ORF50-03 - A BRINP3-Derived Peptide Drives Non-Aversive Appetite Suppression via PVH Circuits

Complex organisms have evolved redundant regulatory systems for critical processes such as energy homeostasis, suggesting that many additional peptide regulators may exist but remain undiscovered. Proprotein convertase (PCSK) enzymes are responsible for processing prohormones into bioactive peptide hormones. Using a peptide prediction algorithm that maps PCSK cleavage sites, we identified a 26-amino acid secreted anorexigenic peptide derived from the human weight-associated gene BRINP3 (bone morphogenetic protein/retinoic acid inducible neural specific 3), named BRP3 (BRINP Related Peptide gene 3). We screened all peptides under 50 amino acids from this precursor and identified a strong anorexigenic peptide. BRINP3 is predominantly expressed in the Paraventricular Nucleus of the Hypothalamus (PVH) of the brain, as well as in the intestinal neurons, and its peptide BRP3 circulates endogenously in humans and mice. Pharmacological administration of BRP3 into mice induces a rapid, dose-dependent suppression of food intake, accompanied by delayed gastric emptying. Chronic administration of BRP3 leads to a lowering of food intake and weight loss in both diet-induced obese and leptin-deficient mice. Furthermore, the weight-reducing effects of BRP3 are additive with glucagon-like peptide-1 receptor agonists. Intracerebroventricular delivery of BRP3 is sufficient to suppress food intake, but does not impact the gastric emptying, suggesting that the anorexigenic effect is centrally mediated and the gastric emptying occurs peripherally. BRP3 does not reduce locomotion, energy expenditure, or conditioned taste preference, and reduces water intake far less than semaglutide. Whole-brain mapping shows neuronal activation in the paraventricular nucleus of the hypothalamus (PVH), posterior hypothalamus, and area postrema but not the nucleus of the solitary tract. BRP3 rapidly increases the firing rate of a subset of PVH neurons in hypothalamic brain slices, suggesting that the effect is PVH-intrinsic. FosTRAP-guided chemogenetic inhibition confirms that BRP3 acts via defined hypothalamic circuits, as inhibition of hypothalamic neurons blunts the appetite-suppressing effect of BRP3. Together, these findings establish BRP3 as a novel peptide that engages discrete brain networks to suppress appetite without aversive responses.