Obesity and adipose tissue biology in fish. Influence of nitritional, genetic and environmental factors

[eng] Obesity is traditionally defined as a complex and chronic health condition characterized by an abnormal or excessive fat accumulation in the body that relies upon the homeostatic relationship between energy intake and expenditure. Although obesity per se might not be considered a health threat in fish as it is for humans, increased fat deposition is also shown to produce adverse metabolic effects in these species. Thus, importance of adipose tissue in health and disease in both, humans and fish, is beyond question. In this regard, it has been extensively demonstrated that its dysfunction can lead to several pathological situations. Perhaps because it is obvious that diet influences its condition, most work has concentrated on the nutritional regulation of adipose tissue. Nevertheless, it is becoming clear that this view might be an oversimplified approach, as more factors are regarded to play an important role. This is particularly evident in the case of obesity, considering that there is no one single cause that completely explains its prevalence. Indeed, even though the common prescription for weight loss is “Eat less, move more”, it has been widely proven that genetics and environment are potentially at least as important as nutrition in this. In this context, the overall purpose of the present thesis is to improve the knowledge on the metabolic role of adipose tissue and its implication in the regulation of lipid homeostasis in fish, specially focusing in adiposity dynamics and the influence of nutritional, genetic and environmental factors. First, in order to investigate the nutritional regulation of lipid metabolism and fat deposition, we have evaluated the anti-obesogenic properties of three antioxidants of plant origin and the effect of a dietary essential amino acid deficiency. Results showed that the natural antioxidants caffeic acid (CA) and hydroxytyrosol (HT) display in vivo and in vitro anti-obesogenic properties, decreasing whole-body adiposity and impairing adipogenesis through negative modulating PPARγ signaling pathway in zebrafish and rainbow trout models. I addition, we have also confirmed that early dietary methionine restriction increases the expression of lipogenic and cholesterol metabolism-related genes in rainbow trout fry. Then, to determine the genetic influence on lipid homeostasis we have examined the effects of nutritional programming and breeding selection. In this regard, we have demonstrated that parental methionine deficiency affects the expression of several key metabolic factors in the offspring, indicating that broodstock methionine supply has an impact on progeny performance, in agreement with previous information about methionine requirements in this species. Moreover, our results showed that rainbow trout selected for low (LL) or high (FL) muscle adiposity present genotype-specific regulatory mechanisms in muscle and adipose tissue at a transcriptional level concerning lipid metabolism, highlighting their specific strategies to cope with food deprivation. Finally, in order to better understand how adipocyte differentiation can be affected by external compounds, we have evaluated the obesogenic potential of two environmental pollutants (the trisubstituted organotins TBT and TPT) on adipocyte development and lipid homeostasis in primary culture rainbow trout preadipocytes. Our results showed that tributyltin (TBT) and triphenyltin (TPT) initiate adipogenic differentiation, inducing lipid accumulation and slightly modulating activation of PPARγ and C/EBPα expression; however, they do not induce complete adipocyte differentiation, since they impair normal adipocyte morphology and most probably functionality. Overall, the works presented provide an integrative view of obesity and adipose tissue biology with potential applications in both, aquaculture and biomedical research, by using zebrafish and rainbow trout models.[spa] Tal vez porque es obvio que la dieta influye en la prevalencia de la obesidad, la mayoría de los trabajos se han concentrado en la regulación nutricional del tejido adiposo en esta condición. Sin embargo, está claro que este punto de vista puede ser un enfoque simplificado, ya que se considera que más factores desempeñan un papel importante. En este contexto, el objetivo general de la presente tesis es mejorar los conocimientos sobre el papel metabólico del tejido adiposo y su implicación en la regulación de la homeostasis lipídica en peces, enfocándose especialmente en la movilización de lípidos y la influencia de factores nutricionales, genéticos y ambientales. En primer lugar, hemos demostrado que el ácido cafeico (CA) y el hidroxitirosol (HT) muestran propiedades anti-obesogénicas in vivo e in vitro, disminuyendo la adiposidad y afectando a la diferenciación de adipocitos a través de la modulación negativa de la ruta de señalización PPARγ en modelos de pez cebra y trucha arco iris. Además, también hemos confirmado que la restricción temprana de metionina en la dieta aumenta la expresión de los genes relacionados con el metabolismo lipogénico y del colesterol en alevines de trucha arco iris. Seguidamente, también hemos demostrado que la deficiencia de metionina en reproductores afecta la expresión de varios factores metabólicos clave en la descendencia, lo que indica que el suministro de metionina en los reproductores tiene un impacto en el rendimiento de la progenie. Además, nuestros resultados mostraron que la trucha arco iris seleccionada por una adiposidad muscular baja (LL) o alta (FL) presenta mecanismos reguladores específicos dependiendo del genotipo en el tejido muscular y adiposo a nivel del metabolismo lipídico, resaltando sus estrategias específicas para hacer frente a la privación de alimentos. Finalmente, nuestros resultados mostraron que el tributilestaño (TBT) y el trifenilestán (TPT) inician la diferenciación adipogénica, induciendo la acumulación de lípidos y una ligera modulación de la activación de la expresión de PPARγ y C/EBPα; sin embargo, no inducen una diferenciación completa de los adipocitos, ya que alteran su morfología normal y muy probablemente su funcionalidad