Detalles del proyecto
Descripción
Obesity is a multifactorial disease, characterized by a chronic inflammatory status. In a complex inflammatory process, there is a wide diversity of mechanisms, involving cellular oxidative stress and adipose tissue hypoxia. According to WHO, in 2016 more than 1.9 billion adults were overweight and 650 million were obese (body mass index > 30) (WHO, 2018); the number is expected to rise in the future not only in high-income countries but also in developing countries. The nutrient overload in obesity promotes hypertrophy of adipocytes, which induces M1-macrophages infiltration in white adipocyte tissue (WAT) and activates cytokines and Toll like receptors (TLRs) pathways, not only in adipocytes, but also in others cellular types such as myocytes, hepatocytes, brain and even pancreatic cells. Hence, the organs in obese people present inflammation, which is modest in comparison to that generated by infection or trauma, but its chronicity impairs the normal metabolism of these organs. Activation of TLRs enhances the c-Jun N-terminal kinase (JNK), inhibitor of κ kinase (IKK) or protein kinase R (PKR) activities with the consequent increase of expression and release of cytokines (TNFα, IL-6, IL-1β and others) amplifying the inflammation in the organs and favoring insulin resistance (Gregor and Hotamisligil, 2011). Adipocytes undergoes hypertrophy due to increased adipogenesis and accumulation of fat. Hence, the blood supply in adipose tissue became more difficult, inducing hypoxia and helping to perpetuate inflammation. Therefore, the oxidation of fatty acids in adipocytes will decrease the hypertrophy and inflammation. AMP-activated protein kinase (AMPK) and Peroxisome Proliferator-activated Receptors (PPARs) are the enzyme and nuclear receptors, respectively, implicated in the metabolism of fatty acids in different tissues. In obese people (BMI > 40) with insulin resistance, it is been reported a decrease in the activity of AMPK compared to obese people sensitive to insulin (Ruderman et al., 2013). In addition, PPARs activation are related to a decrease of inflammation in different tissues in human (Wahli and Michalik 2012). So that, the activation of AMPK and PPARs in adipocytes will represent a strategy to decrease inflammation. The Cannabis plant contains several chemically active compounds, such as cannabinoids, terpenoids, flavonoids and alkaloids. The use of different extract preparations of Cannabis have been associated with therapeutic strategies for many diseases, due to the wide presence of the Endocannabinoid system (ECs) in brain and periphery. Cannabinoids are lipid mediators that produce their effects by activating specific receptors that modulate hunger/satiety and neuroinflammation in the brain, and in the periphery, they are involved in metabolic reactions of the liver, fat, muscles and anti-inflammatory response in the blood cells. Recent studies have shown that Phytocannabinoids can exert anti-inflammatory functions on the gut by primarily activating the CB2 receptor and promoting wound healing via activation of the CB1 receptor, suggesting a roll in chronic inflammatory conditions (Uranga et al., 2018); however, the mechanisms underlying the beneficial effects are not understood yet. In other hand, while acute cannabis use stimulates appetite, there are general population studies suggesting that the chronic use is associated to a reduced risk of obesity and other cardiometabolic risk factors (Meier et al., 2018). It has been shown that cannabinoids are involved in body weight control by interfering with regulatory circuits regarding energy homeostasis. There is evidence of cannabinoids induce the thermogenesis in fat cell lines by the increasing uncoupling respiratory system, which is an antiobesity and anti-inflammatory strategy (Parray and Yun 2016). Besides, the evidence shows an increase of leptin signaling and reduction of corticosterone plasma levels after synthetic CB1/CB2 receptor agonist CP-55,940 treatment (Scherma et al., 2017). 3T3-L1 cells are a well-established line of preadipocytes and can be differentiated into adipocytes. Similarly, the induction of a chronic inflammatory phenotype with LPS treatment is the model to evaluate the potential therapeutic targets, which helps to study obesity from the context of modulation by markers such as AMPK and PPARs, as well as the production of adipokines. This in vitro model can simulate, not only the physio pathological conditions in obesity, but also serve to evaluate the effect that components obtained from Cannabis plant, such as Cannabidiol (CBD), have on an induced chronic inflammatory phenotype. Thus, the evaluation of substances that can exert any effect on key biomarkers in chronic inflammation, are of interest in pathologies associated with this condition, as in the case of obesity. Therefore, this project aims to evaluate the effect that cannabidiol exerts in a model of induced inflammation, in adipocytes, specifically on the activity of AMPK and PPARs, which is well known to promote an increase in the oxidation of fats. The research team will contribute to the success of the project because of in our biochemistry laboratory it will be stablished the inflammatory cell model, and study of the role of CBD on AMPK activity. In addition, the wide experience in molecular biology tools of Institute of Inborn Errors of Metabolism will contribute to isolation, amplification and design of plasmids in the assessment of PPARs activity. Finally, the Cellular and Functional Biology and Biomolecule Engineering team from Antonio Nariño University will contribute to this project by performing the RNA isolation, qPCR techniques, and the cell culture support. References 1. Gregor, M.F., and Hotamisligil, G.S. (2011). Inflammatory mechanisms in obesity. Annu Rev Immunol 29, 415-45. 2. Meier MH, Pardini D, Beardslee J, and Matthews KA. 2018. Associations between cannabis use and cardiometabolic risk factors: A longitudinal study of men. Psychosom Med. doi: 10.1097/PSY.0000000000000665. 3. Parray HA and Yun JW. 2016. Cannabidiol promotes browning in 3T3-L1 adipocytes. Mol Cell Biochem. 416:131-9. 4. Ruderman NB, Carling D, Prentki M and Cacicedo JM. 2013, AMPK, insulin resistance, and the metabolic syndrome. J Clin Invest. 123:2764-72. 5. Scherma M, Satta V, Collu R, Boi MF, Usai P, Fratta W and Fadda P. 2017. Cannabinoid CB1 /CB2 receptor agonists attenuate hyperactivity and body weight loss in a rat model of activity-based anorexia. Br J Pharmacol. 174:2682-95. 6. Uranga JA, Vera G and Abalo R. 2018. Cannabinoid pharmacology and therapy in gut disorders. Biochem Pharmacol. 157:134-47. 7. Wahli W. and Michalik L. 2012. PPARs at the crossroads of lipid signaling and inflammation. Trends Endocrinol Metab. 23:351-63. 8. WHO (2018) Obesity and overweight, taken from https://www.who.int/en/news-room/factsheets/detail/obesity-and-overweight.
Estado | Finalizado |
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Fecha de inicio/Fecha fin | 22/02/21 → 14/01/24 |
Palabras clave
- Ampk
- Cannabidiol
- Inflamación
- Obesidad
- Ppars
Estado del Proyecto
- Sin definir
Financiación de proyectos
- Interna
- Pontificia Universidad Javeriana
Huella digital
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