{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe RFamide-related peptide system, exemplified by RFRP-3, plays a critical inhibitory role in the central regulation of reproduction. In mice, RFRP-3 directly targets both GnRH and kisspeptin neurons, with studies showing that RFRP-3 fibers closely appose approximately one‐quarter of GnRH cells and a smaller fraction of rostral periventricular kisspeptin neurons. These interactions occur predominantly via the receptor GPR147, as its expression is found in a subset of these neurons, while related receptors (e.g., GPR74) are absent. Additionally, the developmental expression of RFRP-3 shows distinct high and low expression subpopulations that are differentially regulated by sex steroids, underscoring its dynamic role in modulating the reproductive axis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nComplementary evidence demonstrates that the broader RFamide system involves multiple receptor subtypes with distinct distributions and functions. Quantitative autoradiography reveals species-specific patterns of neuropeptide FF receptor expression, with NPFF1 and NPFF2 subtypes contributing to functions such as thermoregulation and sensory modulation. Moreover, kisspeptin—traditionally known to signal via GPR54—has been shown to modulate neuronal activity in the arcuate nucleus through NPFF receptors, with pharmacological studies using agonists and antagonists (like RF9 and BIBP‐3226) confirming that RFamide peptides can exert both excitatory and inhibitory effects independent of canonical kisspeptin pathways."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to their central functions, RFamide-related peptides extend their regulatory influence to peripheral tissues that impact metabolic and reproductive homeostasis. RFRP-3 signaling via GPR147 has been implicated in enhancing pancreatic alpha cell survival under hyperglycemic and nutrient-deprived conditions, while in ovarian granulosa cells, it modulates steroidogenesis and can induce apoptosis—suggesting a role in follicle development. Furthermore, the deletion of its canonical receptor, NPFF1R, alters feedback responses to gonadal hormones and dampens the hypogonadotropic effects of metabolic stress, thereby linking the reproductive axis to energy balance. Although none of these abstracts explicitly mention SNORD115-12, the mechanistic insights provided by the RFRP-3 and RFamide receptor studies suggest that molecules within this regulatory network—including SNORD115-12, if functionally related—could contribute to the fine-tuning of neuroendocrine and metabolic processes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Matthew C Poling, Joshua Kim, Sangeeta Dhamija, et al. 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