Leptin regulates parathyroid hormone secretion through <scp>CaSR</scp> ‐ <scp>ERK1</scp> /2 signaling

Leptin and parathyroid hormone (PTH) are key regulators of metabolic and mineral homeostasis. Leptin, primarily secreted by adipose tissue, controls appetite and energy expenditure through its receptors in the central nervous system, while PTH maintains serum calcium and phosphate balance and skeletal integrity by acting on kidneys and bone. The calcium sensing receptor (CaSR) plays a central role in parathyroid function and PTH secretion. While clinical and experimental evidence suggests reciprocal interactions between leptin and PTH, where hyperleptinemia and disrupted leptin signaling in obesity may exacerbate conditions such as secondary hyperparathyroidism, direct effects of leptin on the parathyroid remain poorly defined. We now show that leptin receptor-deficient db/db mice exhibit reduced serum PTH levels at 4 and 7 months of age. Complementary ex vivo experiments in cultured mouse parathyroid glands demonstrate that recombinant leptin increases PTH secretion while downregulating CaSR and c-fos gene expression. Furthermore, CaSR activation using a calcimimetic drug attenuated leptin's stimulatory effect on PTH secretion, indicating that leptin enhances PTH release by down regulating CaSR activity. These findings establish a direct regulatory link between leptin and PTH, highlighting leptin's role in modulating CaSR activity in the parathyroid. By counteracting CaSR-mediated inhibition, leptin may prevent excessive suppression of PTH release by the CaSR. Clinically, these insights may hold implications for conditions such as hyperleptinemia, obesity, and other disorders of PTH dysregulation.