Expression Levels of Predominant Adipokines and Activations of STAT3, STAT6 in an Experimental Mice Model of Obese Asthma
Obese asthma is a new asthma phenotype. The underlying mechanisms are not clearly understood. Leptin and adiponectin are two predominant adipokines produced by adipose tissue. Studies have demonstrated a role of leptin on regulating the Janus kinase/signal transducer and ativator of transcription protein(JAK/STAT) signaling pathway and STAT3, STAT6 were known to have essential role on inflammatory cytokines production. However, whether STAT3 and STAT6 are activated and related to leptin merit further investigation. The aim of this study was to investigate the expression levels of leptin/adiponectin ratio and the activations of STAT3 and STAT6 in the lungs of obese asthma mice. Experiments were carried out on male C57/B6J mice. The proteins in bronchoalveolar lavage fluid (BALF) were measured using ELISA. The expression levels of the transcriptional and translational factors in the lungs were examined using Quantitative Reverse Transcriptase Polymerase Chain reaction (qRT-PCR) and western blot. The expression levels of leptin in the BALF of normal weight group, asthma group, obese group and obese asthma group were 2.032±0.133, 5.375±0.123, 5.418±0.165 and 7.486±0.168, respectively. The expression of leptin in obese asthma group was the highest (p<0.05) ，while the expression of adiponectin the lowest (p<0.05). The expression level of P-STAT3 in the obese asthma group was 0.9244±0.014, and was significantly higher than three other groups (p<0.05). The expressions of P-STAT6 in three other groups were all significantly higher than normal weight group (p<0.05). Our data suggest that the function of leptin on the pulmonary inflammation of obese asthma may be partly through activating the STAT3 signaling pathway.
1. Thomson CC, Clark S, Camargo CJ. Body mass index and asthma severity among adults presenting to the emergency department. Chest. 2003;124(3):795-802.
2. Ahmadizar F, Vijverberg SJ, Arets HG, et al. Childhood obesity in relation to poor asthma control and exacerbation: a meta-analysis. Eur Respir J. 2016;48(suppl 60):A318.
3. Braback L, Hjern A, Rasmussen F. Body mass index, asthma and allergic rhinoconjunctivitis in Swedish conscripts-a national cohort study over three decades. Respir Med. 2005;99(8):1010-1014.
4. Papadopoulos NG, Arakawa H, Carlsen KH, et al. International consensus on (ICON) pediatric asthma. Allergy. 2012;67(8):976-997.
5. Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma. 2016.
6. Suratt BT. Mouse Modeling of Obese Lung Disease: Insights and Caveats. Am J Respir Cell Mol Biol. 2016;55(2):153.
7. Jung SH, Kwon JM, Shim JW, et al. Effects of diet-induced mild obesity on airway hyperreactivity and lung inflammation in mice. Yonsei Med J. 2013;54(6):1430-1437.
8. Sood A. Obesity, adipokines, and lung disease. J Appl Physiol (1985). 2010;108(3):744-753.
9. Beuther DA. Recent insight into obesity and asthma. Curr Opin Pulm Med. 2010;16(1):64-70.
10. Hussain Z, Khan JA. Food intake regulation by leptin: Mechanisms mediating gluconeogenesis and energy expenditure. Asian Pac J Trop Med. 2017;10(10):940-944.
11. Yamauchi T, Kamon J, Waki H, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001;7(8):941-946.
12. Newson RB, Jones M, Forsberg B, et al. The association of asthma, nasal allergies, and positive skin prick tests with obesity, leptin, and adiponectin. Clin Exp Allergy. 2014;44(2):250-260.
13. Bodini A, Tenero L, Sandri M, et al. Serum and exhaled breath condensate leptin levels in asthmatic and obesity children: a pilot study. J Breath Res. 2017;11(4):46005.
14. Zhou L, Ivanov II, Spolski R, et al. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol. 2007;8(9):967-974.
15. Yang Q, Xu W, Long Y, Kuang J, Li J. STAT3 regulates cytokine expression in peripheral blood mononuclear cells from asthma patients. Cell Mol Biol (Noisy-le-grand). 2017;63(9):71-74.
16. Mathew A, MacLean JA, DeHaan E, Tager AM, Green FH, Luster AD. Signal transducer and activator of transcription 6 controls chemokine production and T helper cell type 2 cell trafficking in allergic pulmonary inflammation. J Exp Med. 2001;193(9):1087-1096.
17. Erkasap S, Erkasap N, Bradford B, et al. The effect of leptin and resveratrol on JAK/STAT pathways and Sirt-1 gene expression in the renal tissue of ischemia/reperfusion induced rats. Bratisl Lek Listy. 2017;118(8):443-448.
18. Hao W, Wang J, Zhang Y, Wang Y, Sun L, Han W. Leptin positively regulates MUC5AC production and secretion induced by interleukin-13 in human bronchial epithelial cells. Biochem Biophys Res Commun. 2017;493(2):979-984.
19. Chih AH, Chen YC, Tu YK, Huang KC, Chiu TY, Lee YL. Mediating pathways from central obesity to childhood asthma: a population-based longitudinal study. Eur Respir J. 2016; 48 (3) :748.
20. Ali Z, Ulrik CS. Obesity and asthma: A coincidence or a causal relationship? A systematic review. Resp Med. 2013;107(9):1287-1300.
21. Mohanan S, Tapp H, McWilliams A, Dulin M. Obesity and asthma: pathophysiology and implications for diagnosis and management in primary care. Exp Biol Med (Maywood). 2014;239(11):1531-1540.
22. Shore SA. Obesity and asthma: lessons from animal models. J Appl Physiol (1985). 2007;102(2):516-528.
23. Lutz TA, Woods SC. Overview of animal models of obesity. Curr Protoc Pharmacol. 2012;Chapter 5:t5-t61.
24. Tschöp M, Heiman M. Rodent obesity models: An overview. Exp Clin Endocr Diab. 2001;109(06):307-319.
25. Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med. 2012;18(5):716-725.
26. Bel EH. Clinical phenotypes of asthma. Curr Opin Pulm Med. 2004;10(1):44-50.
27. Chong L, Zhang W, Nie Y, et al. Protective Effect of Curcumin on Acute Airway Inflammation of Allergic Asthma in Mice Through Notch1–GATA3 Signaling Pathway. Inflammation. 2014;37(5):1476-1485.
28. Vijayakanthi N, Greally JM, Rastogi D. Pediatric Obesity-Related Asthma: The Role of Metabolic Dysregulation. Pediatrics. 2016;137(5).
29. Leao DSP, de Mello MT, Cheik NC, et al. Reduction in the leptin concentration as a predictor of improvement in lung function in obese adolescents. Obes Facts. 2012;5(6):806-820.
30. Sood A, Ford ES, Camargo CJ. Association between leptin and asthma in adults. Thorax. 2006;61(4):300-305.
31. de Lima SP, de Mello MT, Elias N, et al. Improvement in HOMA-IR is an independent predictor of reduced carotid intima-media thickness in obese adolescents participating in an interdisciplinary weight-loss program. Hypertens Res. 2011;34(2):232-238.
32. Elloumi M, Ben OO, Makni E, Van Praagh E, Tabka Z, Lac G. Effect of individualized weight-loss programmes on adiponectin, leptin and resistin levels in obese adolescent boys. Acta Paediatr. 2009;98(9):1487-1493.
33. Morales JK, Falanga YT, Depcrynski A, Fernando J, Ryan JJ. Mast cell homeostasis and the JAK-STAT pathway. Genes Immun. 2010;11(8):599-608.
34. Gavino AC, Nahmod K, Bharadwaj U, Makedonas G, Tweardy DJ. STAT3 inhibition prevents lung inflammation, remodeling, and accumulation of Th2 and Th17 cells in a murine asthma model. Allergy. 2016;71(12):1684-1692.
35. Mathur AN, Chang HC, Zisoulis DG, et al. Stat3 and Stat4 direct development of IL-17-secreting Th cells. J Immunol. 2007;178(8):4901-4907.