Abstract
Obesity is an endemic pathophysiological condition and a comorbidity associated with hypercholesterolemia, hypertension, cardiovascular disease, type 2 diabetes mellitus, and cancer. The adipose tissue of obese subjects shows hypertrophic adipocytes, adipocyte hyperplasia, and chronic low-grade inflammation. S100 proteins are Ca2+-binding proteins exclusively expressed in vertebrates in a cell-specific manner. They have been implicated in the regulation of a variety of functions acting as intracellular Ca2+ sensors transducing the Ca2+ signal and extracellular factors affecting cellular activity via ligation of a battery of membrane receptors. Certain S100 proteins, namely S100A4, the S100A8/S100A9 heterodimer and S100B, have been implicated in the pathophysiology of obesity-promoting macrophage-based inflammation via toll-like receptor 4 and/or receptor for advanced glycation end-products ligation. Also, serum levels of S100A4, S100A8/S100A9, S100A12, and S100B correlate with insulin resistance/type 2 diabetes, metabolic risk score, and fat cell size. Yet, secreted S100B appears to exert neurotrophic effects on sympathetic fibers in brown adipose tissue contributing to the larger sympathetic innervation of this latter relative to white adipose tissue. In the present review we first briefly introduce S100 proteins and then critically examine their role(s) in adipose tissue and obesity.
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Abbreviations
- ACTH:
-
Adrenocorticotropin
- ATM:
-
Adipose tissue macrophage
- BAT:
-
Brown adipose tissue
- BMI:
-
Body mass index
- BMP-7:
-
Bone morphogenetic protein 7
- CLSTN3β:
-
Calsyntenin 3β
- DAMP:
-
Damage-associated molecular pattern
- EEC:
-
Enteric endocrine cell
- GIP:
-
Glucose-dependent insulinotropic polypeptide
- GIPR:
-
GIP receptor
- GLP-1:
-
Glucagon-like peptide-1
- HFD:
-
High-fat diet
- IL:
-
Interleukin
- IFN-γ:
-
Interferon-γ
- LC n-3 PUFA:
-
Long-chain omega-3 polyunsaturated fatty acids
- LPS:
-
Lipopolysaccharide
- RAGE:
-
Receptor for advanced glycation endproducts
- RyR:
-
Ryanodine receptor
- SVFC:
-
Stromal vascular fraction cell
- TLR:
-
Toll-like receptor
- TNF-α:
-
Tumor necrosis factor-α
- VAT:
-
Visceral adipose tissue
- UCP1:
-
Uncoupling protein 1
- WAT:
-
White adipose tissue
References
James WPT, McPherson K (2017) The costs of overweight. Lancet Public Health 2:e203–e204
Malik VS, Willett WC, Hu FB (2013) Global obesity: trends, risk factors and policy implications. Nat Rev Endocrinol 9:13–27
Kassotis CD, Stapleton HM (2019) Endocrine-mediated mechanisms of metabolic disruption and new approaches to examine the public health threat. Front Endocrinol (Lausanne) 10:39
NCD Risk Factor Collaboration (2016) Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population- based measurement studies with 19.2 million participants. Lancet 387:1377–1396
Ng M, Fleming T, Robinson M et al (2014) Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 384:766–781
Quail DF, Dannenberg AJ (2019) The obese adipose tissue microenvironment in cancer development and progression. Nat Rev Endocrinol 15:139–154
Chouchani ET, Kajimura S (2019) Metabolic adaptation and maladaptation in adipose tissue. Nat Metab 1:189–200
Ghaben AL, Schere PE (2019) Adipogenesis and metabolic health. Nat Rev Mol Cell Biol 20:242–258
Haider N, Larose L (2019) Harnessing adipogenesis to prevent obesity. Adipocyte 8:1–7
Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, Wang S, Fortier M, Greenberg AS, Obin MS (2005) Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 46:2347–2355
Haka AS, Barbosa-Lorenzi VC, Lee HJ, Falcone DJ, Hudis CA, Dannenberg AJ, Maxfield FR (2016) Exocytosis of macrophage lysosomes leads to digestion of apoptotic adipocytes and foam cell formation. J Lipid Res 57:980–992
Lumeng CN, Bodzin JL, Saltiel AR (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117:175–184
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 (2009) Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med 15:921–929
Smorlesi A, Frontini A, Giordano A, Cinti S (2012) The adipose organ: white-brown adipocyte plasticity and metabolic inflammation. Obes Rev 13(Suppl 2):83–96
Reilly SM, Saltiel AR (2017) Adapting to obesity with adipose tissue inflammation. Nat Rev Endocrinol 13:633–643
Lee YS, Wollam J, Olefsky JM (2018) An integrated view of immunometabolism. Cell 172:22–40
Xue W, Fan Z, Li L, Lu J, Zhai Y, Zhao J (2019) The chemokine system and its role in obesity. J Cell Physiol 234:3336–3346
Koliaki C, Liatis S, Kokkinos A (2019) Obesity and cardiovascular disease: revisiting an old relationship. Metabolism 92:98–107
Kratz M, Coats BR, Hisert KB, Hagman D, Mutskov V, Peris E, Schoenfelt KQ, Kuzma JN, Larson I, Billing PS, Landerholm RW, Crouthamel M, Gozal D, Hwang S, Singh PK, Becker L (2014) Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages. Cell Metab 20:614–625
Coats BR, Schoenfelt KQ, Barbosa-Lorenzi VC, Peris E, Cui C, Hoffman A, Zhou G, Fernandez S, Zhai L, Hall BA, Haka AS, Shah AM, Reardon CA, Brady MJ, Rhodes CJ, Maxfield FR, Becker L (2017) Metabolically activated adipose tissue macrophages perform detrimental and beneficial functions during diet-induced obesity. Cell Rep 20:3149–3161
Hill DA, Lim HW, Kim YH, Ho WY, Foong YH, Nelson VL, Nguyen HCB, Chegireddy K, Kim J, Habertheuer A, Vallabhajosyula P, Kambayashi T, Won KJ, Lazar MA (2018) Distinct macrophage populations direct inflammatory versus physiological changes in adipose tissue. Proc Natl Acad Sci USA 115:E5096–E5105
Cho KW, Zamarron BF, Muir LA, Singer K, Porsche CE, DelProposto JB, Geletka L, Meyer KA, O’Rourke RW, Lumeng CN (2016) Adipose tissue dendritic cells are independent contributors to obesity-induced inflammation and insulin resistance. J Immunol 197:3650–3661
Kolodin D, van Panhuys N, Li C, Magnuson AM, Cipolletta D, Miller CM, Wagers A, Germain RN, Benoist C, Mathis D (2015) Antigen- and cytokine-driven accumulation of regulatory T cells in visceral adipose tissue of lean mice. Cell Metab 21:543–557
Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A, Lee J, Goldfine AB, Benoist C, Shoelson S, Mathis D (2009) Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 15:930–939
Eller K, Kirsch A, Wolf AM, Sopper S, Tagwerker A, Stanzl U, Wolf D, Patsch W, Rosenkranz AR, Eller P (2001) Potential role of regulatory T cells in reversing obesity-linked insulin resistance and diabetic nephropathy. Diabetes 60:2954–2962
Miyawaki K, Yamada Y, Ban N, Ihara Y, Tsukiyama K, Zhou H, Fujimoto S, Oku A, Tsuda K, Toyokuni S, Hiai H, Mizunoya W, Fushiki T, Holst JJ, Makino M, Tashita A, Kobara Y, Tsubamoto Y, Jinnouchi T, Jomori T, Seino Y (2002) Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat Med 8:738–742
Gögebakan Ö, Andres J, Biedasek K, Mai K, Kühnen P, Krude H, Isken F, Rudovich N, Osterhoff MA, Kintscher U, Nauck M, Pfeiffer AF, Spranger J (2012) Glucose-dependent insulinotropic polypeptide reduces fat-specific expression and activity of 11β -hydroxysteroid dehydrogenase type 1 and inhibits release of free fatty acids. Diabetes 61:292–300
Al Massadi O, López M, Tschöp M, Diéguez C, Nogueiras R (2017) Current understanding of the hypothalamic ghrelin pathways inducing appetite and adiposity. Trends Neurosci 40:167–180
Gribble FM, Reimann F (2016) Enteroendocrine cells: chemosensors in the intestinal epithelium. Annu Rev Physiol 78:277–299
Nauck MA, Meier JJ (2018) Incretin hormones: their role in health and disease. Diabetes Obes Metab Suppl 1:5–21
Dupre J, Ross SA, Watson D, Brown JC (1973) Stimulation of insulin secretion by gastric inhibitory polypeptide in man. J Clin Endocrinol Metab 37:826–828
McLaughlin JT, McKie S (2016) Human brain responses to gastrointestinal nutrients and gut hormones. Curr Opin Pharmacol 31:8–12
Monteiro MP, Batterham RL (2017) The importance of the gastrointestinal tract in controlling food intake and regulating energy balance. Gastroenterology 152:1707–1717
Al-Najim W, Docherty NG, le Roux CW (2018) Food intake and eating behavior after bariatric surgery. Physiol Rev 98:1113–1141
Papathanasiou A, Nolen-Doerr E, Farr O, Geoffrey Mantzoros CS, Prize Harris (2018) Novel pathways regulating neuroendocrine function, energy homeostasis and metabolism in humans. Eur J Endocrinol 180:R59–R71
Christensen M, Vedtofte L, Holst JJ, Vilsbøll T, Knop FK (2011) Glucose-dependent insulinotropic polypeptide: a bifunctional glucose-dependent regulator of glucagon and insulin secretion in humans. Diabetes 60:3103–3109
Pfeiffer AFH, Keyhani-Nejad F (2018) High glycemic index metabolic damage—a pivotal role of GIP and GLP-1. Trends Endocrinol Metab 29:289–299
Holst JJ (2019) From the incretin concept and the discovery of GLP-1 to today’s diabetes therapy. Front Endocrinol (Lausanne) 10:260
Nolen-Doerr E, Stockman MC, Rizo I (2019) Mechanism of glucagon-like peptide 1 improvements in type 2 diabetes mellitus and obesity. Curr Obes Rep. https://doi.org/10.1007/s13679-019-00350-4
Donato R, Cannon BR, Sorci G, Riuzzi F, Hsu K, Weber DJ, Geczy CL (2013) Functions of S100 proteins. Curr Mol Med 13:24–57
Marenholz I, Heizmann CW, Fritz G (2004) S100 proteins in mouse and man: from evolution to function and pathology (including an update of the nomenclature). Biochem Biophys Res Commun 322:1111–1122
Santamaria-Kisiel L, Rintala-Dempsey AC, Shaw GS (2006) Calcium-dependent and -independent interactions of the S100 protein family. Biochem J 396:201–214
Goyette J, Geczy CL (2011) Inflammation-associated S100 proteins: new mechanisms that regulate function. Amino Acids 41:821–842
Pruenster M, Vogl T, Roth J, Sperandio M (2016) S100A8/A9: from basic science to clinical application. Pharmacol Ther 167:120–131
Lim SY, Raftery MJ, Geczy CL (2011) Oxidative modifications of DAMPs suppress inflammation: the case for S100A8 and S100A9. Antioxid Redox Signal 15:2235–2248
Austermann J, Spiekermann C, Roth J (2018) S100 proteins in rheumatic diseases. Nat Rev Rheumatol 14:528–541
Donato R (2001) S100: a multigenic family of calcium modulated proteins of the EF-hand type with intracellular and extracellular functional roles. Int J Biochem Cell Biol 33:637–638
Averill MM, Kerkhoff C, Bornfeldt KE (2012) S100A8 and S100A9 in cardiovascular biology and disease. Arterioscler Thromb Vasc Biol 32:223–229
Gross SR, Sin CG, Barraclough R, Rudland PS (2014) Joining S100 proteins and migration: for better or for worse, in sickness and in health. Cell Mol Life Sci 71:1551–1579
Donato R, Sorci G, Giambanco I (2017) S100A6 protein: functional roles. Cell Mol Life Sci 74:2749–2760
Riuzzi F, Sorci G, Arcuri C, Giambanco I, Bellezza I, Minelli A, Donato R (2018) Cellular and molecular mechanisms of sarcopenia: the S100B perspective. J Cachexia Sarcopenia Muscle 9:1255–1268
Wang S, Song R, Wang Z, Jing Z, Wang S, Ma J (2018) S100A8/A9 in inflammation. Front Immunol 9:1298
Most P, Bernotat J, Ehlermann P, Pleger ST, Reppel M, Börries M, Niroomand F, Pieske B, Janssen PM, Eschenhagen T, Karczewski P, Smith GL, Koch WJ, Katus HA, Remppis A (2001) S100A1: a regulator of myocardial contractility. Proc Natl Acad Sci USA 98:13889–13894
Kiewitz R, Acklin C, Schäfer BW, Maco B, Uhrík B, Wuytack F, Erne P, Heizmann CW (2003) Ca2+-dependent interaction of S100A1 with the sarcoplasmic reticulum Ca2+-ATPase2a and phospholamban in the human heart. Biochem Biophys Res Commun 306:550–557
Kettlewell S, Most P, Currie S, Koch WJ, Smith GL (2005) S100A1 increases the gain of excitation-contraction coupling in isolated rabbit ventricular cardiomyocytes. J Mol Cell Cardiol 39:900–910
Most P, Pleger ST, Völkers M, Heidt B, Boerries M, Weichenhan D, Löffler E, Janssen PM, Eckhart AD, Martini J, Williams ML, Katus HA, Remppis A, Koch WJ (2004) Cardiac adenoviral S100A1 gene delivery rescues failing myocardium. J Clin Invest 114:1550–1563
Most P, Seifert H, Gao E, Funakoshi H, Völkers M, Heierhorst J, Remppis A, Pleger ST, DeGeorge BR Jr, Eckhart AD, Feldman AM, Koch WJ (2006) Cardiac S100A1 protein levels determine contractile performance and propensity toward heart failure after myocardial infarction. Circulation 114:1258–1268
Treves S, Scutari E, Robert M, Groh S, Ottolia M, Prestipino G, Ronjat M, Zorzato F (1997) Interaction of S100A1 with the Ca2+ release channel (ryanodine receptor) of skeletal muscle. Biochemistry 36:11496–11503
Prosser BL, Wright NT, Hernãndez-Ochoa EO, Varney KM, Liu Y, Olojo RO, Zimmer DB, Weber DJ, Schneider MF (2008) S100A1 binds to the calmodulin-binding site of ryanodine receptor and modulates skeletal muscle excitation-contraction coupling. J Biol Chem 283:5046–5057
Prosser BL, Hernández-Ochoa EO, Zimmer DB, Schneider MF (2009) The Qγ component of intra-membrane charge movement is present in mammalian muscle fibres, but suppressed in the absence of S100A1. J Physiol 587:4523–4541
Heierhorst J, Kobe B, Feil SC, Parker MW, Benian GM, Weiss KR, Kemp BE (1996) Ca2+/S100 regulation of giant protein kinases. Nature 380:636–639
Yamasaki R, Berri M, Wu Y, Trombitás K, McNabb M, Kellermayer MS, Witt C, Labeit D, Labeit S, Greaser M, Granzier H (2001) Titin-actin interaction in mouse myocardium: passive tension modulation and its regulation by calcium/S100A1. Biophys J 81:2297–2313
Völkers M, Rohde D, Goodman C, Most P (2010) S100A1: a regulator of striated muscle sarcoplasmic reticulum Ca2+ handling, sarcomeric, and mitochondrial function. J Biomed Biotechnol 2010:178614
Rambotti MG, Giambanco I, Spreca A, Donato R (1999) S100B and S100A1 proteins in bovine retina: their calcium-dependent stimulation of a membrane-bound guanylate cyclase activity as investigated by ultracytochemistry. Neuroscience 92:1089–1101
Kato K, Suzuki F, Ogasawara N (1988) Induction of S100 protein in 3T3-L1 cells during differentiation to adipocytes and its liberating by lipolytic hormones. Eur J Biochem 177:461–466
Cinti S, Cigolini M, Morroni M, Zingaretti MC (1989) S-100 protein in white preadipocytes: an immunoelectronmicroscopic study. Anat Rec 224:466–472
Zoico E, Di Francesco V, Olioso D, Fratta Pasini AM, Sepe A, Bosello O, Cinti S, Cominacini L, Zamboni M (2010) In vitro aging of 3T3-L1 mouse adipocytes leads to altered metabolism and response to inflammation. Biogerontology 11:111–122
Grum-Schwensen B, Klingelhofer J, Berg CH, El-Naaman C, Grigorian M, Lukanidin E, Ambartsumian N (2005) Suppression of tumor development and metastasis formation in mice lacking the S100A4(mts1) gene. Cancer Res 65:3772–3780
Dmytriyeva O, Pankratova S, Owczarek S, Sonn K, Soroka V, Ridley CM, Marsolais A, Lopez-Hoyos M, Ambartsumian N, Lukanidin E, Bock E, Berezin V, Kiryushko D (2012) The metastasis-promoting S100A4 protein confers neuroprotection in brain injury. Nat Commun 3:1197
Pankratova S, Klingelhofer J, Dmytriyeva O, Owczarek S, Renziehausen A, Syed N, Porter AE, Dexter DT, Kiryushko D (2018) The S100A4 protein signals through the ErbB4 receptor to promote neuronal survival. Theranostics 8:3977–3990
Arner P, Petrus P, Esteve D, Boulomié A, Näslund E, Thorell A, Gao H, Dahlman I, Rydén M (2018) Screening of potential adipokines identifies S100A4 as a marker of pernicious adipose tissue and insulin resistance. Int J Obes (Lond) 42:2047–2056
EL Naaman C, Grum-Schwensen B, Mansouri A, Grigorian M, Santoni-Rugiu E, Hansen T, Kriajevska M, Schafer BW, Heizmann CW, Lukanidin E, Ambartsumian N (2004) Cancer predisposition in mice deficient for the metastasis-associated Mts1(S100A4) gene. Oncogene 23:3670–3680
Davies MP, Rudland PS, Robertson L, Parry EW, Jolicoeur P, Barraclough R (1996) Expression of the calcium-binding protein S100A4 (p9Ka) in MMTV-neu transgenic mice induces metastasis of mammary tumours. Oncogene 13:1631–1637
Hou S, Jiao Y, Yuan Q, Zhai J, Tian T, Sun K, Chen Z, Wu Z, Zhang J (2018) S100A4 protects mice from high-fat diet-induced obesity and inflammation. Lab Invest 98:1025–1038
Kiryushko D, Novitskaya V, Soroka V, Klingelhofer J, Lukanidin E, Berezin V, Bock E (2006) Molecular mechanisms of Ca2+ signaling in neurons induced by the S100A4 protein. Mol Cell Biol 26:3625–3638
Klingelhöfer J, Møller HD, Sumer EU, Sumer EU, Berg CH, Poulsen M, Kiryushko D, Soroka V, Ambartsumian N, Grigorian M, Lukanidin EM (2009) Epidermal growth factor receptor ligands as new extracellular targets for the metastasis-promoting S100A4 protein. FEBS J 276:5936–5948
Zhang R, Gao Y, Zhao X, Gao M, Wu Y, Han Y, Qiao Y, Luo Z, Yang L, Chen J, Ge G (2018) FSP1-positive fibroblasts are adipogenic niche and regulate adipose homeostasis. PLoS Biol 16:e2001493
Schiopu A, Cotoi OS (2013) S100A8 and S100A9: DAMPs at the crossroads between innate immunity, traditional risk factors, and cardiovascular disease. Mediat Inflamm 2013:828354
Mortensen OH, Nielsen AR, Erikstrup C, Plomgaard P, Fischer CP, Krogh-Madsen R, Lindegaard B, Petersen AM, Taudorf S, Pedersen BK (2009) Calprotectin: a novel marker of obesity. PLoS One 4:e7419
Catalán V, Gómez-Ambrosi J, Rodríguez A, Ramírez B, Rotellar F, Valentí V, Silva C, Gil MJ, Fernández-Real JM, Salvador J, Frühbeck G (2011) Increased levels of calprotectin in obesity are related to macrophage content: impact on inflammation and effect of weight loss. Mol Med 17:1157–1167
Sekimoto R, Kishida K, Nakatsuji H, Nakagawa T, Funahashi T, Shimomura I (2012) High circulating levels of S100A8/A9 complex (calprotectin) in male Japanese with abdominal adiposity and dysregulated expression of S100A8 and S100A9 in adipose tissues of obese mice. Biochem Biophys Res Commun 419:782–789
Yamaoka M, Maeda N, Nakamura S, Mori T, Inoue K, Matsuda K, Sekimoto R, Kashine S, Nakagawa Y, Tsushima Y, Fujishima Y, Komura N, Hirata A, Nishizawa H, Matsuzawa Y, Matsubara K, Funahashi T, Shimomura I (2013) Gene expression levels of S100 protein family in blood cells are associated with insulin resistance and inflammation (Peripheral blood S100 mRNAs and metabolic syndrome). Biochem Biophys Res Commun 433:450–455
Sekimoto R, Fukuda S, Maeda N, Tsushima Y, Matsuda K, Mori T, Nakatsuji H, Nishizawa H, Kishida K, Kikuta J, Maijima Y, Funahashi T, Ishii M, Shimomura I (2015) Visualized macrophage dynamics and significance of S100A8 in obese fat. Proc Natl Acad Sci USA 112:E2058–E2066
Nagareddy PR, Murphy AJ, Stirzaker RA, Hu Y, Yu S, Miller RG, Ramkhelawon B, Distel E, Westerterp M, Huang LS, Schmidt AM, Orchard TJ, Fisher EA, Tall AR, Goldberg IJ (2013) Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis. Cell Metab 17:695–708
Nagareddy PR, Kraakman M, Masters SL, Stirzaker RA, Gorman DJ, Grant RW, Dragoljevic D, Hong ES, Abdel-Latif A, Smyth SS, Choi SH, Korner J, Bornfeldt KE, Fisher EA, Dixit VD, Tall AR, Goldberg IJ, Murphy AJ (2014) Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity. Cell Metab 19:821–835
Shah RD, Xue C, Zhang H, Tuteja S, Li M, Reilly MP, Ferguson JF (2017) Expression of calgranulin genes S100A8, S100A9 and S100A12 is modulated by n-3 PUFA during inflammation in adipose tissue and mononuclear cells. PLoS One 12:e0169614
Kromhout D, Bosschieter EB, de Lezenne Coulander C (1985) The inverse relation between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med 312:1205–1209
Wang C, Harris WS, Chung M, Lichtenstein AH, Balk EM, Kupelnick B, Jordan HS, Lau J (2006) n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review. Am J Clin Nutr 84:5–17
Mantelmacher FD, Zvibel I, Cohen K, Epshtein A, Pasmanik-Chor M, Vogl T, Kuperman Y, Weiss S, Drucker DJ, Varol C, Fishman S (2018) GIP regulates inflammation and body weight by restraining myeloid-cell-derived S100A8/A9. Nat Metab 1:58–69
Kerkhoff C, Klempt M, Kaever V, Sorg C (1999) The two calcium-binding proteins, S100A8 and S100A9, are involved in the metabolism of arachidonic acid in human neutrophils. J Biol Chem 274:32672–32679
Yip RG, Boylan MO, Kieffer TJ, Wolfe MM (1998) Functional GIP receptors are present on adipocytes. Endocrinology 139:4004–4007
Nyberg J, Jacobsson C, Anderson MF, Eriksson PS (2007) Immunohistochemical distribution of glucose dependent insulinotropic polypeptide in the adult rat brain. J Neurosci Res 85:2099–2119
Kim SJ, Nian C, Karunakaran S, Clee SM, Isales CM, McIntosh CH (2012) GIP-overexpressing mice demonstrate reduced diet-induced obesity and steatosis, and improved glucose homeostasis. PLoS One 7:e40156
Varol C, Zvibel I, Spektor L, Mantelmacher FD, Vugman M, Thurm T, Khatib M, Elmaliah E, Halpern Z, Fishman S (2014) Long-acting glucose-dependent insulinotropic polypeptide ameliorates obesity-induced adipose tissue inflammation. J Immunol 193:4002–4009
Liu Y, Zhang R, Xin J, Sun Y, Li J, Wei D, Zhao AZ (2011) Identification of S100A16 as a novel adipogenesis promoting factor in 3T3-L1 cells. Endocrinology 152:903–911
Inoue N, Yahagi N, Yamamoto T, Ishikawa M, Watanabe K, Matsuzaka T, Nakagawa Y, Takeuchi Y, Kobayashi K, Takahashi A, Suzuki H, Hasty AH, Toyoshima H, Yamada N, Shimano H (2008) Cyclin-dependent kinase inhibitor, p21WAF1/CIP1, is involved in adipocyte differentiation and hypertrophy, linking to obesity, and insulin resistance. J Biol Chem 283:21220–21229
Zhang R, Su D, Zhu W, Huang Q, Liu M, Xue Y, Zhang Y, Li D, Zhao A, Liu Y (2014) Estrogen suppresses adipogenesis by inhibiting S100A16 expression. J Mol Endocrinol 52:235–244
Li D, Zhang R, Zhu W, Xue Y, Zhang Y, Huang Q, Liu M, Liu Y (2013) S100A16 inhibits osteogenesis but stimulates adipogenesis. Mol Biol Rep 40:3465–3473
Zhang R, Zhu W, Du X, Xin J, Xue Y, Zhang Y, Li D, Liu Y (2012) S100A16 mediation of weight gain attenuation induced by dietary calcium. Metabolism 61:157–163
D’Amico F, Skarmoutsou E, Granata M, Trovato C, Rossi GA, Mazzarino MC (2016) S100A7: a rAMPing up AMP molecule in psoriasis. Cytokine Growth Factor Rev 32:97–104
Salama RH, Al-Shobaili HA, Al Robaee AA, Alzolibani AA (2013) Psoriasin: a novel marker linked obesity with psoriasis. Dis Markers 34:33–39
Sakurai M, Miki Y, Takagi K, Suzuki T, Ishida T, Ohuchi N, Sasano H (2017) Interaction with adipocyte stromal cells induces breast cancer malignancy via S100A7 upregulation in breast cancer microenvironment. Breast Cancer Res 19:70
Vogl T, Pröpper C, Hartmann M, Strey A, Strupat K, van den Bos C, Sorg C, Roth J (1999) S100A12 is expressed exclusively by granulocytes and acts independently from MRP8 and MRP14. J Biol Chem 274:25291–25296
Hofmann Bowman M, Wilk J, Heydemann A, Kim G, Rehman J, Lodato JA, Raman J, McNally EM (2010) S100A12 mediates aortic wall remodeling and aortic aneurysm. Circ Res 106:145–154
Hofmann Bowman MA, Heydemann A, Gawdzik J, Shilling RA, Camoretti-Mercado B (2011) Transgenic expression of human S100A12 induces structural airway abnormalities and limited lung inflammation in a mouse model of allergic inflammation. Clin Exp Allergy 41:878–889
Yan WX, Armishaw C, Goyette J, Yang Z, Cai H, Alewood P, Geczy CL (2008) Mast cell and monocyte recruitment by S100A12 and its hinge domain. J Biol Chem 283:13035–13043
Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, Avila C, Kambham N, Bierhaus A, Nawroth P, Neurath MF, Slattery T, Beach D, McClary J, Nagashima M, Morser J, Stern D, Schmidt AM (1999) RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 97:889–901
Yang Z, Yan WX, Cai H, Tedla N, Armishaw C, Di Girolamo N, Wang HW, Hampartzoumian T, Simpson JL, Gibson PG, Hunt J, Hart P, Hughes JM, Perry MA, Alewood PF, Geczy CL (2007) S100A12 provokes mast cell activation: a potential amplification pathway in asthma and innate immunity. J Allergy Clin Immunol 119:106–114
Donato R, Sorci G, Riuzzi F, Arcuri C, Bianchi R, Brozzi F, Tubaro C, Giambanco I (2009) S100B’s double life: intracellular regulator and extracellular signal. Biochim Biophys Acta Mol Cell Res 1793:1008–1022
Tsoporis JN, Marks A, Haddad A, Dawood F, Liu PP, Parker TG (2005) S100B expression modulates left ventricular remodeling after myocardial infarction in mice. Circulation 111:598–606
McIlroy M, McCartan D, Early S, Gaora PO, Pennington S, Hill AD, Young LS (2010) Interaction of developmental transcription factor HOXC11 with steroid receptor coactivator SRC-1 mediates resistance to endocrine therapy in breast cancer [corrected]. Cancer Res 70:1585–1594
Sorci G, Giovannini G, Riuzzi F, Bonifazi P, Zelante T, Zagarella S, Bistoni F, Donato R, Romani L (2011) The danger signal S100B integrates pathogen- and danger-sensing pathways to restrain inflammation. PLoS Pathog 7:e1001315
Zhang L, Liu W, Alizadeh D, Zhao D, Farrukh O, Lin J, Badie SA, Badie B (2011) S100B attenuates microglia activation in gliomas: possible role of STAT3 pathway. Glia 59:486–498
Riuzzi F, Beccafico S, Sagheddu R, Chiappalupi S, Giambanco I, Bereshchenko O, Riccardi C, Sorci G, Donato R (2017) Levels of S100B protein drive the reparative process in acute muscle injury and muscular dystrophy. Sci Rep 7:12537
Riuzzi F, Sorci G, Donato R (2011) S100B protein regulates myoblast proliferation and differentiation by activating FGFR1 in a bFGFdependent manner. J Cell Sci 124:2389–2400
Michetti F, Dell’Anna E, Tiberio G, Cocchia D (1983) Immunochemical and immunocytochemical study of S-100 protein in rat adipocytes. Brain Res 262:352–356
Suzuki F, Kato K, Nakajima T (1984) Hormonal regulation of adipose S-100 protein release. J Neurochem 43:1336–1341
Suzuki F, Kato K (1985) Inhibition of adipose S-100 protein release by insulin. Biochim Biophys Acta 845:311–316
Netto CB, Conte S, Leite MC, Pires C, Martins TL, Vidal P, Benfato MS, Giugliani R, Gonçalves CA (2006) Serum S100B protein is increased in fasting rats. Arch Med Res 37:683–686
Holtkamp K, Bühren K, Ponath G, von Eiff C, Herpertz-Dahlmann B, Hebebrand J, Rothermundt M (2008) Serum levels of S100B are decreased in chronic starvation and normalize with weight gain. J Neural Transm (Vienna) 115:937–940
Li D, Li K, Chen G, Xia J, Yang T, Cai P, Yao C, Yang Y, Yan S, Zhang R, Chen H (2016) S100B suppresses the differentiation of C3H/10T1/2 murine embryonic mesenchymal cells into osteoblasts. Mol Med Rep 14:3878–3886
Lin J, Yang Q, Wilder PT, Carrier F, Weber DJ (2010) The calcium-binding protein S100B down-regulates p53 and apoptosis in malignant melanoma. J Biol Chem 285:27487–27498
Esposito G, Capoccia E, Sarnelli G, Scuderi C, Cirillo C, Cuomo R, Steardo L (2012) The antiprotozoal drug pentamidine ameliorates experimentally induced acute colitis in mice. J Neuroinflammation 9:277
Capoccia E, Cirillo C, Marchetto A, Tiberi S, Sawikr Y, Pesce M, D’Alessandro A, Scuderi C, Sarnelli G, Cuomo R, Steardo L, Esposito G (2015) S100B-p53 disengagement by pentamidine promotes apoptosis and inhibits cellular migration via aquaporin-4 and metalloproteinase-2 inhibition in C6 glioma cells. Oncol Lett 9:2864–2870
Yang T, Cheng J, Yang Y, Qi W, Zhao Y, Long H, Xie R, Zhu B, S100B (2017) Mediates stemness of ovarian cancer stem-like cells through inhibiting p53. Stem Cells 35:325–336
Yang T, Cheng J, You J, Yan B, Liu H, Li F (2018) S100B promotes chemoresistance in ovarian cancer stem cells by regulating p53. Oncol Rep 40:1574–1582
Sorci G, Riuzzi F, Giambanco I, Donato R (2013) RAGE in tissue homeostasis, repair and regeneration. Biochim Biophys Acta Mol Cell Res 1833:101–109
Gaens KH, Stehouwer CD, Schalkwijk CG (2013) Advanced glycation endproducts and its receptor for advanced glycation endproducts in obesity. Curr Opin Lipidol 24:4–11
Boyer F, Vidot JB, Dubourg AG, Rondeau P, Essop MF, Bourdon E (2015) Oxidative stress and adipocyte biology: focus on the role of AGEs. Oxid Med Cell Longev 2015:534873
Ramasamy R, Shekhtman A, Schmidt AM (2016) The multiple faces of RAGE-opportunities for therapeutic intervention in aging and chronic disease. Expert Opin Ther Targ 20:431–446
López-Díez R, Shekhtman A, Ramasamy R, Schmidt AM (2016) Cellular mechanisms and consequences of glycation in atherosclerosis and obesity. Biochim Biophys Acta 1862:2244–2252
Zhang J, Zhang L, Zhang S, Yu Q, Xiong F, Huang K, Wang CY, Yang P (2017) HMGB1, an innate alarmin, plays a critical role in chronic inflammation of adipose tissue in obesity. Mol Cell Endocrinol 454:103–111
Steiner J, Schiltz K, Walter M, Wunderlich MT, Keilhoff G, Brisch R, Bielau H, Bernstein HG, Bogerts B, Schroeter ML, Westphal S (2010) S100B serum levels are closely correlated with body mass index: an important caveat in neuropsychiatric research. Psychoneuroendocrinology 35:321–324
Kheirouri S, Ebrahimi E, Alizadeh M (2018) Association of S100B serum levels with metabolic syndrome and its components. Acta Med Port 31:201–206
Monden M, Koyama H, Otsuka Y, Morioka T, Mori K, Shoji T, Mima Y, Motoyama K, Fukumoto S, Shioi A, Emoto M, Yamamoto Y, Yamamoto H, Nishizawa Y, Kurajoh M, Yamamoto T, Inaba M (2013) Receptor for advanced glycation end products regulates adipocyte hypertrophy and insulin sensitivity in mice: involvement of Toll-like receptor 2. Diabetes 62:478–489
Fujiya A, Nagasaki H, Seino Y, Okawa T, Kato J, Fukami A, Himeno T, Uenishi E, Tsunekawa S, Kamiya H, Nakamura J, Oiso Y, Hamada Y (2014) The role of S100B in the interaction between adipocytes and macrophages. Obesity (Silver Spring) 22:371–379
Buckman LB, Anderson-Baucum EK, Hasty AH, Ellacott KLJ (2014) Regulation of S100B in white adipose tissue by obesity in mice. Adipocyte 3:215–220
Bowden-Davies K, Connolly J, Burghardt P, Koch LG, Britton SL, Burniston JG (2015) Label-free profiling of white adipose tissue of rats exhibiting high or low levels of intrinsic exercise capacity. Proteomics 15:2342–2349
Son KH, Son M, Ahn H, Oh S, Yum Y, Choi CH, Park KY, Byun K (2016) Age-related accumulation of advanced glycation end-products-albumin, S100β, and the expressions of advanced glycation end product receptor differ in visceral and subcutaneous fat. Biochem Biophys Res Commun 477:271–276
Hosokawa K, Hamada Y, Fujiya A, Murase M, Maekawa R, Niwa Y, Izumoto T, Seino Y, Tsunekawa S, Arima H (2017) S100B impairs glycolysis via enhanced poly(ADP-ribosyl)ation of glyceraldehyde-3-phosphate dehydrogenase in rodent muscle cells. Am J Physiol Endocrinol Metab 312:E471–E481
Barbatelli G, Morroni M, Vinesi P, Cinti S, Michetti F (1993) S-100 protein in rat brown adipose tissue under different functional conditions: a morphological, immunocytochemical, and immunochemical study. Exp Cell Res 208:226–231
Zeng X, Ye M, Resch JM, Jedrychowski MP, Hu B, Lowell BB, Ginty DD, Spiegelman BM (2019) Innervation of thermogenic adipose tissue via a calsyntenin 3β–S100b axis. Nature. https://doi.org/10.1038/s41586-019-1156-9
Huttunen HJ, Kuja-Panula J, Sorci G, Agneletti AL, Donato R, Rauvala H (2000) Coregulation of neurite outgrowth and cell survival by amphoterin and S100 proteins through receptor for advanced glycation end products (RAGE) activation. J Biol Chem 275(51):40096–40105
Businaro R, Leone S, Fabrizi C, Sorci G, Donato R, Lauro GM, Fumagalli L (2006) S100B protects LAN-5 neuroblastoma cells against Abeta amyloid-induced neurotoxicity via RAGE engagement at low doses but increases Abeta amyloid neurotoxicity at high doses. J Neurosci Res 83:897–906
Morozzi G, Beccafico S, Bianchi R, Riuzzi F, Bellezza I, Giambanco I, Arcuri C, Minelli A, Donato R (2017) Oxidative stress-induced S100B accumulation converts myoblasts into brown adipocytes via an NF-κB/YY1/miR-133 axis and NF-κB/YY1/BMP-7 axis. Cell Death Differ 24:2077–2088
Tseng YH, Kokkotou E, Schulz TJ, Huang TL, Winnay JN, Taniguchi CM et al (2008) New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 454:1000–1004
Seale P, Kajimura S, Yang W, Chin S, Rohas LM, Uldry M et al (2007) Transcriptional control of brown fat determination by PRDM16. Cell Metab 6:38–54
Seale P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S et al (2008) PRDM16 controls a brown fat/skeletal muscle switch. Nature 454:961–967
Boengler K, Kosiol M, Mayr M, Schulz R, Rohrbach S (2017) Mitochondria and ageing: role in heart, skeletal muscle and adipose tissue. J Cachexia Sarcopenia Muscle 8:349–369
Bellezza I, Giambanco I, Minelli A, Donato R (2018) Nrf2-Keap1 signaling in oxidative and reductive stress. Biochim Biophys Acta Mol Cell Res 1865:721–733
Beccafico S, Riuzzi F, Puglielli C, Mancinelli R, Fulle S, Sorci G, Donato R (2011) Human muscle satellite cells show age-related differential expression of S100B protein and RAGE. Age (Dordr) 33:523–541
Asakura A, Komaki M, Rudnicki M (2001) Muscle satellite cells are multipotential stem cells that exhibit myogenic, osteogenic, and adipogenic differentiation. Differentiation 68:245–253
Frühbeck G, Sesma P, Burrell MA (2009) PRDM16: the interconvertible adipo-myocyte switch. Trends Cell Biol 19:141–146
Gupta RK, Mepani RJ, Kleiner S, Lo JC, Khandekar MJ, Cohen P, Frontini A, Bhowmick DC, Ye L, Cinti S, Spiegelman BM (2012) Zfp423 expression identifies committed preadipocytes and localizes to adipose endothelial and perivascular cells. Cell Metab 15:230–239
Tran KV, Gealekman O, Frontini A, Zingaretti MC, Morroni M, Giordano A, Smorlesi A, Perugini J, De Matteis R, Sbarbati A, Corvera S, Cinti S (2012) The vascular endothelium of the adipose tissue gives rise to both white and brown fat cells. Cell Metab 15:222–229
Ouchi N, Parker JL, Lugus JJ, Walsh K (2011) Adipokines in inflammation and metabolic disease. Nat Rev Immunol 11:85–97
Giordano A, Frontini A, Cinti S (2016) Convertible visceral fat as a therapeutic target to curb obesity. Nat Rev Drug Discov 15:405–424
Wang W, Seale P (2016) Control of brown and beige fat development. Nat Rev Mol Cell Biol 17:691–702
Vegiopoulos A, Müller-Decker K, Strzoda D, Schmitt I, Chichelnitskiy E, Ostertag A, Berriel Diaz M, Rozman J, Hrabe de Angelis M, Nüsing RM, Meyer CW, Wahli W, Klingenspor M, Herzig S (2010) Cyclooxygenase-2 controls energy homeostasis in mice by de novo recruitment of brown adipocytes. Science 328:1158–1161
Diaz MB, Herzig S, Vegiopoulos A (2014) Thermogenic adipocytes: from cells to physiology and medicine. Metabolism 63:1238–1249
Sidossis L, Kajimura S (2015) Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis. J Clin Invest 125:478–486
Sidossis LS, Porter C, Saraf MK, Børsheim E, Radhakrishnan RS, Chao T, Ali A, Chondronikola M, Mlcak R, Finnerty CC, Hawkins HK, Toliver-Kinsky T, Herndon DN (2015) Browning of subcutaneous white adipose tissue in humans after severe adrenergic stress. Cell Metab 22:219–227
Lee YH, Petkova AP, Granneman JG (2013) Identification of an adipogenic niche for adipose tissue remodeling and restoration. Cell Metab 18:355–367
Qiu Y, Nguyen KD, Odegaard JI, Cui X, Tian X, Locksley RM, Palmiter RD, Chawla A (2014) Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell 157:1292–1308
Babaei R, Schuster M, Meln I, Lerch S, Ghandour RA, Pisani DF, Bayindir-Buchhalter I, Marx J, Wu S, Schoiswohl G, Billeter AT, Krunic D, Mauer J, Lee YH, Granneman JG, Fischer L, Müller-Stich BP, Amri EZ, Kershaw EE, Heikenwälder M, Herzig S, Vegiopoulos A (2018) Jak-TGFβ cross-talk links transient adipose tissue inflammation to beige adipogenesis. Sci Signal 11:eaai7838
Jung N, Park S, Choi Y, Park JW, Hong YB, Park HH, Yu Y, Kwak G, Kim HS, Ryu KH, Kim JK, Jo I, Choi BO, Jung SC (2016) Tonsil-derived mesenchymal stem cells differentiate into a schwann cell phenotype and promote peripheral nerve regeneration. Int J Mol Sci 17(11):E1867
Xiao YZ, Wang S (2015) Differentiation of Schwann-like cells from human umbilical cord blood mesenchymal stem cells in vitro. Mol Med Rep 11:1146–1152
Garbuglia M, Verzini M, Giambanco I, Spreca A, Donato R (1996) Effects of calcium-binding proteins (S100a0, S100a, S100b) on desmin assembly in vitro. FASEB J 10:317–324
Sorci G, Agneletti AL, Donato R (2000) Effects of S100A1 and S100B on microtubule stability. An in vitro study using triton-cytoskeletons from astrocyte and myoblast cell lines. Neuroscience 99:773–783
Tubaro C, Arcuri C, Giambanco I, Donato R (2010) S100B protein in myoblasts modulates myogenic differentiation via NF-κB-dependent inhibition of MyoD expression. J Cell Physiol 223:270–282
Tubaro C, Arcuri C, Giambanco I, Donato R (2011) S100B in myoblasts regulates the transition from activation to quiescence and from quiescence to activation, and reduces apoptosis. Biochim Biophys Acta Mol Cell Res 1813:1092–1104
Cinti S (2018) Adipose Organ Development and Remodeling. Compr Physiol 8:1357–1431
Kotzbeck P, Giordano A, Mondini E, Murano I, Severi I, Venema W, Cecchini MP, Kershaw EE, Barbatelli G, Haemmerle G, Zechner R, Cinti S (2018) Brown adipose tissue whitening leads to brown adipocyte death and adipose tissue inflammation. J Lipid Res 59:784–794
Acknowledgements
The authors were supported by Association Française contre les Myopathies (Projects 12992 and 16812), Associazione Italiana per la Ricerca sul Cancro (Project 17581), Ministero dell’Istruzione, dell’Università e della Ricerca, Italy (PRIN 2009WBFZYM_002, PRIN 2010R8JK2X_004 and PRIN 2012N8YJC3) and Fondazione Cassa di Risparmio di Perugia (Projects 2012.0241.021, 2015.0325.021 and 2016-0136.021). The authors wish to thank the reviewers for criticism and suggestions.
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Riuzzi, F., Chiappalupi, S., Arcuri, C. et al. S100 proteins in obesity: liaisons dangereuses. Cell. Mol. Life Sci. 77, 129–147 (2020). https://doi.org/10.1007/s00018-019-03257-4
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DOI: https://doi.org/10.1007/s00018-019-03257-4