Abstract: TH-OR058
Linking Energy and Mineral Metabolism: Leptin Inhibits the Calcium-Sensing Receptor to Stimulate Parathyroid Hormone Release
Session Information
- New Developments in Bones, Stones, and Mineral Metabolism
November 06, 2025 | Location: Room 370A, Convention Center
Abstract Time: 05:00 PM - 05:10 PM
Category: Bone and Mineral Metabolism
- 501 Bone and Mineral Metabolism: Basic
Authors
- Hassan, Alia, Hadassah Hebrew University Department of Nephrology, Jerusalem, Israel
- Levin, Rachel, Hadassah Hebrew University Department of Nephrology, Jerusalem, Israel
- Melloul, Danielle, Hadassah Hebrew University medical Center, Endocrinology, Jerusalem, Israel
- Naveh-Many, Tally, Hadassah Hebrew University Department of Nephrology, Jerusalem, Israel
Background
Leptin and parathyroid hormone (PTH) are key regulators of energy and mineral homeostasis. Leptin, predominately produced by adipose tissue, controls appetite and energy expenditure via its receptors in the central nervous system. PTH maintains calcium and phosphate balance through actions on bone and kidney. Parathyroid gland function is tightly controlled by the calcium-sensing receptor (CaSR). Dysregulated leptin signaling, common in obesity and hyperleptinemia, has been linked to abnormal PTH levels, but the mechanisms remain unclear. Here, we show that leptin directly increases PTH secretion by attenuating CaSR signaling in the parathyroid.
Methods
Leptin receptor-deficient (db/db) and control mice were analyzed for serum PTH and calcium levels. Parathyroid glands were examined by IF staining. To assess direct leptin effects, we isolated and cultured parathyroid glands from tdTomato-expressing mice that allow fluorescent identification and excision of the parathyroid glands. Glands were treated with recombinant leptin (1 µg/ml) and/or the Calcimimetic R568 (1 µM). and PTH secreted to the growth medium measured. mRNA levels were determined by qRT-PCR.
Results
db/db mice exhibited reduced serum PTH levels at both 4 and 7 months of age compared to controls. IF staining revealed decreased PTH protein content in the parathyroid glands of db/db mice, despite unchanged PTH mRNA levels. This dissociation suggests that leptin signaling deficiency suppresses PTH synthesis, stability, and/or secretion through post-transcriptional mechanisms. Ex vivo, in cultured parathyroid glands, leptin increased PTH secretion while downregulating CaSR and c-fos gene expression. Co-treatment with the calcimimetic R568 blunted the leptin-induced rise in PTH secretion, indicating that leptin's stimulatory effect is mediated, at least in part, by inhibition of CaSR activity.
Conclusion
These findings identify leptin as a direct modulator of PTH secretion, acting through inhibition of CaSR signaling. By suppressing CaSR activity, leptin may serve as a physiological regulator, counterbalancing CasR-mediated suppression of PTH and preventing excessive inhibition of PTH release by the CaSR. These findings offer mechanistic insight into leptin’s role in disorders such as obesity and hyperleptinemia associated with PTH dysregulation.