Experimental Medicine and Biology, vol 1090. Springer, Singapore. https://doi.org/10.1007/978-981-13-1286-1_9
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