Abstract
Obesity arises from the interplay between genetic predisposition, metabolic signaling, and neural circuits that regulate feeding and energy expenditure. Large-scale association studies repeatedly implicate regulators of Ras/Rap GTPase signaling in adiposity and metabolic risk, but the mechanisms linking these intracellular switch modules to neural control of energy balance remain unclear. We used a translational approach centered on Drosophila RasGAP1, the closest ortholog of mammalian RASA2/3. Pan-neuronal RasGAP1 knockdown was assessed for effects on locomotor behavior, feeding interactions, systemic metabolic markers, expression of the leptin analog unpaired 1 (upd1), and protein-interaction networks. We then extended these findings to humans using protein-network and phenome-wide association analyses focused on RASA2/3-related pathways. Pan-neuronal RasGAP1 knockdown shifted behavior toward an obesity-like phenotype, combining reduced locomotor output with increased feeding interactions. This was accompanied by elevated lipid storage, increased circulating sugars, and reduced expression of upd1. Protein-interactome mapping positioned RasGAP1 within a connected signaling neighborhood linking Ras signaling with cytokine pathways relevant to feeding control. In humans, protein-network and phenome-wide association analyses converged on a KRAS-centered pathway in which RASA2/3, KRAS, and LEP were consistently associated with fat mass, BMI, and lipid dysregulation. These findings support RasGAP1/RASA2/3 as a candidate conserved neuro-metabolic regulator. More broadly, they provide hypothesis-generating evidence that RasGAP dysfunction may bias neural and metabolic control systems toward adiposity-linked phenotypes.
