Leptin corrects increased gene expression of renal 25-hydroxyvitamin D3-1α-hydroxylase and -24-hydroxylase in leptin-deficient, ob/ob mice
Leptin corrects increased gene expression of renal 25-hydroxyvitamin D3-1α-hydroxylase and -24-hydroxylase in leptin-deficient, ob/ob mice
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DOI：
10.1210/en.2003-1010
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发表时间：
2004-03-01
期刊：
影响因子：
4.8
通讯作者：
Horiuchi, N
中科院分区：
文献类型：
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作者：
Matsunuma, A;Kawane, T;Horiuchi, N
瘦素是ob基因的产物，由脂肪细胞分泌，控制整体能量平衡。我们用瘦素缺乏的肥胖（ob/ob）雄性小鼠研究瘦素对骨代谢的影响。肥胖小鼠的骨密度（BMD）比瘦（？/+）小鼠低，股骨短对照血清钙，磷酸盐，抗酒石酸酸性磷酸酶（骨吸收标志物）和碱性磷酸酶，尿钙和磷酸盐排泄的浓度显着升高，而尿中脱氧吡啶啉浓度在ob/ob和对照小鼠之间没有差异。由于ob/ob小鼠发生严重的性腺功能减退，因此对这些小鼠给予睾酮10周（5 mg/kg，sc，每周两次）;这不影响股骨BMD。对照组和ob/ob小鼠在骨骼和肾脏中显示出相似的维生素D受体密度;与对照组小鼠相比，肥胖小鼠的血清1，25-二羟维生素D-3 [1，25-（OH）（2）D-3]以及肾脏25-羟基维生素D-3- 1 α-羟化酶（CYP 27 B1）和-24-羟化酶（CYP 24）的mRNA表达和活性显着增加。肥胖基因野生型小鼠腹腔注射瘦素（4 mg/kg体重，每12 h一次，连续2 d），可显著降低1 α-羟化酶和24-羟化酶的mRNA表达和活性。血清钙、磷酸盐和1，25-（OH）2D 3浓度升高通过瘦素治疗而正常化。因此，瘦素抑制肾脏基因1 α-羟化酶和24-羟化酶的过度表达，并纠正肥胖症/肥胖症小鼠血清钙和磷浓度的升高。因此，瘦素缺乏小鼠的低BMD似乎与1，25-（OH）（2）D-3刺激骨吸收有关。
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 D-3 [1,25-(OH)(2)D-3] and in mRNA expression and activities of renal 25-hydroxyvitamin D-3- 1alpha-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 1alpha-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 1alpha-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)(2)D-3.