TOR AND NEUROGENESIS

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

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 Obiettivo del progetto (Objective)

'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.'

Introduzione (Teaser)

Obesity is a major health problem with severe human and economic implications. One promising research avenue is to unravel the biochemistry of how the body balances its energy requirements.

Descrizione progetto (Article)

A staggering 8;% of health costs in Europe are due to obesity-related diseases; genetic, socioeconomic and environmental factors can contribute to an individual being overweight or underweight. The EU-funded TOR and neurogenesis project has just finished investigations into the influence of the central nervous system (CNS) on weight gain.

As the control centre for energy balance throughout the body, the brain must be able to pick up signals from the CNS through a variety of sensory inputs. Information on the balance between energy from stores such as fat cells compared with that on tap from food just eaten reaches the hypothalamus. Signals from this area of the brain regulate body weight and food intake.

Sensor mechanisms that gauge levels of adenosine triphosphate (ATP), the cell's molecular energy store also signal to the hypothalamus. A fuel-sensing mechanism, the mammalian target of rapamycin (mTOR) signalling cascade, is implicated in integrating the information about the hormones leptin and insulin involved in energy balance and nutrient signals.

The project team hypothesised that a cell signalling protein ciliary neurotrophic factor (CNTF) may be involved in hypothalamic control. This small molecule, a so-called cytokine, can reduce weight even during diet-induced obesity. Interestingly, weight loss continues even after the therapy has been discontinued due to this appetite controller.

The TOR and neurogenesis researchers have found that more CNTF means greater activity for mTOR in the rat hypothalamus. Furthermore, mice with defective mTOR signalling do not respond to CNTF. Future research will focus on what types of cells are activated in the hypothalamus during CNTF therapy and whether mTOR signalling is needed for long-term action of CNTF.

The project's research has far-reaching significance as there is a distinct lack of efficient anti-obesity treatments. Targeting the biochemical nuts and bolts of appetite control and energy balance promises to deliver pharmaceutical answers to obesity.