Nutrient-sensing by POMC neurons is a critical process to monitor the metabolic status of the organism and to coordinate adaptive neuroendocrine, behavioural and metabolic effectors of energy balance. Mitochondria, as central commanders of cellular energy production and primary sources of bioenergetic signals, are logical candidates to play a key role in metabolic control. However, a comprehensive understanding of the mitochondria as nutrient-sensors and modulators of systemic energy homeostasis is lacking. MITOSENSING hypothesizes that dedicated mitochondrial networks in POMC neurons are able to sense, integrate and respond to alterations in the nutritional milieu and engage physiological actions to maintain energy balance. Thus, defects in these mitochondrial nutrient-sensing programs in this subset of neurons underlie the development of metabolic conditions such as obesity and type-2 diabetes (T2D). To test it, we will pursue three aims: 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. By providing neuron-specific, integrative, functional and mechanistic in vivo strategies, MITOSENSING will represent a major step forward into the understanding of mitochondria as a nutrient-sensing entity, the gene programs involved and their physiological regulatory functions in the context of energy balance control. Adequate coordination of neuronal nutrient-sensing with energy balance control is critical to sustain life, and thus understanding the molecular mechanisms governing these physiological programs will have an enormous scientific impact and also potential therapeutical implications for obesity and T2D.

Despite titanic social and scientific efforts, rates of obesity continue to increase in Europe. Unfortunately, safe and effective treatments are currently unavailable. Obesity is a multifactorial disease that is largely the consequence of enigmatic and complex genetic-environmental interactions. Evidence suggests that the prevalent western-diet triggers epigenetic changes that contribute to the current obesity epidemics. Hypothalamic proopiomelanocortin (POMC)-expressing neurons are crucial elements of energy balance, and its dysfunction cause severe obesity in experimental models and humans. Our hypothesis is that over nutrition causes epigenetic changes in POMC neurons that in turn lead to dysregulated energy homeostasis and obesity. The objective of this proposal is to establish for the first time a genome-wide epigenetic map of POMC neurons in the context of over nutrition during adulthood and fetal programming. To pursue this aim we will use an innovative cell-specific in vivo strategy to tag and reliably isolate POMC neurons, followed by next generation sequencing to evaluate chromatin accessibility and histone marks distribution across the genome. As a result, we will provide a novel framework for understanding the underlying epigenetic signatures related with obesity development and susceptibility. Hence, this project is in line with the Horizon 2020 Framework for improving our knowledge of the causes underlying a disease. Furthermore, the outcomes of this project may have potential therapeutic implications for the treatment of obesity since most epigenetic marks are reversible and therefore potentially targetable. The multidisciplinary nature of the project is strong, involving a combination of genetic engineering techniques, molecular biology and bioinformatics. This proposal includes the transfer of knowledge to the host institution and the training of the candidate in new techniques and transferable skills.