Sex differences in calcitonin receptor (CalcR) neurons of the ventral premammillary nucleus (PMv): potential role in neuroendocrine regulation

In addition to the well-known role of calcitonin in reducing serum calcium, there are reports of its effects on metabolism. Subpopulations of leptin receptor (LepRb) neurons, essential in controlling food intake and body weight, coexpress CalcR in some regions of the brain. The ablation of Calcr in LepRb neurons in arcuate nucleus of the hypothalamus leads to hyperphagic obesity. CalcR is also expressed in the PMv, a hypothalamic nucleus with dense LepRb expression. We investigated expression of CalcR and its relationship with LepRb in the PMv of prepubertal and adult male and female mice. Using RNAscope assay, we found a higher number of Calcr expressing cells in females compared to males, before puberty. The expression intensity, evaluated by in situ hybridization, did not differ between sexes. However, in adulthood, the number of cells expressing Calcr was similar between sexes, while the intensity of expression was higher in males. Using CalcR-Cre reporter mice, we found that a subpopulation of the PMv CalcR neurons responded to acute leptin treatment by phosphorylation of the intracellular marker signal transducer and activator of transcription 3 (pSTAT3) in all groups. RNAscope assay also confirmed the coexpression of Calcr and Lepr in male and female mice with the same percentage in puberty and adulthood. Using Cre-inducible AAV as molecular tracer, we assessed the downstream targets of the PMv CalcR neurons. A very dense projection to the ventromedial nucleus of the hypothalamus was observed. We also identified projections to the bed nucleus of the stria terminalis and medial preoptic area. Our results demonstrate that a subpopulation of the PMv LepRb neurons coexpressing CalcR show sex differences in CalcR mRNA expression and project to areas relevant for neuroendocrine and behavioral regulation. Ongoing studies aim at defining the PMv CalcR neuronal circuitry and associated metabolic and/or reproductive responses in a sex-specific manner. This work has been supported by a NIH funding R01HD106962. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.