Adipokine & klinische Bedeutung

Zusammenfassung

Adipositas führt zu einer gestörten Funktion des Fettgewebes, die sich in ektoper Fettverteilung, Hypertrophie von Adipozyten, Veränderungen der zellulären Zusammensetzung und der intrazellulären Matrix sowie zu einer gestörten endokrinen Funktion manifestiert. Neben den wichtigen Funktionen als Energiespeicher, mechanischer Schutz und Wärmeisolator produziert das Fettgewebe auch Peptidhormone, sogenannte Adipokine, die zu sekundären Veränderungen an Organen wie der Leber, dem Hirn oder dem Gefäßsystem beitragen. Mit der Vermehrung des Fettgewebes bei Adipositas entwickelt sich häufig ein diabetogenes, pro-inflammatorisches und atherogenes Adipokinmuster. Adipokine tragen zumindest zum Teil zum Adipositas-assoziierten Risiko für Typ-2-Diabetes, Fettlebererkrankung, endotheliale Dysfunktion, Arteriosklerose, Bluthochdruck, Fettstoffwechselstörungen und bestimmte Krebserkrankungen bei. Zukünftig könnten Adipokine deshalb als Risikomarker und als Substrat oder Therapeutikum für pharmakologische Therapiestrategien klinisch relevant werden. Im Rahmen dieses Beitrages sollen aktuelle Erkenntnisse zur potentiellen klinischen Bedeutung von Adipokinen vorgestellt und diskutiert werden.

Abstract

Obesity causes adipose tissue dysfunction which manifests as ectopic fat distribution, adipocyte hypertrophy, changes in the cellular composition and intracellular matrix as well as its endocrine function. In addition to its important functions as energy storage organ, mechanical organ protection and insulator, adipose tissue produces peptide hormones, so called adipokines which may contribute to secondary changes of liver, brain, vascular system function. With increasing fat mass, adipokine secretion changes towards a pro-inflammatory, diabetogenic and atherogenic pattern. Adipokines may at least in part underly the increased risk for obesity-related diseases including type 2 diabetes, fatty liver disease, endothelial dysfunction, atherosclerosis, hypertension, dyslipidemia and some types of cancer. In the future, adipokines may become clinically relevant as risk parameters, for the monitoring of obesity treatment and have the potential for pharmacological treatment strategies for obesity and its related diseases. This review focuses on the clinical relevance of adipokines as markers or predictors of obesity related diseases and as potential therapeutic tools or targets in metabolic and cardiovascular diseases.

Schlüsselwörter

Adipokine - Adipositas - Fettgewebe - Insulinresistenz - Leptin - Adiponektin

Key words

Adipokines - obesity - adipose tissue - insulin resistance - leptin - adiponectin

• Literatur

• 1 NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128·9 million children, adolescents, and adults. Lancet 2017; 390: 2627-2642
• 2 Wirth A, Wabitsch M, Hauner H. Clinical practice guideline: The prevention and treatment of obesity. Dtsch Arztebl Int 2014; 111: 705-13
• 3 Adams KF, Schatzkin A, Harris TB. et al. Overweight, obesity, and mortality in a large prospective cohort of persons 50 to 71 years old. N Engl J Med 2006; 355: 763-778
• 4 Van Gaal LF, Mertens IL, De Block CE. Mechanisms linking obesity with cardiovascular disease. Nature 2006; 444: 875-80
• 5 Kurth BM. Erste Ergebnisse aus der “Studie zur Gesundheit Erwachsener in Deutschland“ (DEGS). Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2012; 55: 980-90
• 6 Lehr S, Hartwig S, Sell H. Adipokines: a treasure trove for the discovery of biomarkers for metabolic disorders. Proteomics Clin Appl 2012; 1–2: 91-101
• 7 Blüher M. Adipose tissue-an endocrine organ. Internist (Berl) 2014; 55: 687-97
• 8 Fasshauer M, Blüher M. Adipokines in health and disease. Trends Pharmacol Sci 2015; 36: 461-70
• 9 Zhu Q, Scherer PE. Immunologic and endocrine functions of adipose tissue: implications for kidney disease. Nat Rev Nephrol 2018; ; 14: 105-120
• 10 Blüher M. Adipokines – removing road blocks to obesity and diabetes therapy. Mol Metab 2014; 3: 230-40
• 11 Zhang Y, Proenca R, Maffei M. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372: 425-432
• 12 Blüher M, Mantzoros CS. From leptin to other adipokines in health and disease: facts and expectations at the beginning of the 21st century. Metabolism 2015; 64: 131-45
• 13 Scherer PE, Williams S, Fogliano M. et al. A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 1995; 270: 26746-9
• 14 Kharitonenkov A, Shiyanova TL, Koester A. et al. FGF-21 as a novel metabolic regulator. J Clin Invest 2005; 115: 1627-35
• 15 Spranger J, Kroke A, Möhlig M. et al. Adiponectin and protection against type 2 diabetes mellitus. Lancet 2003; 361: 226-8
• 16 Blüher M, Rudich A, Klöting N. et al. Two patterns of adipokine and other biomarker dynamics in a long-term weight loss intervention. Diabetes Care 2012; 35: 342-9
• 17 Romere C, Duerrschmid C, Bournat J. et al. Asprosin, a Fasting-Induced Glucogenic Protein Hormone. Cell 2016; 165: 566-79
• 18 Cook KS, Min HY, Johnson D. et al. Adipsin: a circulating serine protease homolog secreted by adipose tissue and sciatic nerve. Science 1987; 237: 402-5
• 19 Dahlman I, Elsen M, Tennagels N. et al. Functional annotation of the human fat cell secretome. Arch Physiol Biochem 2012; 118: 84-91
• 20 Flehmig G, Scholz M, Klöting N. et al. Identification of adipokine clusters related to parameters of fat mass, insulin sensitivity and inflammation. PLoS One 2014; 9: e99785
• 21 Harman-Boehm I, Blüher M, Redel H. et al. Macrophage infiltration into omental versus subcutaneous fat across different populations: effect of regional adiposity and the comorbidities of obesity. J Clin Endocrinol Metab 2007; 92: 2240-7
• 22 Fink MP. Leaky gut hypothesis: a historical perspective. Crit Care Med 1990; 18: 579-580
• 23 Skurk T, Alberti-Huber C, Herder C. Relationship between adipocyte size and adipokine expression and secretion. J Clin Endocrinol Metab 2007; 92: 1023-33
• 24 Klöting N, Fasshauer M, Dietrich A. et al. Insulin-sensitive obesity. Am J Physiol Endocrinol Metab 2010; 299: E506-15
• 25 Chen H, Charlat O, Tartaglia LA. et al. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 1996; 84: 491-495
• 26 Montague CT, Farooqi IS, Whitehead JP. et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997; 387: 903-938
• 27 Savage DB, O’Rahilly S. Leptin: a novel therapeutic role in lipodystrophy. J Clin Invest 2002; 109: 1285-1286
• 28 Chou K, Perry CM. Metreleptin: first global approval. Drugs 2013; 73: 989-997
• 29 www.ema.europa.eu/medicines/human/EPAR/myalepta
• 30 Ahima RS, Flier JS. Leptin. Annu Rev Physiol 2000; 62: 413-437
• 31 Scherer PE. Adiponectin: basic and clinical aspects. Best Pract Res Clin Endocrinol Metab 2014; 28: 1-2
• 32 Aleksandrova K, Drogan D, Boeing H. et al. Adiposity, mediating biomarkers and risk of colon cancer in the European prospective investigation into cancer and nutrition study. Int J Cancer 2014; 134: 612-621
• 33 Okamoto M, Ohara-Imaizumi M, Kubota N. et al. Adiponectin induces insulin secretion in vitro and in vivo at a low glucose concentration. Diabetologia 2008; 51: 827-835
• 34 Okada-Iwabu M, Yamauchi T, Iwabu M. et al. A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity. Nature 2013; 503: 493-499
• 35 Gaich G, Chien JY, Fu H. et al. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metabolism 2013; 18: 333-340
• 36 Frayling TM, Beaumont RN, Jones SE. et al. A Common Allele in FGF21 Associated with Sugar Intake Is Associated with Body Shape, Lower Total Body-Fat Percentage, and Higher Blood Pressure. Cell Rep 2018; 23: 327-336
• 37 Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993; 259: 87-91
• 38 Wascher TC, Lindeman JH, Sourij H. et al. Chronic TNF-α neutralization does not improve insulin resistance or endothelial function in “healthy” men with metabolic syndrome. Molecular Medicine 2011; 17: 189-193
• 39 Larsen CM, Faulenbach M, Vaag A. et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med 2007; 356: 1517-1526
• 40 Schulz TJ, Huang P, Huang TL. et al. Brown-fat paucity due to impaired BMP signalling induces compensatory browning of white fat. Nature 2013; 495: 379-83
• 41 Schulz TJ, Tseng YH. Emerging role of bone morphogenetic proteins in adipogenesis and energy metabolism. Cytokine Growth Factor Rev 2009; 20: 523-31
• 42 Tseng YH, Kokkotou E, Schulz TJ. et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 2008; 454: 1000-4
• 43 Townsend KL, Suzuki R, Huang TL. et al. Bone morphogenetic protein 7 (BMP7) reverses obesity and regulates appetite through a central mTOR pathway. FASEB J 2012; 26: 2187-96
• 44 Vaccaro AR, Lawrence JP, Patel T. et al. The safety and efficacy of OP-1 (rhBMP-7) as a replacement for iliac crest autograft for posterolateral lumbar arthrodesis: minimum 4-year follow-up of a pilot study. Spine J 2008; 8: 457-65