An inflammatory cascade leading to hyperresistinemia in humans
Michael Lehrke, Muredach P Reilly, Segan C Millington, Nayyar Iqbal, Daniel J Rader, Mitchell A Lazar, Michael Lehrke, Muredach P Reilly, Segan C Millington, Nayyar Iqbal, Daniel J Rader, Mitchell A Lazar
Abstract
Background: Obesity, the most common cause of insulin resistance, is increasingly recognized as a low-grade inflammatory state. Adipocyte-derived resistin is a circulating protein implicated in insulin resistance in rodents, but the role of human resistin is uncertain because it is produced largely by macrophages.
Methods and findings: The effect of endotoxin and cytokines on resistin gene and protein expression was studied in human primary blood monocytes differentiated into macrophages and in healthy human participants. Inflammatory endotoxin induced resistin in primary human macrophages via a cascade involving the secretion of inflammatory cytokines that circulate at increased levels in individuals with obesity. Induction of resistin was attenuated by drugs with dual insulin-sensitizing and anti-inflammatory properties that converge on NF-kappaB. In human study participants, experimental endotoxemia, which produces an insulin-resistant state, causes a dramatic rise in circulating resistin levels. Moreover, in patients with type 2 diabetes, serum resistin levels are correlated with levels of soluble tumor necrosis factor alpha receptor, an inflammatory marker linked to obesity, insulin resistance, and atherosclerosis.
Conclusions: Inflammation is a hyperresistinemic state in humans, and cytokine induction of resistin may contribute to insulin resistance in endotoxemia, obesity, and other inflammatory states.
Conflict of interest statement
Competing Interests: MPR has received research funding or honoraria from GlaxoSmithKline, Merck, Ely Lilly, and KOS Pharmaceuticals. MAL has received a research grant from GlaxoSmithKline and has a United States patent application pending for therapeutic antagonism of human resistin. MAL and the University of Pennsylvania have licensed to Linco the monoclonal antibodies used in the human resistin assay.
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References
- Ogden CL, Carroll MD, Flegal KM. Epidemiologic trends in overweight and obesity. Endocrinol Metab Clin North Am. 2003;32:741–760.
- Flier JS. Obesity wars: Molecular progress confronts an expanding epidemic. Cell. 2004;116:337–350.
- Sowers JR, Frohlich ED. Insulin and insulin resistance: Impact on blood pressure and cardiovascular disease. Med Clin North Am. 2004;88:63–82.
- Haffner SM. Insulin resistance, inflammation, and the prediabetic state. Am J Cardiol. 2003;92:18J-26J.
- Rajala MW, Scherer PE. Minireview: The adipocyte—at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology. 2003;144:3765–3773.
- Hotamisligil GS. Inflammatory pathways and insulin action. Int J Obes Relat Metab Disord. 2003;27(Suppl 3):S53–S55.
- Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112:1796–1808.
- Xu H, Barnes GT, Yang Q, Tan G, Yang D, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112:1821–1830.
- Charriere G, Cousin B, Arnaud E, Andre M, Bacou F, et al. Preadipocyte conversion to macrophage. Evidence of plasticity. J Biol Chem. 2003;278:9850–9855.
- Glass CK, Witztum JL. Atherosclerosis: The road ahead. Cell. 2001;104:503–516.
- Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, et al. The hormone resistin links obesity to diabetes. Nature. 2001;409:307–312.
- Kim KH, Lee K, Moon YS, Sul HS. A cysteine-rich adipose tissue-specific secretory factor inhibits adipocyte differentiation. J Biol Chem. 2001;276:11252–11256.
- Rajala MW, Obici S, Scherer PE, Rossetti L. Adipose-derived resistin and gut-derived resistin-like molecule-beta selectively impair insulin action on glucose production. J Clin Invest. 2003;111:225–230.
- Banerjee RR, Rangwala SM, Shapiro JS, Rich AS, Rhoades B, et al. Regulation of fasted blood glucose by resistin. Science. 2004;303:1195–1198.
- Savage DB, Sewter CP, Klenk ES, Segal DG, Vidal-Puig A, et al. Resistin/Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma action in humans. Diabetes. 2001;50:2199–2202.
- Patel L, Buckels AC, Kinghorn IJ, Murdock PR, Holbrook JD, et al. Resistin is expressed in human macrophages and directly regulated by PPAR gamma activators. Biochem Biophys Res Commun. 2003;300:472–476.
- Tan MS, Chang SY, Chang DM, Tsai JC, Lee YJ. Association of resistin gene 3′-untranslated region +62G→A polymorphism with type 2 diabetes and hypertension in a Chinese population. J Clin Endocrinol Metab. 2003;88:1258–1263.
- Smith SR, Bai F, Charbonneau C, Janderova L, Argyropoulos G. A promoter genotype and oxidative stress potentially link resistin to human insulin resistance. Diabetes. 2003;52:1611–1618.
- Youn BS, Yu KY, Park HJ, Lee NS, Min SS, et al. Plasma resistin concentrations measured by enzyme-linked immunosorbent assay using a newly developed monoclonal antibody are elevated in individuals with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2004;89:150–156.
- Fujinami A, Obayashi H, Ohta K, Ichimura T, Nishimura M, et al. Enzyme-linked immunosorbent assay for circulating human resistin: Resistin concentrations in normal subjects and patients with type 2 diabetes. Clin Chim Acta. 2004;339:57–63.
- Silha JV, Krsek M, Skrha JV, Sucharda P, Nyomba BL, et al. Plasma resistin, adiponectin and leptin levels in lean and obese subjects: Correlations with insulin resistance. Eur J Endocrinol. 2003;149:331–335.
- Pfutzner A, Langenfeld M, Kunt T, Lobig M, Forst T. Evaluation of human resistin assays with serum from patients with type 2 diabetes and different degrees of insulin resistance. Clin Lab. 2003;49:571–576.
- McTernan PG, Fisher FM, Valsamakis G, Chetty R, Harte A, et al. Resistin and type 2 diabetes: Regulation of resistin expression by insulin and rosiglitazone and the effects of recombinant resistin on lipid and glucose metabolism in human differentiated adipocytes. J Clin Endocrinol Metab. 2003;88:6098–6106.
- Lee JH, Chan JL, Yiannakouris N, Kontogianni M, Estrada E, et al. Circulating resistin levels are not associated with obesity or insulin resistance in humans and are not regulated by fasting or leptin administration: Cross-sectional and interventional studies in normal, insulin-resistant, and diabetic subjects. J Clin Endocrinol Metab. 2003;88:4848–4856.
- Degawa-Yamauchi M, Bovenkerk JE, Juliar BE, Watson W, Kerr K, et al. Serum resistin (FIZZ3) protein is increased in obese humans. J Clin Endocrinol Metab. 2003;88:5452–5455.
- Azuma K, Katsukawa F, Oguchi S, Murata M, Yamazaki H, et al. Correlation between serum resistin level and adiposity in obese individuals. Obes Res. 2003;11:997–1001.
- Reilly MP, Iqbal N, Schutta M, Wolfe ML, Scally M, et al. Plasma leptin levels are associated with coronary atherosclerosis in type 2 diabetes. J Clin Endocrinol Metab. 2004;89:3872–3878.
- Kaser S, Kaser A, Sandhofer A, Ebenbichler CF, Tilg H, et al. Resistin messenger-RNA expression is increased by proinflammatory cytokines in vitro. Biochem Biophys Res Commun. 2003;309:286–290.
- Idriss HT, Naismith JH. TNF alpha and the TNF receptor superfamily: Structure-function relationship(s) Microsc Res Tech. 2000;50:184–195.
- Van Amersfoort ES, Van Berkel TJ, Kuiper J. Receptors, mediators, and mechanisms involved in bacterial sepsis and septic shock. Clin Microbiol Rev. 2003;16:379–414.
- Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation. Nature. 1998;391:79–82.
- Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science. 2001;293:1673–1677.
- Palombella VJ, Rando OJ, Goldberg AL, Maniatis T. The ubiquitinproteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell. 1994;78:773–785.
- Lin YZ, Yao SY, Veach RA, Torgerson TR, Hawiger J. Inhibition of nuclear translocation of transcription factor NF-kappa B by a synthetic peptide containing a cell-permeable motif and nuclear localization sequence. J Biol Chem. 1995;270:14255–14258.
- Soop M, Duxbury H, Agwunobi AO, Gibson JM, Hopkins SJ, et al. Euglycemic hyperinsulinemia augments the cytokine and endocrine responses to endotoxin in humans. Am J Physiol Endocrinol Metab. 2002;282:E1276–E1285.
- Fernandez-Real JM, Ricart W. Insulin resistance and chronic cardiovascular inflammatory syndrome. Endocr Rev. 2003;24:278–301.
- Agwunobi AO, Reid C, Maycock P, Little RA, Carlson GL. Insulin resistance and substrate utilization in human endotoxemia. J Clin Endocrinol Metab. 2000;85:3770–3778.
- Suffredini AF, Fromm RE, Parker MM, Brenner M, Kovacs JA, et al. The cardiovascular response of normal humans to the administration of endotoxin. N Engl J Med. 1989;321:280–287.
- Martich GD, Boujoukos AJ, Suffredini AF. Response of man to endotoxin. Immunobiology. 1993;187:403–416.
- Levi M, van der Poll T, ten Cate H, van Deventer SJ. The cytokine-mediated imbalance between coagulant and anticoagulant mechanisms in sepsis and endotoxaemia. Eur J Clin Invest. 1997;27:3–9.
- Panidis D, Koliakos G, Kourtis A, Farmakiotis D, Mouslech T, et al. Serum resistin levels in women with polycystic ovary syndrome. Fertil Steril. 2004;81:361–366.
- Zhang JL, Qin YW, Zheng X, Qiu JL, Zou DJ. Serum resistin level in essential hypertension patients with different glucose tolerance. Diabet Med. 2003;20:828–831.
- Bajaj M, Suraamornkul S, Hardies LJ, Pratipanawatr T, DeFronzo RA. Plasma resistin concentration, hepatic fat content, and hepatic and peripheral insulin resistance in pioglitazone-treated type II diabetic patients. Int J Obes Relat Metab Disord. 2004;28:783–789.
- Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-α: Direct role in obesity-linked insulin resistance. Science. 1993;259:87–91.
- Tsigos C, Papanicolaou DA, Kyrou I, Defensor R, Mitsiadis CS, et al. Dose-dependent effects of recombinant human interleukin-6 on glucose regulation. J Clin Endocrinol Metab. 1997;82:4167–4170.
- Lehrke M, Lazar MA. Inflamed about obesity. Nat Med. 2004;10:126–127.
- Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol. 2003;21:335–376.
- Cohen J. The immunopathogenesis of sepsis. Nature. 2002;420:885–891.
- Satoh H, Nguyen MT, Miles PD, Imamura T, Usui I, et al. Adenovirus-mediated chronic “hyper-resistinemia” leads to in vivo insulin resistance in normal rats. J Clin Invest. 2004;114:224–231.
- Rangwala SM, Rich AS, Rhoades B, Shapiro JS, Obici S, et al. Abnormal glucose homeostasis due to chronic hyperresistinemia. Diabetes. 2004;53:1937–1941.
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