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Leptin Corrects Increased Gene Expression of Renal 25-Hydroxyvitamin D₃-1-Hydroxylase and -24-Hydroxylase in Leptin-Deficient, ob/ob Mice

Departments of Biochemistry (A.M., T.K., T.M., N.H.) and Pharmacy (S.H.), Ohu University School of Dentistry, Koriyama 963-8611, Japan

Address all correspondence and requests for reprints to: Noboru Horiuchi, Ph.D., Department of Biochemistry, Ohu University School of Dentistry, Koriyama 963-8611, Japan. E-mail: fwga4746{at}mb.infoweb.ne.jp.

Leptin, the ob gene product secreted by adipocytes, controls overall energy balance. We investigated leptin effects on bone metabolism using male leptin-deficient obese (ob/ob) mice, which had lower bone mineral density (BMD) and shorter femurs than lean (?/+) controls. Serum concentrations of calcium, phosphate, tartrate-resistant acid phosphatase (a bone resorption marker) and alkaline phosphatase, and urinary calcium and phosphate excretion were significantly elevated in ob/ob mice, whereas urinary concentrations of deoxypyridinoline did not differed between ob/ob and control mice. Because ob/ob mice develop severe hypogonadism, testosterone was administered to these mice for 10 wk (5 mg/kg, sc, twice weekly); this did not affect femoral BMD. Control and ob/ob mice showed similar vitamin D-receptor densities in bone and kidney; the obese mice had marked increases in serum 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃] and in mRNA expression and activities of renal 25-hydroxyvitamin D₃-1-hydroxylase (CYP27B1) and -24-hydroxylase (CYP24) compared with control mice. Leptin administration to ob/ob mice (4 mg/kg body weight, ip, every 12 h for 2 d) greatly reduced mRNAs and activities of 1-hydroxylase and 24-hydroxylase. Elevated concentrations of serum calcium, phosphate, and 1,25-(OH)₂D₃ were normalized by leptin treatment. Thus, leptin suppresses renal gene overexpression for 1-hydroxylase and 24-hydroxylase and corrects increased serum concentrations of calcium and phosphate in ob/ob mice. Therefore, low BMD in leptin-deficient mice appears to be related to stimulation of bone resorption by 1,25-(OH)₂D₃.

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