NPF-Driven Gart Expression Fuels Gut Absorption and Modulates Feeding via a Negative Feedback Loop

Energy homeostasis requires precise coordination between brain-derived appetitive signals and peripheral nutrient-handling mechanisms. Although Neuropeptide F (NPF) and its mammalian homolog NPY are well-established central stimulators of feeding, whether and how they regulate nutrient assimilation in the gut remains unknown. Here, using Drosophila, we identify a previously unrecognized transcriptional circuit between NPF and the purine synthesis enzyme GART trifunctional enzyme (Gart) that governs feeding by controlling gut absorptive efficiency. We show that NPF signaling acts via its receptor NPFR to positively regulate Gart expression specifically within the intestine. Conversely, Gart activity exerts negative feedback on NPF expression, forming a reciprocal regulatory loop. Functionally, gut-specific, but not glial or fat body-specific, Gart is necessary and sufficient for promoting food absorption and consumption. Genetic epistasis experiments demonstrate that Gart acts downstream of NPF to execute its function. Strikingly, peripheral NPF from the fat body and gut, rather than brain-derived NPF, serves as the primary systemic signal driving this loop. Our findings reveal a gut-centered homeostatic module where NPF activates Gart to boost nutrient absorption, while the resultant feeding activity in turn curbs the signal, ensuring calibrated energy intake. This work redefines a canonical neuropeptide’s role from a pure behavioral driver to a key regulator of peripheral metabolic efficiency, and establishes a novel framework for understanding gut–brain communication in energy balance.