NUTRIent Partitioning in Astrocyte and the regulation of energy HOmeoStasis – NUTRIPATHOS

Obesity and correlated diseases such as hypertension, dyslipidemia, coronary diseases and diabetes mellitus have more than doubled since 1980 and are now clearly identified as a worldwide pandemic in both developing and developed countries. Whereas some genetic loci were clearly identified and extensively studied as monogenic causes for obesity, it is widely accepted that the metabolic syndrome is in essence a multifactorial disease that encloses a complex network of molecular, cellular and physiologic alterations. Energy homeostasis results from the exquisite balance between energy expenditure and nutrient intake. To accomplish this, nervous inputs and circulating factors are integrated by discrete neural circuits in the brain, which in turn provide an adaptive behavioral, neuroendocrine and metabolic response. The hypothalamus in the brain contains a dedicated neurocircuit that directly regulates feeding and metabolism. The activity of hypothalamic neurons is tightly dependent on adequate delivery of energy substrates by a specific subset of glial cells: the astrocytes. Astrocytes are abundant in the brain, yet at times, they have only recently emerged as a prominent regulator of brain synaptic plasticity. Astrocytes acutely regulate oxygen and nutrient supply to neurons, neurotransmitter availability and synaptic function. Hypothalamic astrocytes express most receptors for energy-related signals (e.g., leptin, insulin) and are directly affected by nutrient overload and obesity. Despite these observations it has not yet been explored whether hypothalamic astrocytes play an active role in the central regulation of energy balance under both, physiologic and pathophysiologic condition. The consortium assembled here has gathered strong evidence that astrocytes are able to respond to energy-related signals and play a fundamental role in energy homeostasis.
The consortium will take advantage of cutting edge genetic tools developed and mastered by Partner 2 allowing to selectively monitor and modulate astrocyte activity either in vitro or in vivo. These tools will be combined with astrocyte-specific high-throughput analysis methods developed by Partner 3 to identify and knock-down astrocyte-specific targets. The consequences on metabolic efficiency, insulin sensitivity and glucose metabolism will be specifically explored by Partner 1.

The overachieving goals of this proposal lie in 2 main aims:
AIM 1-Defining the specific molecular and functional signature of hypothalamic astrocytes during high fat feeding/obesity
AIM 2-Leverage astrocyte-targeted approaches to harness obesity-associated disorders.
The expected outcome of the International Collaborative Research Program is
1-A better understanding on the cellular and molecular mechanism underpinning the regulation of hypothalamic astrocyte function and
2- A significant breakthrough in anti-obesity, anti-diabetes therapy.