Karsenty G
Baylor College of Medicine, Houston, Texas 77030, USA.
Recent Prog Horm Res. 2001;56:401-15. doi: 10.1210/rp.56.1.401.
Menopause favors osteoporosis and obesity protects from it. In an attempt to decipher the molecular bases of these two well-known clinical observations, we hypothesized that they meant that bone remodeling, body weight, and reproduction are controlled by identical endocrine pathways. We used mouse genetics as a tool to translate these clinical observations into a molecular hypothesis. The ob/ob and db/db mice were valuable models, since two of the three functions thought to be co-regulated are affected in these mice: they are obese and hypogonadic. Surprisingly, given their hypogonadism, both mouse mutant strains have a high bone mass phenotype. Subsequent analysis of the mechanism leading to this high bone mass revealed that it was due to an increase of bone formation. All data collected indicate that, in vivo, leptin does not act directly on osteoblasts but rather through a central pathway following binding to its specific receptors located on hypothalamic nuclei. This result revealed that bone remodeling, like most other homeostatic functions, is under hypothalamic control. The nature of the signal downstream of the hypothalamus is unknown but current experiments are attempting to identify it.
绝经易引发骨质疏松，而肥胖对其有预防作用。为了探究这两个广为人知的临床现象的分子基础，我们推测它们意味着骨重塑、体重和生殖受相同内分泌途径的控制。我们利用小鼠遗传学作为工具，将这些临床观察结果转化为分子假说。ob/ob和db/db小鼠是有价值的模型，因为被认为共同调节的三种功能中的两种在这些小鼠中受到影响：它们肥胖且性腺功能减退。令人惊讶的是，尽管它们性腺功能减退，但这两种小鼠突变品系都具有高骨量表型。随后对导致这种高骨量的机制进行分析发现，这是由于骨形成增加所致。收集到的所有数据表明，在体内，瘦素并非直接作用于成骨细胞，而是在与位于下丘脑核的特异性受体结合后，通过中枢途径发挥作用。这一结果表明，骨重塑与大多数其他稳态功能一样，受下丘脑控制。下丘脑下游信号的性质尚不清楚，但目前的实验正试图确定它。
