Los dos proyectos científicos que ofrecemos este año son:
Stress in the brain, metabolic effects: Obesity has become a new pandemic. It is known that obesity induces molecular changes in the brain that are fundamental for the development of diseases and for maintaining excess energy intake. However, little is known about how these changes appear and the molecular mechanisms that mediate them. We will study how modulating stress in the central nervous system induced by high fat diet affects the development of cardiometabolic diseases. For this purpose, genetically modified animals will be used and whole organism metabolism will be evaluated, and how the signalling of this stress in the brain affects the response of distant organs through inter-tissue communication.
Role of adipose tissue controling whole body homeostasis: Cardiometabolic diseases (CMDs)—e.g., diabetes, steatohepatitis, and cardiomyopathy— are the leading cause of death worldwide. Adipose tissue (AT) heterogeneity and dysfunction might be involved in the CMD pathogenesis. We have recently demonstrated that i) AT regulates whole-body metabolism independently of obesity and predisposes to hepatic cancer in mice and humans; and ii) molecules secreted by AT trigger liver steatosis and insulin resistance. Our studies suggest that dysfunctional AT communicates with other organs and induces pathogenic adaptive responses through evolutionarily conserved mechanisms (rodent to humans). Our preliminary results show that AT dysfunction caused by mitochondrial alteration induces cardiomyopathy in lean mice, reinforcing that AT has a central role in controlling heart functionality.
Obesity, which has long since reached epidemic proportions worldwide, is associated with long-term stress to a variety of organs and results in diseases including type 2 diabetes. In the brain, overnutrition induces hypothalamic stress associated with the activation of several signalling pathways, together with central insulin and leptin resistance. This central action of nutrient overload appears very rapidly, suggesting that nutrition-induced hypothalamic stress is a major upstream initiator of obesity and associated diseases. The cellular response to nutrient overload includes the activation of the stress-activated c-Jun N-terminal kinases (JNKs) JNK1, JNK2 and JNK3, which are widely expressed in the brain.
Here, we review recent findings on the regulation and effects of these kinases, with particular focus on the hypothalamus, a key brain region in the control of energy and glucose homeostasis. JNK1 blocks the hypothalamic–pituitary–thyroid axis, reducing energy expenditure and promoting obesity. Recently, opposing roles have been identified for JNK1 and JNK3 in hypothalamic agouti gene-related protein (AgRP) neurons: while JNK1 activation in AgRP neurons induces feeding and weight gain and impairs insulin and leptin signalling, JNK3 (also known as MAPK10) deletion in the same neuronal population produces very similar effects. The opposing roles of these kinases, and the unknown role of hypothalamic JNK2, reflect the complexity of JNK biology.
Future studies should address the specific function of each kinase, not only in different neuronal subsets, but also in non-neuronal cells in the central nervous system. Decoding the puzzle of brain stress kinases will help to define the central stimuli and mechanisms implicated in the control of energy balance.