Palavras-chave
Lipogénesis
Lipólisis
Glucosa
Insulina
Como Citar
Resumo
Introducción: la obesidad es considerada un factor de riesgo para desarrollar resistencia a la insulina. La expansión del tejido adiposo se ha relacionado con el aumento de la producción de citoquinas proinflamatorias que, junto a los ácidos grasos son responsables, al menos en parte, del desarrollo de la resistencia a la insulina y esta a su vez, facilita el desarrollo de diabetes mellitus tipo 2 (DMT2). Objetivo: el propósito de este estudio fue realizar y caracterizar un modelo in vitro de obesidad empleando concentraciones altas de glucosa e insulina en una línea de células adipocitarias. Métodos: se indujo modelo de hipertrofia celular realizando un estímulo en adipocitos maduros con una concentración de glucosa (450 mg/dL) e insulina (106 pmol/L) (modelo HGHI). Tras estímulo se realizaron ensayos de viabilidad celular, diámetro celular, movilización de lípidos y marcadores de señalización de insulina. Resultados: tras el tratamiento con HGHI, se evidencia hipertrofia adipocitaria, incremento en la acumulación de lípidos, reducción de la ruptura de éstos, alteración de la señalización de insulina y tendencia a modificación de proteínas de marcadores de estrés de retículo y estrés oxidativo. Conclusión: estos resultados demuestran la validez del modelo in vitro que simula al menos en parte la obesidad asociada a insulino resistencia, siendo una herramienta útil para estudiar los mecanismos de susceptibilidad a obesidad y resistencia a la insulina inducida in vitro con diferentes moléculas.
Referências
Abarca L, Abdeen Z, Hamid Z, Abu N, Acosta B, Acuin C. et al. 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(10113): 2627-2642. doi:10.1016/S0140-6736(17)32129-3
Zatterale F, Longo M, Naderi J, Raciti G, Desiderio A, Miele C. et al. Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes. Front Physiol. 2020; 10. doi: https://doi.org/10.3389/fphys.2019.01607
Bai Y, Sun Q. Macrophage recruitment in obese adipose tissue. Obes Rev. 2015; 16(2): 127-136. doi: https://doi.org/10.1111/obr.12242
Longo M, Zatterale F, Naderi J, Parrillo L, Formisano P, Raciti G. et al. Adipose tissue dysfunction as determinant of obesity-associated metabolic complications. Int J Mol Sci. 2019; 20(9). doi: https://doi.org/10.3390/ijms20092358
Nakatani Y, Kaneto H, Kawamori D, Yoshiuchi K, Hatazaki M, Matsuoka T. et al. Involvement of endoplasmic reticulum stress in insulin resistance and diabetes. J Biol Chem. 2005; 280(1): 847-851. doi: https://doi.org/10.1074/jbc.M411860200
Lowell BB, Shulman GI. Mitochondrial dysfunction and type 2 diabetes. Science (80- ). 2005; 307(5708): 384-387. doi: https://doi.org/10.1126/science.1104343
Lin Y, Berg AH, Iyengar P, Lam TK, Giacca A, Combs TP. et al. The hyperglycemia-induced inflammatory response in adipocytes: The role of reactive oxygen species. J Biol Chem. 2005; 280(6): 4617-4626. doi: https://doi.org/10.1074/jbc.M411863200
Li A, Liu J, Ding F, Wu X, Pan C, Wang Q. et al. Maca extracts regulate glucose and lipid metabolism in insulin-resistant HepG2 cells via the PI3K/AKT signalling pathway. Food Sci Nutr. 2021; 9(6): 2894-2907. doi: https://doi.org/10.1002/fsn3.2246
Lo KA, Labadorf A, Kennedy NJ, Han MS, Yap YS, Matthews B. et al. Analysis of In Vitro Insulinresistance models and their physiological relevance to InVivo diet-induced adipose insulin resistance. Cell Rep. 2013; 5(1): 259-270. doi: https://doi.org/10.1016/j.celrep.2013.08.039
Reed MJ, Scribner KA. In-vivo and in-vitro models of type 2 diabetes in pharmaceutical drug discovery. Diabetes, Obes Metab. 1999; 1(2): 75-86. doi: https://doi.org/10.1046/j.1463-1326.1999.00014.x
Monickaraj F, Aravind S, Nandhini P, Prabu P, Sathishkumar C, Mohan V. et al. Accelerated fat cell aging links oxidative stress and insulin resistance in adipocytes. J Biosci. 2013; 38(1): 113-122. doi: https://doi.org/10.1007/s12038-012-9289-0
Moreno-Castellanos N, Rodríguez A, Rabanal-Ruiz Y, Fernández-Vega A, López-Miranda J, Vázquez-Martínez R. et al. The cytoskeletal protein septin 11 is associated with human obesity and is involved in adipocyte lipid storage and metabolism. Diabetologia. 2017; 60(2): 324-335. doi: https://doi.org/10.1007/s00125-016-4155-5
Mantilla G, Ángel A, Moreno N. Effects of oleic ( 180 ) fatty acids on the metabolic state of adipocytes. Salud UIS. 2021. 53: e21009. doi: https://doi.org/10.18273/saluduis.53.e:21009
Stockert JC, Horobin RW, Colombo LL, Blázquez-Castro A. Tetrazolium salts and formazan products in Cell Biology: Viability assessment, fluorescence imaging, and labeling perspectives. Acta Histochem. 2018; 120(3): 159-167. doi: https://doi.org/10.1016/j.acthis.2018.02.005
Armani A, Mammi C, Marzolla V, Calanchini M, Antelmi A,Rosano G. et al. Cellular models for understanding adipogenesis, adipose dysfunction, and obesity. J Cell Biochem. 2010; 110(3): 564-572. doi: https://doi.org/10.1002/jcb.22598
Zhang Y, Liu X, Han L, Gao X, Liu E, Wang T. Regulation of lipid and glucose homeostasis by mango tree leaf extract is mediated by AMPK and PI3K/AKT signaling pathways. Food Chem. 2013; 141(3): 2896-2905. doi: https://doi.org/10.1016/j.foodchem.2013.05.121
Chan P-C, Hsieh P-S. The role of adipocyte hypertrophy and hypoxia in the development of obesity-associated adipose tissue inflammation and insulin resistance. Adiposity - Omi Mol Underst. 2017. doi: https://doi.org/10.5772/65458
Sullivan J, Brocklehurst K, Marley A, Carey F, Carling D, Beri R. Inhibition of lipolysis and lipogenesis in isolated rat adipocytes with AICAR, a cell-permeable activator of AMP-activated protein kinase. FEBS Lett. 1994; 353: 33-36. doi: https://doi.org/10.1016/0014-5793(94)01006-4
Stöckli J, Fazakerley DJ, James DE. GLUT4 exocytosis. J Cell Sci. 2011; 124(24): 4147-4159. doi: https://doi.org/10.1242/jcs.097063
Manning BD, Cantley LC. AKT/PKB Signaling: Navigating downstream. Cell. 2007; 129(7): 1261-1274. doi: https://doi.org/10.1016/j.cell.2007.06.009
Patel N, Huang C, Klip A. Cellular location of insulin-triggered signals and implications for glucose uptake. Pflugers Arch Eur J Physiol. 2006; 451(4): 499-510. doi: https://doi.org/10.1007/s00424-005-1475-6
Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001; 414(6865): 799-806. doi: https://doi.org/10.1038/414799a
Lazar DF, Wiese RJ, Brady MJ, Mastick CC, Waters SB, Yamauchi K. et al. Mitogen-activated protein kinase kinase inhibition does not block the stimulation of glucose utilization by insulin. J Biol Chem. 1995; 270(35): 20801-20807. doi: https://doi.org/10.1074/jbc.270.35.20801
Lee YH, Giraud J, Davis RJ, White MF. c-Jun N-terminal kinase (JNK) mediates feedback inhibition of the insulin signaling cascade. J Biol Chem. 2003; 278(5): 2896-2902. doi: https://doi.org/10.1074/jbc.M208359200
Chang L, Chiang SH, Saltiel AR. Insulin signaling and the regulation of glucose transport. Mol Med. 2004; 10(7-12): 65-71. doi: https://doi.org/10.2119/2005-00029.Saltiel
Bánhegyi G, Baumeister P, Benedetti A, Dong D, Fu Y, Lee A. et al. Endoplasmic reticulum stress. Ann N Y Acad Sci. 2007; 1113: 58-71. doi: https://doi.org/10.1196/annals.1391.007
Batista TM, Jayavelu AK, Wewer Albrechtsen NJ, Iovino S, Lebastchi J, Pan H. et al. A cell-autonomous signature of dysregulated protein phosphorylation underlies muscle insulin resistance in type 2 Diabetes. Cell Metab. 2020; 32(5): 844-859.e5. doi: https://doi.org/10.1016/j.cmet.2020.08.007
Xuguang H, Aofei T, Tao L, Longyan Z, Weijian B, Jiao G. Hesperidin ameliorates insulin resistance by regulating the IRS1-GLUT2 pathway via TLR4 in HepG2 cells. Phyther Res. 2019;33(6):1697-1705. doi: https://doi.org/10.1002/ptr.6358
Eizirik DL, Cardozo AK, Cnop M. The role for endoplasmic reticulum stress in diabetes mellitus. Endocr Rev. 2008;29(1):42-61. doi: https://doi. org/10.1210/er.2007-0015
Guerrero-Hernández A, Leon-Aparicio D, Chavez-Reyes J, Olivares-Reyes JA, De Jesus S. Endoplasmic reticulum stress in insulin resistance and diabetes. Cell Calcium. 2014; 56(5): 311-322. doi: https://doi.org/10.1016/j.ceca.2014.08.006
Este trabalho está licenciado sob uma licença Creative Commons Attribution 4.0 International License.
Copyright (c) 2022 Alberto Ángel-Martín, Katherin Bonilla-Carvajal, Natalia Moreno-Castellanos