FATE OF THE ADIPOCYTE

新生哺乳动物的脂肪主要是棕色脂肪， 满足出生时对热量的强烈需求。 为 随着动物年龄的增长，棕色脂肪往往会不同程度地消失，这取决于 而白色脂肪同时增加。 这种正常 在转基因小鼠中， 过表达甘油3-磷酸的结构基因 脱氢酶（Gdc-1）。 在这只转基因小鼠中， 渐开线，而白色脂肪生长被阻止;总体上， 动物已经减少。 Gdc-1转基因的效果最好 这在db/db小鼠中是明显的，db/db小鼠通常可以具有25克的体脂，但是当 携带转基因的身体脂肪实际上是检测不到的。 的 本建议的具体目标是确定一种机制， Gdc-1的过表达控制体脂肪的沉积。 工作 一种假说认为，高水平的Gdc-1表达已经形成了一种 消耗动物体内多余能量的无效ATP酶。 这一假设 将通过首先确定产热增加发生 在Gdc-1转基因小鼠中-通过间接量热法在整个动物中， 通过测量体内细胞培养物中的呼吸作用。 然后我们将 分析甘油代谢的中间产物和产物以及碳通量 通过受Gdc-1过度表达影响的途径， 以确定无效ATP酶的机制。 假设数据 是证实性的，第二个具体目标将表征甘油3- 磷酸磷酸酶，我们假设它是一种无用的 ATP酶 第三个具体目标是培育新的同类系小鼠 携带Gdc-1转基因与肥胖突变体db的组合 从而可以分析转基因对肥胖症的影响 在受控的遗传背景下;此外，新的转基因品系将 其中Gdc-1转基因表达被限制为 特定的组织和激素控制下，并在其中的其他基因， 甘油代谢将被过度表达。 在最后的具体目标 我们将在转基因小鼠的棕色脂肪中表征 线粒体的mRNA和蛋白质是重要的产热。

The fat in the newborn mammal is principally brown fat in order to satisfy the acute requirement for heat which occurs at birth. As the animal ages, brown fat tends to disappear to varying degrees, depending on the species, while white fat concurrently increases. This normal developmental process has been drastically altered in a transgenic mouse that overexpresses the structural gene for glycerol 3-phosphate dehydrogenase (Gdc-1). In this transgenic mouse brown fat does not involute while white fat growth is arrested; overall the total fat of the animal has been reduced. The effect of the Gdc-1 transgene is most evident in db/db mice which normally can have 25 gm of body fat, but when carrying the transgene the body fat can be virtually undetectable. The specific aims of this proposal seek to determine the mechanism by which overexpression of Gdc-1 controls the deposition of body fat. The working hypothesis is that the high levels of Gdc-1 expression have formed a futile ATPase which expends excess energy in the animal. This hypothesis will be tested by first establishing that increased thermogenesis occurs in Gdc-1 transgenic mice - by indirect calorimetry in whole animals and by measurements of respiration in cell cultures in vivo. We will then analyze intermediates and products of glycerol metabolism and carbon flux through pathways which are affected by over-expression of Gdc-1 in order to identify a mechanism for the futile ATPase. Assuming that the data is confirmatory, the second specific aim will characterize a glycerol 3- phosphate phosphatase which we hypothesize to be a component of a futile ATPase. The third specific aim will breed new congenic lines of mice carrying the Gdc-1 transgenes in combination with the obesity mutants db and ob so that the effects of the transgene on obesity can be analyzed in controlled genetic backgrounds; in addition, new transgenic lines will be created in which the Gdc-1 transgene expression is restricted to specific tissues and under hormonal control, and in which other genes of glycerol metabolism will be over-expressed. In the final specific aim we will characterize in the brown fat of transgenic mice the expression of mitochondrial mRNA and proteins which are important to thermogenesis.