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Final Report Summary - TOR AND NEUROGENESIS (The role of the mtor signaling pathway in neurogenesis and its implications for the regulation of energy balance)

Obesity is a major health problem in developed countries and a growing one in the developing world. Obesity-related diseases account for up to 8 % of health costs in Europe. The causes of this alarming 'epidemic' include genetic, socioeconomic and environmental factors. However, despite the human and economic costs of this disease, efficient anti-obesity treatments are currently lacking.

One of the avenues that is believed could lead to gain significant insights into the causes and potential treatments of obesity, is the unravelling of the biological mechanisms regulating energy balance. The brain is critical for the coordination of complex metabolic processes across various tissues that ensure the right nutrients to get to the tissues at the time they need them. To assure adequate levels of energy to properly perform physiological functions, the central nervous system (CNS) must have evolved specific ways to monitor metabolic activity in the organism through a variety of sensory inputs.

In fact, growing evidence suggests that signals informing about the status of currently available fuels (derived from recently ingested food, such as glucose and fatty acids) and stored fuels (derived from the adipose mass, such as the hormone leptin) converge on brain structures, mostly within the hypothalamus, and act on the same neuronal targets modulating intracellular metabolic pathways. Intracellular fuel-sensing mechanisms, which are used by cells to sense ATP levels and to modulate cellular functions, have been recently found to have a role in the hypothalamic regulation of energy balance. The latest fuel-sensing mechanism to be implicated in such function is the mammalian target of Rapamycin (mTOR) signalling cascade. Indeed, this pathway works in the hypothalamus as an intracellular integrator of hormone and nutrient signals controlling energy balance (Cota D et al., Science, 2006; 312: 927-30). However, the downstream molecular mechanisms that are engaged by the mTOR pathway for the hypothalamic control of food intake and body weight are currently unknown.

The ciliary neurotrophic factor (CNTF) is a cytokine whose administration within the brain 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 on energy balance likely resides in the newly described ability of CNTF to induce neurogenesis within the adult murine hypothalamus (Kokoeva M et al., Science, 2005; 310:679-83).

Taking this evidence into account, the major objective of the current project has been to determine whether the hypothalamic mTOR signalling pathway mediates CNTF effects on energy balance and adult neurogenesis.

Since the start of the project, we have demonstrated that the acute central administration of CNTF is able to increase the activity of the mTOR signalling pathway within the rodent hypothalamus (Cota D et al. J Neurosci, 2008; 28: 7202-8). Moreover, mice with defective mTOR signalling are resistant to the acute, appetite-suppressant action of CNTF (Cota D et al. J Neurosci, 2008; 28: 7202-8). Using diet-induced obese animal models, studies are currently determining the type of hypothalamic cells in which the mTOR signalling is activated during and after CNTF treatment, as well as whether mTOR signalling is required for the long term actions of CNTF on energy balance.