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

Información del proyecto

MITOSENSING

Identificador del acuerdo de subvención: 725004

DOI

10.3030/725004

Proyecto cerrado

Fecha de la firma de la CE 22 Febrero 2017

Fecha de inicio 1 Abril 2017

Fecha de finalización 30 Septiembre 2022

Financiado con arreglo a

• EXCELLENT SCIENCE - European Research Council (ERC)

Coste total

€ 1 999 573,00

Aportación de la UE

€ 1 999 573,00

Coordinado por

FUNDACIO DE RECERCA CLINIC BARCELONA-INSTITUT D INVESTIGACIONS BIOMEDIQUES AUGUST PI I SUNYER
Spain

Periodic Reporting for period 4 - MITOSENSING (Decoding mitochondrial nutrient-sensing programs in POMC neurons as key determinants of metabolic health)

Período documentado: 2021-10-01 hasta 2022-09-30

Resumen del contexto y de los objetivos generales del proyecto

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.

Collectively, the results derived from this action evidenced that mitochondria in POMC neurons act as key signaling platforms integrating appetite, the metabolic function of peripheral tissues and cognitive performance.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

We have established the transcriptional signatures induced by glucose, Leucine and oleic acid in POMC neurons. We have also investigated the role of diverse mitochondrial functions in POMC neurons upon metabolic health. Our studies have revealed novel and unsuspected facets at the interface of appetite, peripheral metabolism control and cognitive performance. 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. In conclusion, this action has provided novel insights on the role of mitochondria in POMC neurons in the context of highly prevalent metabolic conditions such as obesity and type-2 diabetes.

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

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