Kokolski Marie, Ebling Francis J, Henstock James R, Anderson Susan I
Division of Medical Sciences and Graduate Entry Medicine, School of Medicine, University of Nottingham, Royal Derby Hospital, Derby, United Kingdom.
School of Life Sciences, University of Nottingham, Nottingham, United Kingdom.
Front Endocrinol (Lausanne). 2017 Dec 19;8:357. doi: 10.3389/fendo.2017.00357. eCollection 2017.
The adipokine leptin regulates energy balance, appetite, and reproductive maturation. Leptin also acts on bone growth and remodeling, but both osteogenic and anti-osteogenic effects have been reported depending on experimental conditions. Siberian hamsters () have natural variation in circulating leptin concentrations, where serum leptin is significantly decreased during the short day (SD)-induced winter state. In summer long day (LD) photoperiods, appetite and body adiposity increase with associated central leptin insensitivity. This natural change in leptin secretion was exploited to investigate leptin's effect on bone growth. Hamsters were injected with calcium-chelating fluorescent dyes to measure bone mineral apposition rate (MAR). Measurements were initially obtained from 5-week and 6-month-old animals maintained in low leptin (SD) or high leptin (LD) states. A further study investigated effects of chronic administration of recombinant mouse leptin to hamsters housed in SD and LD conditions; growth plate thickness and bone density were also assessed. As expected, a reduction in body mass was seen in hamsters exposed to SD, confirming the phenotype change in all studies. Serum leptin concentrations were significantly reduced in SD animals in all studies. MAR was reproducibly and significantly increased in the femurs of SD animals in all studies. Vitamin D and growth plate thickness were significantly increased in SD animals at 6 months. No effect on bone density was observed in any study. Taken together these data suggest that bone growth is associated with the low leptin, winter, lean state. In leptin-treated animals, there was a significant interaction effect of leptin and photoperiod. In comparison to their vehicle counterparts, SD animals had decreased and LD animals had increased MAR, which was not apparent prior to leptin administration. In conclusion, increased MAR was associated with low serum leptin levels in early life and sustained over 6 months, implying that leptin has a negative effect on bone growth in this model. The unexpected finding that MAR increased after peripheral leptin administration in LD suggests that leptin exerts different effects on bone growth dependent on initial leptin status. This adds further weight to the hypothesis that leptin-treated LD animals display central leptin resistance.
脂肪因子瘦素调节能量平衡、食欲和生殖成熟。瘦素也作用于骨骼生长和重塑，但根据实验条件，既有成骨作用也有抗成骨作用的报道。西伯利亚仓鼠循环瘦素浓度存在自然变异，在短日照（SD）诱导的冬季状态下血清瘦素显著降低。在夏季长日照（LD）光周期中，食欲和身体脂肪增加，伴有中枢性瘦素不敏感。利用瘦素分泌的这种自然变化来研究瘦素对骨骼生长的影响。给仓鼠注射钙螯合荧光染料以测量骨矿物质沉积率（MAR）。测量最初取自维持在低瘦素（SD）或高瘦素（LD）状态的5周龄和6月龄动物。进一步的研究调查了向处于SD和LD条件下的仓鼠长期注射重组小鼠瘦素的影响；还评估了生长板厚度和骨密度。正如预期的那样，暴露于SD的仓鼠体重减轻，证实了所有研究中的表型变化。在所有研究中，SD动物的血清瘦素浓度显著降低。在所有研究中，SD动物股骨中的MAR可重复且显著增加。6个月时，SD动物的维生素D和生长板厚度显著增加。在任何研究中均未观察到对骨密度的影响。综合这些数据表明，骨骼生长与低瘦素、冬季、消瘦状态相关。在接受瘦素治疗的动物中，瘦素和光周期存在显著的交互作用。与相应的对照组相比，SD动物的MAR降低，LD动物的MAR增加，这在给予瘦素之前并不明显。总之，MAR增加与生命早期血清瘦素水平低相关，并持续超过6个月，这意味着在该模型中瘦素对骨骼生长有负面影响。在LD条件下外周给予瘦素后MAR增加这一意外发现表明，瘦素对骨骼生长的影响取决于初始瘦素状态。这进一步支持了瘦素治疗的LD动物表现出中枢性瘦素抵抗的假说。
