Dimorfismo sexual en la función y biogénesis mitocondriales en el tejido adiposo blanco de rata. Respuesta a una dieta hiperlipídica

Abstract

[spa] Los resultados obtenidos demuestran que la función y la biogénesis mitocondriales del tejido adiposo blanco dependen del sexo, del depósito y de la dieta ingerida, y que el dimorfismo sexual se manifiesta ya a edades tempranas. Las hormonas ováricas serían responsables, en parte, de este dimorfismo sexual, especialmente en el depósito gonadal, lo que vincula, por tanto, a los estrógenos, al mayor grado de diferenciación mitocondrial y a la expresión de adiponectina. La dieta hiperlipídica atenúa el dimorfismo sexual observado en los animales controles a nivel de la función y la biogénesis mitocondriales y desvincula la relación existente entre la función mitocondrial y la síntesis de adiponectina. Además, induce un mayor incremento del peso corporal y de la adiposidad en las ratas hembra, lo que sugiere una mayor capacidad de expansión de su tejido adiposo. Esto les permite evitar la acumulación de grasa ectópica, manteniendo una mejor sensibilidad a la insulina al evitar los efectos de la lipotoxicidad

[eng] White adipose tissue (WAT) has been considered a simple fat storage depot for a long time, but nowadays it has become recognized as a major endocrine organ in the whole body. Its capacity to synthesize over 50 protein factors known as adipokines, which are able to regulate insulin sensitivity, the inflammatory response or the coagulation process, has led to reconsider its function. Firstly, the mitochondrion has become an important organelle in the adipocyte, playing a relevant role in adipogenesis and in the synthesis of some adipokines, such as adiponectin and, secondly, it is thought that WAT mitochondrial function may be involved in the development of insulin resistance. The main objective of this thesis was based on the study of the influence of sex on alterations in WAT mitochondrial function and biogenesis, both in the control situation and in response to a high-fat diet (HFD). Moreover, the aim was to go further into the relationship between mitochondrial function and obesity-associated insulin resistance development as well as to study the role of sex hormones in the differences found between sexes. The results show that mitochondrial function and biogenesis in WAT depend on the sex, the depot and the diet consumed, and that sexual dimorphism is already present at an early age. Female rats show that the retroperitoneal depot has a more abundant but less differentiated mitochondrial population than males, in contrast to what happens in the periovarian depot, which has more differentiated mitochondria than the epididymal one. Greater mitochondrial differentiation in the periovarian depot leads to the increased adiponectin expression in this depot and higher systemic HMW adiponectin levels (the more active form of this adipokine, with insulin-sensitizing effects) found in female rats. These characteristics lead to a better insulin sensitivity profile in this sex, both at a systemic and tissue level, as female rats show a more activated insulin signaling pathway than males. Ovarian hormones would be responsible, in part, for this sexual dimorphism, with the gonadal depot being more sensitive to estrogenic regulation, which links estrogens to greater mitochondrial differentiation and adiponectin expression. HFD diminishes the sexual dimorphism found in control animals at the level of mitochondrial function and biogenesis and dissociates the existing relationship between mitochondrial function and adiponectin synthesis. Moreover, HFD leads to a greater increase in body weight and adiposity in female rats compared to males, which suggests a higher WAT expandability capacity in this sex. This allows them to avoid ectopic fat accumulation, thus maintaining better insulin sensitivity as a result of avoiding the effects of lipotoxicity. Despite the fact that oxidative stress has been described as a factor underlying HFD-induced insulin resistance development, the results obtained after administration of the antioxidant SkQ suggest that mitochondrial oxidative stress would not be the main factor related to insulin resistance development either in WAT or in skeletal muscle.