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Examination of the Influence of Leptin and Acute Metabolic Challenge on RFRP-3 Neurons of Mice in Development and Adulthood

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The neuropeptide RFamide-related peptide-3 (RFRP-3; mammalian ortholog to gonadotropin-inhibiting hormone) can inhibit luteinizing hormone (LH) release and increases feeding, but the regulation and development of RFRP-3 neurons remains poorly characterized, especially in mice.

Methods and results

We first confirmed that peripheral injections of murine RFRP-3 peptide could markedly suppress LH secretion in adult mice, as in other species. Second, given RFRP-3's reported orexigenic properties, we performed double-label in situ hybridization for metabolic genes in Rfrp neurons of mice. While Rfrp neurons did not readily coexpress neuropeptide Y, thyrotropin-releasing hormone, or MC4R, a small subset of Rfrp neurons did express the leptin receptor in both sexes. Surprisingly, we identified no changes in Rfrp expression or neuronal activation in adult mice after acute fasting. However, we determined that Rfrp mRNA levels in the dorsal-medial nucleus were significantly reduced in adult obese (Ob) mice of both sexes. Given the lower Rfrp levels observed in adult Ob mice, we asked whether leptin might also regulate RFRP-3 neuron development. Rfrp gene expression changed markedly over juvenile development, correlating with the timing of the juvenile 'leptin surge' known to govern hypothalamic feeding circuit development. However, the dramatic developmental changes in juvenile Rfrp expression did not appear to be leptin driven, as the pattern and timing of Rfrp neuron development were unaltered in Ob juveniles.


Leptin status modulates RFRP-3 expression in adulthood, but is not required for normal development of the RFRP-3 system. Leptin's regulation of adult RFRP-3 neurons likely occurs primarily via indirect signaling, and may be secondary to obesity, as only a small subset of RFRP-3 neurons express the long form of the leptin receptor (LepRb).

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