TOR AND NEUROGENESIS · THE ROLE OF THE MTOR SIGNALING PATHWAY IN NEUROGENESIS AND ITS IMPLICATIONS FOR THE REGULATION OF ENERGY BALANCE

The major interest of my research activity is to understand the pathophysiological mechanisms leading to the development of obesity, particularly focusing on the role of the central nervous system (CNS) in this context. The CNS is the critical organ for the coordination of intracellular metabolic processes that are essential to guarantee energy homeostasis at the organism level. Thus, centering my studies on the atypical kinase mammalian Target Of Rapamycin (mTOR), I recently demonstrated that this evolutionarily conserved fuel sensing pathway integrates sensory inputs from nutrients and hormones within the hypothalamus, in order to modulate food intake and body weight. The ciliary neurotrophic factor (CNTF) is a cytokine whose central administration reduces body weight even in leptin-resistant states, including diet-induced obesity, and causes a weight loss that is maintained after therapy discontinuation. The explanation for this long-term effect of CNTF on energy balance likely resides in its newly described ability to induce neurogenesis within the adult murine hypothalamus. Cellular development and differentiation are tightly coordinated with nutritional status; and induction of mitogenic signaling and neuronal differentiation is known to involve modulation of the mTOR signaling. Thus, I propose that the CNTF effects on neurogenesis and energy balance require the activation of the hypothalamic mTOR signaling pathway. To investigate this hypothesis, I will use a multidisciplinary approach, including the use of genetically modified mice, specific behavioral paradigms and molecular strategies. These studies will clarify the role of cellular fuel sensing mechanisms in the regulation of energy balance and possibly highlight the function of processes, such as neurogenesis and neuronal differentiation, which might be important for the appropriate regulation of energy balance within the hypothalamus and that might require a functional mTOR signaling cascade.