Yeni Adipokinler: MetrnL, TGF-Β2, Fibroblast Growth Factor-21 (FGF21), Apelin
Özet
Son yıllarda gerçekleştirilen bilimsel çalışmalar, yağ dokusunun yalnızca pasif bir enerji depolama rezervuarı olmadığını, adipokin adı verilen biyolojik olarak aktif molekülleri sentezleyip salgılayan oldukça dinamik bir endokrin organ olduğunu ortaya koymuştur. Adipokinler; beslenme, iştah kontrolü, insülin sekresyonu, insülin duyarlılığı, vasküler fonksiyonlar ve enerji dengesi gibi pek çok kritik fizyolojik işlemi düzenlemektedir. Bu derleme çalışmasında, tedavi alanında umut verici potansiyellere sahip dört yeni adipokin ele alınmaktadır: Metrnl, TGF-β2, Fibroblast Growth Factor-21 (FGF21) ve Apelin. Metrnl, beyaz yağ dokusunun esmerleşmesini uyararak termogenezi destekler ve PPARγ ekspresyonu üzerinden adiposit farklılaşmasını teşvik ederek insülin direncini antagonize eder. Egzersiz ile indüklenen bir adipokin olan TGF-β2, glikoz toleransı ve insülin duyarlılığını artırmanın yanı sıra obeziteden kaynaklanan yağ dokusu enflamasyonunu hafifletir. FGF21, proliferatif etkisi bulunmayan bir metabolik efektör olarak lipit profilini ve glikoz toleransını iyileştirir, termojenik etkiler sunar ve pankreatik beta hücrelerini korur. Apelin ise glikoz metabolizması, lipoliz ve kardiyovasküler homeostazda rol oynayıp AMPK aktivasyonu vasıtasıyla yağ asidi oksidasyonunu ve insülin duyarlılığını geliştirir. Bu adipokinlerin ayrıntılı olarak anlaşılması, obezite, insülin direnci ve bunlarla ilişkili komorbiditelerin yönetiminde yeni terapötik stratejilerin geliştirilmesine olanak sağlamaktadır.
Referanslar
Miao CY. Introduction: adipokines and cardiovascular disease. Clin Exp Pharmacol Physiol 2011; 38: 860–3
Ohashi K, Shibata R, Murohara T, Ouchi N.: O. Role of anti-inflammatory adipokines in obesity-related diseases. Trends Endocrinol Metab 2014; 25: 348–55.
Dardeno TA, Chou SH, Moon HS, Chamberland JP, Fiorenza CG, Mantzoros CS. Leptin in human physiology and therapeutics. Front Neuroendocrinol 2010; 31: pp. 377-393.
Mantzoros CS, Li T, Manson JE, Meigs JB, Hu FB.: Circulating adiponectin levels are associated with better glycemic control, more favorable lipid profile, and reduced inflammation in women with type 2 diabetes. J Clin Endocrinol Metab 2005; 90: pp. 4542-4548.
Blüher M, Mantzoros SC: From leptin to other adipokines in health and disease: facts and expectations at the beginning of the 21st century. Metabolism 2015; 64: pp. 131-145.
Şahin-Efe A, Katsikeris F, Mantzoros SC.: Advances in adipokines. Metabolism 2012; 61: pp. 1659-1665.
Blüher M.: Adipose tissue dysfunction in obesity. Exp Clin Endocrinol Diabetes 2009; 117: pp. 241-250.
Kelesidis T, Kelesidis I, Chou S, Mantzoros C.S: Narrative review: the role of leptin in human physiology: emerging clinical applications. Ann Intern Med 2010; 152: pp. 93-100.
Si-li Zheng, Zhi-yong Li, Jie Song, Jian-min Liu. Metrnl: a secreted protein with new emerging functions. Acta Pharmacologica Sinica 37, 571-579(2016)
Li ZY, Zheng SL, Wang P, Xu TY, Guan YF, Zhang YJ, et al. Subfatin is a novel adipokine and unlike Meteorin in adipose and brain expression. CNS Neurosci Ther 2014; 20: 344–54.
Jorgensen JR, Fransson A, Larsen LF, Thompson LH, Houchins JP, Andrade N, et al. Cometin is a novel neurotrophic factor that promotes neurite outgrowth and neuroblast migration in vitro and supports survival of spiral ganglion neurons in vivo. Exp Neurol 2012; 233: 172–81.
Nishino J, Yamashita K, Hashiguchi H, Fujii H, Shimazaki T, Hamada H. Meteorin: a secreted protein that regulates glial cell differentiation and promotes axonal extension. EMBO J 2004; 23: 1998–2008.
Li ST, Pan J, Hua XM, Liu H, Shen S, Liu JF, et al. Endothelial nitric oxide synthase protects neurons against ischemic injury through regulation of brain-derived neurotrophic factor expression. CNS Neurosci Ther 2014; 20: 154–64.
Chen XM, Wang NN, Zhang TY, Wang F, Wu CF, Yang JY. Neuroprotection by sildenafil: neuronal networks potentiation in acute experi mental stroke. CNS Neurosci Ther 2014; 20: 40–9.
Zeve D, Tang W, Graff J. Fighting fat with fat: the expanding field of adipose stem cells. Cell Stem Cell 2009; 5: 472–81.
Cao L, Choi EY, Liu X, Martin A, Wang C, Xu X, et al. White to brown fat phenotypic switch induced by genetic and environmental activation of a hypothalamic-adipocyte axis. Cell Metab 2011; 14: 324–38.
Fenzl A, Kiefer FW. Brown adipose tissue and thermogenesis. Horm Mol Biol Clin Investig 2014; 19: 25–37.
Porter C, Chondronikola M, Sidossis LS. The therapeutic potential of brown adipocytes in humans. Front Endocrinol (Lausanne) 2015; 6: 156.
Rao RR, Long JZ, White JP, Svensson KJ, Lou J, Lokurkar I, et al. Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell 2014; 157: 1279– 91.
Ma X, Lee P, Chisholm DJ, James DE. Control of adipocyte differentiation in different fat depots; implications for pathophysiology or therapy. Front Endocrinol (Lausanne) 2015; 6: 1.
Li ZY, Song J, Zheng SL, Fan MB, Guan YF, Qu Y, et al. Adipocyte Metrnl antagonizes insulin resistance through PPARγ signaling. Diabetes 2015; 64: 4011–22.
Semple RK, Chatterjee VK, O’Rahilly S. PPAR gamma and human metabolic disease. J Clin Invest 2006; 116: 581–9.
Gustafson B, Smith U. Regulation of white adipogenesis and its relation to ectopic fat accumulation and cardiovascular risk. Atherosclerosis 2015; 241: 27–35.
McLaughlin T, Sherman A, Tsao P, Gonzalez O, Yee G, Lamendola C, et al. Enhanced proportion of small adipose cells in insulin-resistant vs insulin-sensitive obese individuals implicates impaired adipogenesis. Diabetologia 2007; 50: 1707–15.
Massague J. TGF-b signal transduction.Annu Rev Biochem67, 753–791 (1998).
de Martin R, Haendler B, Hofer-Warbinek R, Gaugitsch H, Wrann M, Schlüsener H, et al. Complementary DNA for human glioblastoma-derived T cell suppressor factor, a novel member of the transforming growth factor-beta gene family. EMBO J.6, 3673–7 (1987).
Maheshwari A, Kelly DR, Nicola T, Ambalavanan N, Jain SK, Murphy-Ullrich J, et al. TGF-??2 suppresses macrophage cytokine production and mucosal inflammatory responses in the developing intestine. Gastroenterology 140, 242–253 (2011).
Shimizu C, Jain S, Davila S, Hibberd ML, Lin KO, Molkara D, et al.: Transforming growth factor-beta signaling pathway in patients with Kawasaki disease. Circ. Cardiovasc. Genet 4, 16–25 (2011).
Takashi H, Alves CR, Stanford KI, Middelbeek RJ, Nigro P, Ryan RE, et al. TGF-β2 is an exercise-induced adipokine that regulates glucose and fatty acid metabolism. Nat Metab. 2019 Feb; 1(2): 291–303.
Goodwin ML, Harris JE, Hernández A & Gladden LB Blood lactate measurements and analysis during exercise: a guide for clinicians. J. Diabetes Sci. Technol 1, 558–69 (2007).
Carrier A, Jeanson Y, Berger-MüllerS, Andre M, Chenouard V, Arnaud E, et al. Browning of white adipose cells by intermediate metabolites: An adaptive mechanism to alleviate redox pressure. Diabetes 63, 3253–3265 (2014).
Schenk S, Saberi M & Olefsky JM. Insulin sensitivity: Modulation by nutrients and inflammation. J Clin Invest 118, 2992–3002 (2008).
Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest 112, 1821–30 (2003).
de Martin R, Haendler B, Hofer-Warbinek R, Gaugitsch H, Wrann M, Schlüsener H, et al. Complementary DNA for human glioblastoma-derived T cell suppressor factor, a novel member of the transforming growth factor-beta gene family. EMBO J. 6, 3673–7 (1987).
Itoh N.: FGF21 as a hepatokine, adipokine, and myokine in metabolism and diseases. Front. Endocrinol. 2014; 5: pp. 107.
Gaich G, Chien JY, Fu H, Glass LC, Deeg MA, Holland WL, et al.: The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab. 2013; 18: pp. 333-340.
Fisher FM, Kleiner S, Douris N, Fox EC, Mepani RJ, Verdeguer F, et al.: FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis. Genes Dev. 2012; 26: pp. 271-281.
Kharitonenkov A., Adams A.C.: Inventing new medicines: the FGF21 story. Mol. Metab. 2014; 3: pp. 221-229.
Cheng X., Zhu B., Jiang F., Fan H.: Serum FGF-21 levels in type 2 diabetic patients. Endocr. Res. 2011; 36: pp. 142-148. Yamakage H, Tanaka M, Inoue T, Odori S, Kusakabe T, Satoh-Asahara N.
Wente W., Efanov A.M., Brenner M., Kharitonenkov A., Köster A., Sandusky G.E., et. al.: Fibrobalst growth factor-21 improves pancreatic beta-cell function and survival by activation of extracellular signal-regulated kinase ½ and Akt signaling pathways. Diabetes 2006; 55: pp. 2470-2478.
Kharitonenkov A., Wroblewski V.J., Koester A., Chen Y.F., Clutinger C.K., Tigno X.T., et. al.: The metabolic state of diabetic monkeys is regulated by fibrobalst growth factor-21. Endocrinology 2007; 148: pp. 774-781.
Sarruf D.A., Thaler J.P., Morton G.J., German J., Fischer J.D., Ogimoto K., et. al.: Fibroblast growth factor 21 action in the brain increases energy expenditure and insulin sensitivity in obese rats. Diabetes 2010; 59: pp. 1817-1824.
Zhang Y.: The starvation hormone, fibroblast growth factor–21, extends lifespan in mice. Elife 2012; 1: pp. e00065.
Castan-Laurell I., Dray C., Knauf C., Kunduzova O., Valet P.: Apelin, a promising target for type 2 diabetes treatment?. Trends Endocrinol Metab 2012; 23: pp. 234-241.
Boucher J., Masri B., Daviaud D., Gesta S., Guigné C., Mazzucotelli A., et. al.: Apelin, a newly identified adipokine up-regulated by insulin and obesity. Endocrinology 2005; 146: pp. 1764-1771.
Chapman N.A., Dupré D.J., Rainey J.K.: The apelin receptor: physiology, pathology, cell signalling, and ligand modulation of a peptide-activated class A GPCR. Biochem Cell Biol 2014; 92: pp. 431-440.
Knauf C., Drougard A., Fournel A., Duparc T., Valet P.: Hypothalamic actions of apelin on energy metabolism: new insight on glucose homeostasis and metabolic disorders. Horm Metab Res 2013; 45: pp. 928-934.
Sörhede Winzell M, Magnusson C, Ahrén B.: The apj receptor is expressed in pancreatic islets and its ligand, apelin, inhibits insulin secretion in mice. Regul. Pept. 2005; 131: pp. 12-17.
Dray C, Knauf C, Daviaud D, Waget A, Boucher J, Buléon M, et al: Apelin stimulates glucose utilization in normal and obese insulin-resistant mice. Cell Metab. 2008; 8: pp. 437-445.
Sörhede Winzell M., Magnusson C., Ahrén B.: The APJ receptor is expressed in pancreatic islets and its ligand, apelin, inhibits insulin secretion in mice. Regul Pept 2005; 131: pp. 12-17.
Dray C., Sakar Y., Vinel C., Daviaud D., Masri B., Garrigues L., et. al.: The intestinal glucose-apelin cycle controls carbohydate absorption in mice. Gastroenterology 2013; 144: pp. 771-780.
Wattez J.S., Ravallec R., Cudennec B., Knauf C., Dhulster P., Valet P., et. al.: Apelin stimulates both cholecystokinin and glucagon-like peptide 1 secretions in vitro and in vivo in rodents. Peptides 2013; 48: pp. 134-136.
Castan-Laurell I., Dray C., Attané C., Duparc T., Knauf C., Valet P.: Apelin, diabetes, and obesity. Endocrine 2011; 40: pp. 1-9.
Habchi M., Duvillard L., Cottet V., Brindisi M.C., Bouillet B., Beacco M., et. al.: Circulating apelin is increased in patients with type 1 or type 2 diabetes and is associated with better glycemic control. Clin Endocrinol 2014; 81: pp. 696-701.
Alexiadou K., Kokkinos A., Liatis S., Perrea D., Katsilambros N., Tentolouris N.: Differences in plasma apelin and visfatin levels between patients with type 1 diabetes mellitus and healthy subjects and response after acute hyperglycemia and insulin administration. Hormones (Athens) 2012; 11: pp. 444-450.
Attané C., Daviaud D., Dray C., Dusaulcy R., Masseboeuf M., Prévot D., et. al.: Apelin stimulates glucose uptake but not lipolysis in human adipose tissue ex vivo. J Mol Endocrinol 2011; 46: pp. 21-28.
Higuchi K., Masaki T., Gotoh K., Chiba S., Katsuragi I., Tanaka K., et. al.: Apelin, an APJ receptor ligand, regulates body adiposity and favors the messenger ribonucleic acid expression of uncoupling proteins in mice. Endocrinology 2007; 148: pp. 2690-2697.
Yamamoto T., Habata Y., Matsumoto Y., Yasuhara Y., Hashimoto T., Hamajyo H., et. al.: Apelin-transgenic mice exhibit a resistance against diet-induced obesity by increasing vascular mass and mitochondrial biogenesis in skeletal muscle. Biochim Biophys Acta 2011; 1810: pp. 853-862.
Attané C., Foussal C., Le Gonidec S., Benani A., Daviaud D., Wanecq E., et. al.: Apelin treatement increases complete fatty acid oxidation, mitochondrial oxidative capacity, and biogenesis in muscle of insulin-resistant mice. Diabetes 2012; 61: pp. 310-320.
Alfarano C., Foussal C., Lairez O., Calise D., Attané C., Anesia R., et. al.: Transition from metabolic adapatation to maladaptation of the heart in obesity: role of apelin. Int J Obes 2015; 39: pp. 312-320.
