Papel de la enterocina FGF15/19 en la plasticidad adiposa y cardíaca

Abstract

[spa] El objetivo de la presente tesis se basa en establecer, mediante el uso de modelos experimentales animales y celulares, cuál es el papel de la enterocina FGF15/19: a) en la adiposidad y plasticidad de los tejidos adiposos en respuesta al estímulo termogénico, y b) en la plasticidad cardiaca frente a estímulos fisiológicos y patológicos.

[eng] FGF19 in humans (ortholog of FGF15 in mice) is a fibroblast growth factor (FGF) with endocrine effects. It is an enterokine secreted by the ileum after food intake in response to bile acids. The main target of FGF15/19 is the liver, where it regulates the synthesis of bile acids and their release (negative feed-back). However, FGF15/19 may also have hormone-like functions in other tissues and in the whole-body homeostasis, such as the improvement of insulin sensitivity or lowering the body weight. In this thesis we explored the role of FGF15/19 in favoring the thermogenic capacity of brown adipose tissue (non-shivering thermogenesis) and white adipose tissue (browning) in response to environmental stimuli. Fgf15-null mice showed impaired browning when exposed to cold. Moreover, the overexpression of FGF15 and FGF19 in wild-type mice increased the expression of thermogenic genes in white adipose tissue. Our results suggest that the role of FGF15/19 in browning is likely to be due to indirect effects mediated either by the central nervous system or by intermediate batokines, such as CXCL14. On the other hand, we described that human patients with cardiac pathologies show lowered levels of FGF19 in plasma. Fgf15-null mice fed a high fat diet showed reduced heart weight and reduced area of their cardiomyocytes compared to wild-type mice. Fgf15-null mice had smaller hearts in physiological and pathological conditions eliciting cardiac hypertrophy Fgf15-null mice also had impaired development of fibrosis and altered gene expression in relation to the use of glucose or fatty acids as substrates in cardiac hypertrophy. We conclude that FGF15/19 is able to affect the functionality of cardiomyocyte and is necessary to an appropriate cardiac plasticity and correct cardiac adaptation to physiopathological events. FGF15/19 may be considered as a potential therapeutic agent in relation to adipose tissue and cardiac dysfunction. Further studies must be taken to further explore the mechanisms, either direct and/or indirect, by which FGF15/19 targets organs such as adipose tissues and heart.