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Decoding mitochondrial nutrient-sensing programs in POMC neurons as key determinants of metabolic health

Periodic Reporting for period 2 - MITOSENSING (Decoding mitochondrial nutrient-sensing programs in POMC neurons as key determinants of metabolic health)

Reporting period: 2018-10-01 to 2020-03-31

Obesity has reached epidemic dimensions worldwide causing major human and economic repercussions. However, and despite the magnitude of this health problem, non-invasive treatments are scarce and insufficient in terms of efficacy. This is the consequence of our limited understanding of the molecular mechanisms underlying energy balance control.

Nutrient-sensing by hypothalamic neurons is a crucial process to monitor the metabolic status of the organism and to coordinate adaptive responses to maintain energy homeostasis. Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus are prototypical cellular sensors and key regulators of appetite, energy expenditure and metabolism. The hypothesis of MITOSENSING is that alterations in specific mitochondrial nutrient-sensing programs in POMC neurons cause energy balance defects that underlie the development of obesity and associated metabolic disorders such as type-2 diabetes (T2D).

The objectives are: 1) to identify transcriptionally-modulated mitochondrial nutrient-sensing programs in POMC neurons; 2) to investigate whether disruption of specific nutrient-sensing programs in POMC neurons cause metabolic disorders; 3) to investigate whether the development of lifestyle-associated metabolic disorders are caused by defective mitochondrial nutrient-sensing programs in POMC neurons.
So far, we have established the transcriptional patters induced by glucose, Leucine and oleic acid in POMC neurons and selected potential candidates for further studies. We have also investigated the role of a crucial proteins implicated in diverse mitochondrial functions in the aforementioned population of neurons upon energy balance and system metabolism control. Furthermore, our research has also identified alterations in distinct transcriptional signatures of POMC neurons, in neonatal and perinatal developmental stages, associated with maternal obesogenic conditions.
MITOSENSING will represent a big step forward into the understanding of neuron type-specific nutrient-sensing programs in the context of obesity and metabolic alterations. The identification of such networks will open new and unexpected lines of investigation with potential therapeutical implications for obesity and T2D.
POMC neurons (green) in the arcuate nucleus of the hypothalamus