Zemel M B
Department of Nutrition, University of Tennessee, Knoxville 37996, USA.
Nutr Rev. 1998 Sep;56(9):271-4. doi: 10.1111/j.1753-4887.1998.tb01764.x.
The cloning of mouse obesity genes and their human homologues provides unique opportunities to identify novel cellular targets for therapeutic intervention. The first of these to be cloned, agouti, antagonizes central nervous system melanocortin receptor (MCR) binding, resulting in hyperphagia and an obesity/hyperinsulinemia syndrome. There appears to be significant cross-talk between the agouti and leptin signaling systems. Agouti antagonism of central nervous system (CNS) MCR binding inhibits the anorexic effects of leptin, whereas agouti up-regulates adipocyte leptin expression, serving to limit the magnitude of agouti-induced obesity. The effects of agouti and leptin mutations on obesity, however, are independent and additive. Agouti also regulates adipocyte lipid metabolism, functioning both to increase the expression and activity of lipogenic genes and to inhibit lipolysis. Both of these actions occur via a Ca(2+)-dependent mechanism, suggesting that modulation of adipocyte Ca2+ transport may be a key target for further investigation.
小鼠肥胖基因及其人类同源基因的克隆为确定治疗干预的新细胞靶点提供了独特的机会。其中第一个被克隆的基因——刺鼠基因，可拮抗中枢神经系统黑皮质素受体（MCR）的结合，导致食欲亢进和肥胖/高胰岛素血症综合征。刺鼠基因和瘦素信号系统之间似乎存在显著的相互作用。刺鼠基因对中枢神经系统（CNS）MCR结合的拮抗作用会抑制瘦素的厌食作用，而刺鼠基因会上调脂肪细胞瘦素的表达，以限制刺鼠基因诱导的肥胖程度。然而，刺鼠基因和瘦素突变对肥胖的影响是独立且累加的。刺鼠基因还调节脂肪细胞的脂质代谢，既能增加生脂基因的表达和活性，又能抑制脂肪分解。这两种作用均通过钙（Ca2+）依赖机制发生，这表明调节脂肪细胞Ca2+转运可能是进一步研究的关键靶点。
