Resumen de Cpt1c in specific hypothalamic nuclei and its role in lipid sensing and metabolic adaptation
Obesity has become a pandemic disease in the last 40 years. The WHO estimates that the population with overweight has nearly tripled since 1975, and the tendency is still growing. These data have an impact on health and on country's healthcare costs. Obesity is a chronic disease of multifactorial origin that is associated to other pathophysiological conditions such as Type 2 Diabetes mellitus. Obesity appears due to an imbalance in the energy metabolism, which is primarily regulated by the hypothalamus, the central structure responsible for integrating signals from the periphery and orchestrating a homeostatic response. In the last years, research has been focused on the molecular mechanisms and the hypothalamic nuclei involved in the dysregulation of energy homeostasis of obesity in order to identify potential therapeutic targets.
This thesis studies the role of the protein carnitine palmitoyltransferase 1c (CPT1c), a neuronal energy sensor, in the regulation of energy homeostasis within the hypothalamus in response to different metabolic challenges. Recently, its expression in the ventromedial nucleus of the hypothalamus (VMH) has been found as necessary for the activation of thermogenesis in brown adipose tissue (BAT) in response to a high-fat diet. The most abundant neuronal population of the VMH nucleus are SF1 neurons. Thus, we have generated a new genetic mouse model deficient in CPT1c in these neurons (SF1-CPT1c-KO) to explore the specific function of the protein in these neurons. At the same time, we have studied the role of CPT1c in the central response to long-chain fatty acids (LCFAs). First, we defined the differential effects that saturated and unsaturated LCFAs have on food intake, body weight and brown adipose tissue thermogenesis, as well as the hypothalamic nuclei involved and the possible signalling pathways involved, in wild-type mice (WT). Then we evaluated the same effects on mice deficient for CPT1c (CPT1c-KO).
Results of this thesis showed, on the one hand, that CPT1c in the SF1 neurons is necessary for the metabolic adaptation, facilitating that the peripheral tissues use fat but not glucose as the energy substrate, during the first days of high-fat diet administration and under fasting or cold exposure situation. On the other hand, we have defined that centrally administered LCFAs differently activate satiety and BAT thermogenesis depending on the level of saturation. We have also identified that the hypothalamic nuclei arcuate, paraventricular and VMH are mediators of unsaturated LCFA signals and that LCFAs differently activate the AMPK-ACC axis and FAS expression depending on the level of saturation. Finally, we have described that CPT1c is involved in this axis.
Overall, our results confirm the important role of CPT1c under metabolic challenges and provide new knowledge of the central processes underlying obesity development.
