Rowe Glenn C, Choi Cheol Soo, Neff Lynn, Horne William C, Shulman Gerald I, Baron Roland
Department of Orthopaedics, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Endocrinology. 2009 Jan;150(1):135-43. doi: 10.1210/en.2008-0678. Epub 2008 Sep 4.
Obesity and osteoporosis are major health issues affecting millions of individuals. Transgenic mice overexpressing DeltaFosB, an activator protein-1 transcription factor, under the control of the enolase 2 (ENO2) promoter exhibit both an increase in bone density and a decrease in adipose mass. Here we demonstrate that DeltaFosB overexpression increases fatty-acid oxidation and energy expenditure, leading to a decrease in adipocyte size and adipose mass. In addition, the ENO2-DeltaFosB mice exhibit increased insulin sensitivity and glucose tolerance. Targeted overexpression of DeltaFosB in adipocytes using the adipocyte protein 2 promoter failed to induce changes in fat or in bone, showing that the effect on metabolic activity is not due to cell-autonomous effects of DeltaFosB within adipocytes. Detailed analysis of the ENO2-DeltaFosB mice demonstrated that energy expenditure was increased in muscle, independent of locomotor activity. These findings provide evidence that signaling downstream of DeltaFosB is a potential target for not only osteoporosis but also obesity and diabetes.
肥胖和骨质疏松是影响数百万人的主要健康问题。在烯醇化酶2（ENO2）启动子控制下过表达激活蛋白-1转录因子DeltaFosB的转基因小鼠，骨密度增加且脂肪量减少。在此我们证明，DeltaFosB过表达增加脂肪酸氧化和能量消耗，导致脂肪细胞大小和脂肪量减少。此外，ENO2-DeltaFosB小鼠表现出胰岛素敏感性和葡萄糖耐量增加。使用脂肪细胞蛋白2启动子在脂肪细胞中靶向过表达DeltaFosB未能诱导脂肪或骨骼发生变化，表明对代谢活性的影响并非由于DeltaFosB在脂肪细胞内的细胞自主效应。对ENO2-DeltaFosB小鼠的详细分析表明，肌肉中的能量消耗增加，与运动活动无关。这些发现提供了证据，表明DeltaFosB下游信号不仅是骨质疏松的潜在靶点，也是肥胖和糖尿病的潜在靶点。
