OBrAgeing · Studying the role of Tbx-3 expressing neurons during obesity and ageing

As global life expectancy rises, societies are concurrently facing a growing burden of obesity, a condition known to exacerbate the metabolic decline naturally associated with ageing. While ageing disrupts metabolic function across multiple organs, the role of specific brain neurons in this decline remains poorly defined, despite the brain's central role in coordinating whole-body energy homeostasis. The hypothalamus is a critical brain region for regulating systemic metabolism and is particularly vulnerable to age-related molecular and cellular alterations, notably within neurons expressing the transcription factor T-box 3 (Tbx3). Dr. Quarta’s research has identified Tbx3 as a critical determinant of neuronal identity through life, with its loss leading to metabolic dysfunction and obesity. Both ageing and chronic exposure to obesogenic diets diminish hypothalamic Tbx3 expression.Tbx3 also modulates cellular senescence, a key hallmark of neuronal ageing. Therefore, I hypothesize that obesogenic diets may accelerate hypothalamic neuronal ageing through Tbx3-dependent mechanisms, thereby contributing to systemic metabolic decline in ageing individuals. To test this, we will employ reporter mouse models to profile Tbx3-expressing hypothalamic neurons under ageing in both control and obesogenic diets at single cell resolution (single cell transcriptomics and electrophysiology assessments). We will examine how dietary and age-related cues modulate Tbx3 expression and induce molecular features of neuronal ageing. Finally, using in vivo viral-mediated gain- and loss-of-function approaches, we will assess whether modulating Tbx3 levels can restore neuronal integrity and systemic metabolic control in aged mice exposed to control or obesogenic diets. This project seeks to unravel the neurobiological underpinnings of neuronal and whole-body metabolic ageing in response to dietary cues, with potential implications for maintaining metabolic health across the lifespan.