Unmasking Mechanisms of Neuroendocrine Fate Reprogramming in Response to Maternal Obesity – NeuroEndoFate

Maternal obesity has become a major public health concern. Children born to obese mothers are at increased risk of developing obesity, diabetes, cognitive impairment and reproductive problems. Neurodevelopmental defects in one brain region, the hypothalamus, contribute to the maternal transmission of metabolic and reproductive disorders. However, the hypothalamus contains a remarkable heterogeneity of neurons and there is a notable gap in our understanding of the cell-specific biological mechanisms underlying altered neurodevelopment following maternal metabolic cues. Based on published and preliminary data, we hypothesise that maternal obesity alters the cell fate specification of key hypothalamic neuroendocrine neurons in the offspring through changes in the transcription factor T-box 3 (Tbx3). This mechanism influences whole-body neuroendocrine adaptations and the development of obesity and fertility disorders throughout the lifespan. The NeuroFateMetab project will address this central hypothesis using an integrated, state-of-the-art, multidisciplinary approach. Using mouse models of maternal obesity and neuronal fate mapping, we will uncover neurodevelopmental responses in hypothalamic neurons at the single cell level in response to changes in the maternal metabolic milieu and Tbx3 ablation. We will also investigate the role of hypothalamic Tbx3 in mediating the maternal transmission of obesity and reproductive dysfunction to offspring and its relevance to the human context. Our project will provide an innovative framework for elucidating the cell-intrinsic mechanisms that control hypothalamic development in response to changes in the maternal metabolic and and hormonal uterine environment, which may greatly improve our understanding of the origins and treatment of metabolic disorders and beyond.