Endocrine Abstracts

Obesity and its consequences, such as type-2 diabetes, cardiovascular disease and cancer, are serious health threats. However, despite what the obesity epidemic might suggest, the balance between caloric intake and expenditure is regulated with tremendous precision under most circumstances. Thus, a regulatory system exists, where deviations from the defended body adiposity level trigger signals that can be monitored by specific intracellular metabolic pathways. Such pathways are linked to adaptive responses in energy intake and oxidation, ensuring that body weight remains relatively stable over time. Growing evidence suggests that signals from both currently available fuels (i.e. recently ingested food) and stored fuels derived from the adipose mass converge on brain centers, mostly within the hypothalamus, and act on neuronal targets by modulating intracellular metabolic pathways. Cells use fuel sensing mechanisms to sense ATP levels and to modulate anabolic and catabolic processes. Intriguingly, ‘fuel sensors’ such as the enzymes AMP-activated protein kinase (AMPK) and target of rapamycin (TOR), have been recently implicated in the regulation of feeding behavior. In particular, our studies focusing on the TOR signaling cascade have demonstrated how such pathway has been co-opted by an important subset of hypothalamic neurons as one sensory input that might affect a variety of metabolic functions. As a consequence, the dysregulation of fuel sensing mechanisms within the hypothalamus may contribute to metabolic dysregulation underlying diseases, such as obesity and type 2 diabetes.