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Daniela Cota "Role of hypothalamic mTOR signaling in energy balance regulation"

Abstract :

Obesity and its consequences, such as type-2 diabetes, cardiovascular diseases and cancer, represent serious health threats.
Recent published reports even project a decline in life expectancy due to the rapidly increasing prevalence of obesity. The World Health Organization has concluded that the fundamental causes of this epidemic are sedentary lifestyles, consumption of high-fat, energy-dense diets, and increased urbanization. Therefore, in search for potential pharmaceutical targets to treat obesity, the molecular mechanisms underlying the coordinated regulation of energy and glucose homeostasis have attracted significant attention over the past few years.
The circuitry that matches caloric intake to caloric expenditure is extremely accurate. Indeed, to achieve such accuracy, the control system over caloric homeostasis integrates signals from both stored fuels (the amount of fat in the white adipose tissue) and currently available fuels (the nutrients provided by the meal). An emerging notion is that specific neuronal populations, particularly in the hypothalamus, integrate fuel availability signals with signals mediated by hormones such as leptin.
Recently, we demonstrated that the atypical serine/threonine kinase mTOR (mammalian target of rapamycin), which integrates nutrient signals with hormonal signals to control growth and development in peripheral cells, has a role as an energy sensor in the hypothalamic pathways controlling food intake (Cota D. et al., Science, 2006). mTOR signaling is regulated by nutritional status in specific areas of the hypothalamus and co-localizes with both orexigenic (AgRP/NPY) and anorexigenic neuropeptides (POMC/CART) in the arcuate nucleus. Moreover, the central anorectic action of leptin itself depends on activation of the mTOR pathway. Interestingly, central administration of certain types of amino acids, and especially leucine, induces a reduction in food intake that is accompanied by increased hypothalamic mTOR signaling. These recent findings highlight an important role for cellular mechanisms processing energy/nutrient availability in the overall regulation of energy balance. Moreover, these data emphasize the importance of understanding the relation between metabolic substrates (including amino acids) and hormonal signaling pathways in diseases such as obesity and diabetes.

Selected publications

Hypothalamic mTOR Signaling
Regulates Food Intake
Daniela Cota,1 Karine Proulx,1 Kathi A. Blake Smith,1 Sara C. Kozma,2 George Thomas,2
Stephen C. Woods,1 Randy J. Seeley1*
Cota D, Proulx K, Blake smith KA, Kozma SC, Thomas G, Woods SC & Seeley RJ. Hypothalamic mTOR signaling regulates food intake. Science, 2006; 312, 927-30
Cota D, Barrera JG & Seeley RJ. Leptin in energy balance and reward: two faces of the same coin? Neuron, 2006 (in press)

Giovanni Marsicano