Mitogen-activated protein kinase and phosphatidylinositol 3-kinase/akt signaling pathways in the pathogenesis of obesity

Yıl 2023, Cilt: 6 Sayı: 2, 109 - 113, 30.12.2023

Adem Keskin

https://doi.org/10.46239/ejbcs.1365464

Öz

Obesity, a major health problem worldwide and characterized by excess fat accumulation in the body, sharply increases the risk of a number of chronic diseases, such as type 2 diabetes, cardiovascular diseases and non-alcoholic fatty liver disease. Although lifestyle interventions such as diet and exercise have significant effects in combating obesity, long-term success in weight loss is extremely difficult to achieve and the prevalence of obesity continues to increase worldwide. Over the past few decades, the pathophysiology of obesity has been extensively investigated and an increasing number of signaling pathways have been associated with obesity, focusing on signaling pathways to combat obesity more effectively and precisely. While the mitogen-activated protein kinase (MAPK) signaling pathway contributes to appetite control, regulation of glucose levels and fat cell formation, it may also lead to the development of insulin resistance. The role of MAPK has been particularly emphasized in the hypothalamus and adipose tissue. The phosphatidylinositol 3-kinase/AKT signaling pathway plays a critical role in regulating cell growth and proliferation. Abnormal activation of this pathway may promote the development of obesity and contribute to insulin resistance. Research shows that there is a need for a better understanding of the relationships between signaling pathways, adipose tissue metabolism, and energy balance in the regulation of appetite. As a result, innovative and safe measures for obesity management need to be investigated. Signaling pathways play an important role in the pathogenesis of obesity, and future studies need to focus more on this issue.

Anahtar Kelimeler

Obesity, Signaling pathway, MAPK signaling pathway, PI3K/AKT signaling pathway

Obezite patogenezinde mitojenle aktifleşen protein kinaz ve fosfatidilinositol 3-kinaz/akt sinyal yolları

Öz

Dünya çapında önemli bir sağlık sorunu olan ve vücutta aşırı yağ birikmesiyle karakterize edilen obezite, tip 2 diyabet, kalp-damar hastalıkları ve alkole bağlı olmayan yağlı karaciğer hastalığı gibi bir dizi kronik hastalık riskini keskin bir şekilde artırır. Diyet ve egzersiz gibi yaşam tarzı müdahalelerinin obeziteyle mücadelede önemli etkileri olmasına rağmen, kilo vermede uzun vadeli başarıyı yakalamak son derece zordur ve obezite prevalansı dünya çapında artmaya devam etmektedir. Geçtiğimiz birkaç on yılda, obezitenin patofizyolojisi kapsamlı bir şekilde araştırılmış ve artan sayıda sinyal yolu obezite ile ilişkilendirilmiş, obeziteyle daha etkili ve kesin bir şekilde mücadele etmek için sinyal yollarına odaklanılmıştır. Mitojenle aktifleşen protein kinaz (MAPK) sinyal yolu iştah kontrolüne, glukoz seviyelerinin düzenlenmesine ve yağ hücresi oluşumuna katkıda bulunurken aynı zamanda insülin direncinin gelişmesine de yol açabilir. MAPK'nın rolü özellikle hipotalamus ve yağ dokusunda vurgulanmıştır. Fosfatidilinositol 3-kinaz/AKT sinyal yolu, hücre büyümesinin ve çoğalmasının düzenlenmesinde kritik bir rol oynar. Bu yolun anormal aktivasyonu obezitenin gelişimini teşvik edebilir ve insülin direncine katkıda bulunabilir. Araştırmalar, iştahın düzenlenmesinde sinyal yolları, yağ dokusu metabolizması ve enerji dengesi arasındaki ilişkilerin daha iyi anlaşılması gerektiğini göstermektedir. Sonuç olarak obezite yönetimine yönelik yenilikçi ve güvenli önlemlerin araştırılması gerekmektedir. Sinyal yolakları obezitenin patogenezinde önemli bir rol oynamaktadır ve gelecekteki çalışmaların bu konuya daha fazla odaklanması gerekmektedir.

Anahtar Kelimeler

Obezite, Sinyal yolu, MAPK sinyal yolu, PI3K/AKT sinyal yolu

Kaynakça

• Aouadi M, Laurent K, Prot M, Le Marchand-Brustel Y, Binétruy B, Bost F. 2006. Inhibition of p38MAPK increases adipogenesis from embryonic to adult stages. Diabetes. 55(2): 281-289.
• Aouadi M, Jager J, Laurent K, Gonzalez T, Cormont M, Binétruy B, Le Marchand-Brustel Y, Tanti JF, Bost F. 2007. p38MAP Kinase activity is required for human primary adipocyte differentiation. FEBS Lett., 581(29): 5591-5596.
• Azpeitia E, Balanzario EP, Wagner A. 2020. Signaling pathways have an inherent need for noise to acquire information. BMC Bioinformatics. 21(1): 462.
• Bashan N, Dorfman K, Tarnovscki T, Harman-Boehm I, Liberty IF, Blüher M, Ovadia S, Maymon-Zilberstein T, Potashnik R, Stumvoll M, Avinoach E, Rudich A. 2007. Mitogen-activated protein kinases, inhibitory-kappaB kinase, and insulin signaling in human omental versus subcutaneous adipose tissue in obesity. Endocrinology. 148(6): 2955-2962.
• Friedrichsen M, Poulsen P, Richter EA, Hansen BF, Birk JB, Ribel-Madsen R, Stender-Petersen K, Nilsson E, Beck-Nielsen H, Vaag A, Wojtaszewski JF. 2010. Differential aetiology and impact of phosphoinositide 3-kinase (PI3K) and Akt signalling in skeletal muscle on in vivo insulin action. Diabetologia. 53(9): 1998-2007. Ghaben AL, Scherer PE. 2019. Adipogenesis and metabolic health. Nat Rev Mol Cell Biol. 20(4): 242-258. Gustafson B, Nerstedt A, Smith U. 2019. Reduced subcutaneous adipogenesis in human hypertrophic obesity is linked to senescent precursor cells. Nature communications, 10(1): 2757.
• Hemmings BA, Restuccia DF. 2015. PI3K-PKB/Akt pathway. Cold Spring Harb Perspect Biol. 2012 Sep 1;4(9):a011189. doi: 10.1101/cshperspect.a011189. Erratum in: Cold Spring Harb Perspect Biol. 7(4). pii: a026609.
• Hill JW, Williams KW, Ye C, Luo J, Balthasar N, Coppari R, Cowley MA, Cantley LC, Lowell BB, Elmquist JK. 2008. Acute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mice. J Clin Invest., 118(5): 1796-1805.
• Hu E, Kim JB, Sarraf P, Spiegelman BM. 1996. Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPARgamma. Science. 274(5295): 2100-2103.
• Hopkins BD, Goncalves MD, Cantley LC. 2016. Obesity and Cancer Mechanisms: Cancer Metabolism. J Clin Oncol. 34(35): 4277-4283.
• Huang R, Ding X, Fu H, Cai Q. 2019. Potential mechanisms of sleeve gastrectomy for reducing weight and improving metabolism in patients with obesity. Surg Obes Relat Dis. 15(10): 1861-1871.
• Kassouf T, Sumara G. 2020. Impact of Conventional and Atypical MAPKs on the Development of Metabolic Diseases. Biomolecules., 10(9): 1256.
• Kent S, Jebb SA, Gray A, Green J, Reeves G, Beral V, Mihaylova B, Cairns BJ. 2019. Body mass index and use and costs of primary care services among women aged 55–79 years in England: a cohort and linked data study. International Journal of Obesity, 43(9): 1839-1848.
• Keskin A. 2023. Impact of Polyphenolic Compounds on the MAPK Signaling Pathway against Carcinogenesis. Journal of Clinical Practice and Research, 45(3): 217-221.
• Keskin A. 2023. Hücre yaşamı ile ilgili sinyal yolakların düzenlenmesinde diyet polifenollerin rolü Turk J Health S. 4(1): 32-36.
• Keskin A, Aci R, Ari M, Duran U. 2023. Cellular senescence, mTOR signaling pathway and polyphenol. International Journal of Advanced Biochemistry Research, 7(1): 01-04.
• Keskin A, Aci R. 2022. Investıgatıon of Lipid Profile, Malondialdehyde, Sodium, Potassium, Chloride Levels in Rats with Weight Loss. Türkiye Diyabet ve Obezite Dergisi, 6(1): 10-15.
• Kivimäki M, Strandberg T, Pentti J, Nyberg ST, Frank P, Jokela M, Ervasti J, Suominen SB, Vahtera J, Sipilä PN, Lindbohm JV, Ferrie JE. 2022. Body-mass index and risk of obesity-related complex multimorbidity: an observational multicohort study. Lancet Diabetes Endocrinol, 10 (2022): 253-263.
• Khoubai FZ, Grosset CF. 2021. DUSP9, a Dual-Specificity Phosphatase with a Key Role in Cell Biology and Human Diseases. Int J Mol Sci. 22(21):11538.
• Kwon O, Kim KW, Kim MS. 2016. Leptin signalling pathways in hypothalamic neurons. Cell Mol Life Sci., 73(7): 1457-1477.
• Li J, Chen C, Li Y, Matye DJ, Wang Y, Ding WX, Li T. 2017. Inhibition of insulin/PI3K/AKT signaling decreases adipose Sortilin 1 in mice and 3T3-L1 adipocytes. Biochim Biophys Acta Mol Basis Dis., 1863(11): 2924-2933.
• Li T, Zhang Z, Kolwicz SC Jr, Abell L, Roe ND, Kim M, Zhou B, Cao Y, Ritterhoff J, Gu H, Raftery D, Sun H, Tian R. 2017. Defective Branched-Chain Amino Acid Catabolism Disrupts Glucose Metabolism and Sensitizes the Heart to Ischemia-Reperfusion Injury. Cell Metab. 25(2): 374-385.
• Li Z, Fang X, Yu D. 2021. Transdermal Drug Delivery Systems and Their Use in Obesity Treatment. Int J Mol Sci. 22(23): 12754.
• Mackenzie RW, Elliott BT. 2014. Akt/PKB activation and insulin signaling: a novel insulin signaling pathway in the treatment of type 2 diabetes. Diabetes Metab Syndr Obes., 7:55-64.
• Müller TD, Blüher M, Tschöp MH, DiMarchi RD. 2022. Anti-obesity drug discovery: advances and challenges. Nature Reviews Drug Discovery, 21(3): 201-223.
• Okunogbe A, Nugent R, Spencer G, Ralston J, Wilding J. 2021. Economic impacts of overweight and obesity: current and future estimates for eight countries. BMJ global health, 6(10): e006351.
• Pudewell S, Wittich C, Kazemein Jasemi NS, Bazgir F, Ahmadian MR. 2021. Accessory proteins of the RAS-MAPK pathway: moving from the side line to the front line. Commun Biol., 4(1): 696.
• Sabio G, Cavanagh-Kyros J, Barrett T, Jung DY, Ko HJ, Ong H, Morel C, Mora A, Reilly J, Kim JK, Davis RJ. 2010. Role of the hypothalamic-pituitary-thyroid axis in metabolic regulation by JNK1. Genes Dev. 24(3): 256-264.
• Shen H, Huang X, Zhao Y, Wu D, Xue, K, Yao J, Wang Y, Tang T, Qiu Y. 2022. The Hippo pathway links adipocyte plasticity to adipose tissue fibrosis. Nature Communications, 13(1): 6030.
• Sun F, Wang J, Sun Q, Li F, Gao H, Xu L, Zhang J, Sun X, Tian Y, Zhao Q, Shen H, Zhang K, Liu J. 2019. Interleukin-8 promotes integrin β3 upregulation and cell invasion through PI3K/Akt pathway in hepatocellular carcinoma. J Exp Clin Cancer Res. 38(1): 449.
• Sun Y, Liu WZ, Liu T, Feng X, Yang N, Zhou HF. 2015. Signaling pathway of MAPK/ERK in cell proliferation, differentiation, migration, senescence and apoptosis. J Recept Signal Transduct Res., 35(6): 600-604.
• Trepanowski JF, Kroeger CM, Barnosky A, Klempel MC, Bhutani S, Hoddy KK, Gabel K, Freels S, Rigdon J, Rood J, Ravussin E, Varady KA. 2017. Effect of Alternate-Day Fasting on Weight Loss, Weight Maintenance, and Cardioprotection Among Metabolically Healthy Obese Adults: A Randomized Clinical Trial. JAMA Intern Med. 177(7): 930-938.
• Xu Q, Ding H, Li S, Dong S, Li L, Shi B, Zhong M, Zhang G. 2021. Sleeve Gastrectomy Ameliorates Diabetes-Induced Cardiac Hypertrophy Correlates With the MAPK Signaling Pathway. Front Physiol. 12: 785799.
• Wang Z, Zhu M, Wang M, Gao Y, Zhang C, Liu S, Qu S, Liu Z, Zhang C. 2021. Integrated Multiomic Analysis Reveals the High-Fat Diet Induced Activation of the MAPK Signaling and Inflammation Associated Metabolic Cascades via Histone Modification in Adipose Tissues. Front Genet. 12: 650863.
• Wen X, Zhang B, Wu B, Xiao H, Li Z, Li R, Xu X, Li T. 2022. Signaling pathways in obesity: mechanisms and therapeutic interventions. Signal Transduct Target Ther. 7(1): 298.
• Wolfe BM, Kvach E, Eckel RH. 2016. Treatment of Obesity: Weight Loss and Bariatric Surgery. Circ Res. 118(11): 1844-1855.
• Zeng X, Du X, Zhang J, Jiang S, Liu J, Xie Y, Shan W, He G, Sun Q, Zhao J. 2018. The essential function of CARD9 in diet-induced inflammation and metabolic disorders in mice. J Cell Mol Med., 22(6): 2993-3004.
• Zhang J, Zhou Y, Chen C, Yu F, Wang Y, Gu J, Ma L, Ho G. 2015. ERK1/2 mediates glucose-regulated POMC gene expression in hypothalamic neurons. J Mol Endocrinol., 54(2): 125-135.