Leptin, the ob gene product secreted by adipocytes, controls overall energy balance. We previously showed that leptin administration to leptin-deficient obese (oblob) mice suppressed mRNA expression and activity of renal 25-hydroxyvitamin D-3-1 alpha-hydroxylase (CYP27B1). In leptin receptor-deficient (db/db) mice, we presently examined whether leptin affects 1 alpha-hydroxylase expression in renal tubules through the active form of the leptin receptor (ObRb). Elevated serum concentrations of calcium and 1,25-dihydroxyvitamin D-3 [1,25-(OH)ZD(3)] in untreated oblob mice showed sharp reduction with leptin administration (4 mg/kg, i.p. every 12 h for 2 days); no such reduction of elevation occurred in dbldb mice. ObRb mRNA was expressed in kidney, brain, fat, lung, and bone in wild-type and oblob mice, but not dbldb mice. The oblob and dbldb mice showed large increases in renal la-hydroxylase mRNA expression and activity. Leptin administration (4 mg/kg) completely abrogated these increases in oblob but not dbldb mice. Renal 25-hydroxyvitamin D-3-24-hydroxylase (CYP24) mRNA synthesis also was greatly elevated in oblob and dbldb mice; excesses decreased significantly with leptin administration in oblob mice, but increased in dbldb mice. Renal tubular cells in primary culture expressed mRNAs including proximal tubules markers (1 alpha-hydroxylase and megalin), parathyroid hormone receptor, and vitamin D receptor. Calcitonin receptor mRNA, synthesized mainly in distal tubules, was scant, indicating that most cultured cells were from proximal tubules. Cells did not express ObRb mRNA. Forskolin exposure at 10(-6) M for 3 or 6 h significantly increased 1 alpha-hydroxylase mRNA. Leptin at 10-6 M did not change mRNA expression in either presence or absence of forskolin. Accordingly, leptin attenuates renal 1 alpha-hydroxylase gene expression through ObRb. Furthermore, leptin appears to act indirectly on renal proximal tubules to regulate la-hydroxylase gene expression. (c) 2007 Elsevier Inc. All rights reserved.