Publication: Papel de la lipoatrofia marrón, las isoformas del receptor de insulina y el receptor de IGF-I en la aterosclerosis experimental y humana
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2018-02-28
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Universidad Complutense de Madrid
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Abstract
La obesidad es uno de los principales factores de riesgo para el desarrollo de enfermedades cardiovasculares y ocurre cuando la ingesta excede al gasto energético (Mathieu et al., 2010). Se caracteriza por la acumulación excesiva o anormal de tejido adiposo, incluyendo el tejido adiposo perivascular (PVAT), capaz de secretar numerosas sustancias biológicamente activas y que ha sido implicado en la inflamación vascular (Brown et al., 2014; Omar et al., 2014). Actualmente, está bien establecida la capacidad del tejido adiposo marrón (BAT) de proteger frente a la obesidad. Además, los individuos con menor cantidad de BAT son más propensos a la acumulación excesiva de tejido adiposo blanco (WAT), existiendo una relación inversa entre los niveles de BAT y el índice de masa corporal (Cypess et al., 2009; Saito et al., 2009). Es por ello que el estudio de este tejido ha adquirido un gran interés como una posible diana terapéutica para el tratamiento de la obesidad y sus complicaciones metabólicas y vasculares asociadas. En este contexto, trabajos previos de nuestro grupo pusieron de manifiesto que la ausencia del receptor de insulina (IR) específica del BAT (modelo BATIRKO) conduce a una pérdida de la masa de este tejido (Guerra et al., 2001), y que esta lipoatrofia marrón confiere una mayor susceptibilidad a la obesidad, junto con la presencia de alteraciones vasculares como disfunción vascular y resistencia vascular a la insulina (Gómez-Hernández et al., 2012). Por otro lado, es conocido que la aterosclerosis es la principal causa de las enfermedades cardiovasculares. La progresión de las lesiones vasculares iniciales hasta la formación de placas avanzadas es un proceso complejo en el que las células de músculo liso vascular (VSMCs) juegan un papel relevante (Bennett et al., 2016). En las etapas tempranas, como resultado de la lesión vascular, se producen cambios en el entorno de las VSMCs, entre los que se incluyen el aumento de la disponibilidad de factores de crecimiento y alteraciones celulares, que conducen a la proliferación y migración de las VSMCs y, con ello, a la formación de una placa aterosclerótica organizada (Johnson, 2014). En estadios más avanzados, en los que existe un alto riesgo de que se desencadenen eventos cardiovasculares agudos, uno de los principales mecanismos que contribuye a la inestabilidad de la placa aterosclerótica es la pérdida de VSMCs como consecuencia de un aumento de su apoptosis (Littlewood y Bennett, 2003)...
Obesity occurs when energy intake exceeds energy expenditure and it is a major risk factor for the development of associated metabolic diseases and cardiovascular damage (Mathieu et al., 2010). It is characterized by excessive or abnormal accumulation of adipose tissue, including perivascular adipose tissue (PVAT) that secretes numerous biologically active substances and it is involved in vascular inflammation (Brown et al., 2014; Omar et al., 2014). Currently, it is well-established that brown adipose tissue (BAT) is able to protect against obesity. In addition, individuals with low BAT levels are prone to excessive accumulation of white adipose tissue (WAT), BAT levels being inversely correlated with body mass index (Cypess et al., 2009; Saito et al., 2009). For this reason, the study of BAT has been of great interest as a therapeutic target for the treatment of obesity and its associated metabolic and vascular complications. In this context, previous works of our group revealed that the specific lack of insulin receptor (IR) in BAT (BATIRKO mice) leads to a loss of BAT mass (Guerra et al., 2001), brown fat lipoatrophy confering obesity susceptibility together with vascular alterations such as vascular dysfunction and vascular insulin resistance (Gómez-Hernández et al., 2012). On the other hand, it is well known that atherosclerosis is the major cause of cardiovascular disease. The progression of initial vascular lesions to more advanced plaques is a complex process where vascular smooth muscle cells (VSMCs) play a major role. In early stages, vascular injury results in changes in the VSMC environment, including increases in growth factor availability and cell alterations, leading to proliferation and migration of VSMCs and thereby to an organized atherosclerotic plaque (Johnson, 2014). In advanced stages, in which there is a high risk of acute cardiovascular events, one of the main mechanisms contributing to the instability of atherosclerotic plaques is the loss of VSMCs as a result of increased apoptosis (Littlewood y Bennett, 2003)...
Obesity occurs when energy intake exceeds energy expenditure and it is a major risk factor for the development of associated metabolic diseases and cardiovascular damage (Mathieu et al., 2010). It is characterized by excessive or abnormal accumulation of adipose tissue, including perivascular adipose tissue (PVAT) that secretes numerous biologically active substances and it is involved in vascular inflammation (Brown et al., 2014; Omar et al., 2014). Currently, it is well-established that brown adipose tissue (BAT) is able to protect against obesity. In addition, individuals with low BAT levels are prone to excessive accumulation of white adipose tissue (WAT), BAT levels being inversely correlated with body mass index (Cypess et al., 2009; Saito et al., 2009). For this reason, the study of BAT has been of great interest as a therapeutic target for the treatment of obesity and its associated metabolic and vascular complications. In this context, previous works of our group revealed that the specific lack of insulin receptor (IR) in BAT (BATIRKO mice) leads to a loss of BAT mass (Guerra et al., 2001), brown fat lipoatrophy confering obesity susceptibility together with vascular alterations such as vascular dysfunction and vascular insulin resistance (Gómez-Hernández et al., 2012). On the other hand, it is well known that atherosclerosis is the major cause of cardiovascular disease. The progression of initial vascular lesions to more advanced plaques is a complex process where vascular smooth muscle cells (VSMCs) play a major role. In early stages, vascular injury results in changes in the VSMC environment, including increases in growth factor availability and cell alterations, leading to proliferation and migration of VSMCs and thereby to an organized atherosclerotic plaque (Johnson, 2014). In advanced stages, in which there is a high risk of acute cardiovascular events, one of the main mechanisms contributing to the instability of atherosclerotic plaques is the loss of VSMCs as a result of increased apoptosis (Littlewood y Bennett, 2003)...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Farmacia, Departamento de Bioquímica y Biología Molecular II, leída el 08-06-2017