Vannucci S J, Klim C M, Martin L F, LaNoue K F
Department of Physiology, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey 17033.
Am J Physiol. 1989 Dec;257(6 Pt 1):E871-8. doi: 10.1152/ajpendo.1989.257.6.E871.
Hormone-stimulated lipolysis is reduced in genetically obese rodents and may contribute to the increased adiposity characteristic of the obese state. Endogenously released adenosine, acting via the A1 receptor coupled to the inhibitory guanosine 5'-triphosphate binding protein, Gi, provides a tonic inhibition of lipolysis in rat adipocytes. Removal of this inhibition by the addition of adenosine deaminase frequently results in maximal lipolytic activity. Adipocytes isolated from lean Zucker (Fa/?) rats responded normally to adenosine deaminase, where lipolysis in adipocytes from obese Zucker (fa/fa) rats remained approximately 50% inhibited. Adipocyte adenylate cyclase was equally responsive to activation by forskolin, but lipolytic hormones were significantly less effective in stimulating adenosine 3',5'-cyclic monophosphate (cAMP) production in the obese adipocytes. These cells also exhibited an increased sensitivity to inhibition by the adenosine agonist, N6-(L-2-phenylisopropyl)-adenosine, either in combination with forskolin or beta-adrenergic hormone stimulation. Treatment of isolated adipocytes with pertussis toxin, which uncouples receptor-mediated Gi function, had little effect in cells from lean rats but increased isoproterenol stimulated cAMP production of cells from obese rats to levels observed in the lean cells. In addition, the adenosine A1 antagonist, 8-phenyltheophylline, increased cAMP and lipolytic activity in the obese adipocytes while having little significant effect in the lean adipocytes. These results suggest that hormonal control of lipolysis is altered in the obese Zucker rat because of an alteration in A1-adenosine receptor-mediated inhibition of adenylate cyclase.
在遗传性肥胖啮齿动物中，激素刺激的脂肪分解作用减弱，这可能导致肥胖状态下肥胖特征的增加。内源性释放的腺苷通过与抑制性鸟苷5'-三磷酸结合蛋白Gi偶联的A1受体发挥作用，对大鼠脂肪细胞的脂肪分解产生持续抑制。添加腺苷脱氨酶消除这种抑制作用通常会导致最大脂肪分解活性。从瘦型 Zucker（Fa/?）大鼠分离的脂肪细胞对腺苷脱氨酶反应正常，而肥胖 Zucker（fa/fa）大鼠脂肪细胞中的脂肪分解仍被抑制约50%。脂肪细胞腺苷酸环化酶对福斯可林的激活反应相同，但脂肪分解激素在刺激肥胖脂肪细胞中3',5'-环磷酸腺苷（cAMP）生成方面的效果明显较差。这些细胞对腺苷激动剂N6-(L-2-苯异丙基)-腺苷与福斯可林或β-肾上腺素能激素刺激联合使用时的抑制作用也表现出更高的敏感性。用百日咳毒素处理分离的脂肪细胞，该毒素可使受体介导的Gi功能解偶联，对瘦大鼠的细胞影响不大，但可使肥胖大鼠细胞中异丙肾上腺素刺激的cAMP生成增加到瘦细胞中观察到的水平。此外，腺苷A1拮抗剂8-苯基茶碱可增加肥胖脂肪细胞中的cAMP和脂肪分解活性，而对瘦脂肪细胞几乎没有显著影响。这些结果表明，肥胖 Zucker 大鼠脂肪分解的激素控制发生了改变，这是由于A1-腺苷受体介导的腺苷酸环化酶抑制作用发生了改变。
