Xue B, Wilkison W O, Zemel M B
Departments of Nutrition and Medicine, The University of Tennessee, Knoxville, Tennessee 37996,
FASEB J. 1998 Oct;12(13):1391-6.
Overexpression of the murine agouti gene results in obesity. The human homologue of agouti is expressed primarily in human adipocytes, and we have shown recombinant agouti protein to increase adipocyte intracellular Ca2+([Ca2+]i) and thereby stimulate lipogenesis. However, since recent data demonstrate that increasing adipocyte [Ca2+]i may also inhibit lipolysis, we have investigated the role of agouti-induced [Ca2+]i increases in regulating lipolysis in human adipocytes. Short-term (1 h) exposure to recombinant agouti (100 nM) protein had no effect on basal lipolysis, although longer term treatment (24 h) caused a 60% decrease in basal lipolysis (P<0.0001). Short-term agouti treatment totally inhibited ACTH-induced lipolysis (P<0.05). Since melanocortin receptors (MCR) are involved in some actions of agouti, we next determined whether agouti's antilipolytic effect is exerted through competitive antagonism of the ACTH receptor (MCR-2). Forskolin (1 microM), an adenylate cyclase activator, induced a 48% increase in lipolysis in human adipocytes (P<0.05); this effect was reversed by 100 nM agouti (P<005), demonstrating that the antilipolytic effect of agouti is distal to the ACTH receptor. To determine the role of [Ca2+]i in the antilipolytic effect of agouti, human adipocytes were treated with KCl or arginine vasopressin to stimulate voltage- and receptor-stimulated Ca2+ influx, respectively. Both agents caused inhibition of forskolin-induced lipolysis (P<0.005). Furthermore, agouti's antilipolytic effect was also blocked by the Ca2+ channel blocker nitrendipine. These data demonstrate that agouti exerts a potent antilipolytic effect in human adipocytes via a Ca2+-dependent mechanism. This effect, combined with agouti-induced lipogenesis, represents a coordinate control of adipocyte lipid metabolism that may contribute to an agouti-induced obesity syndrome.
小鼠刺鼠基因的过表达会导致肥胖。刺鼠基因的人类同源物主要在人类脂肪细胞中表达，并且我们已经证明重组刺鼠蛋白可增加脂肪细胞内的钙离子浓度（[Ca2+]i），从而刺激脂肪生成。然而，由于最近的数据表明增加脂肪细胞内的[Ca2+]i也可能抑制脂肪分解，我们研究了刺鼠蛋白诱导的[Ca2+]i增加在调节人类脂肪细胞脂肪分解中的作用。短期（1小时）暴露于重组刺鼠蛋白（100 nM）对基础脂肪分解没有影响，尽管长期处理（24小时）导致基础脂肪分解减少了60%（P<0.0001）。短期刺鼠蛋白处理完全抑制了促肾上腺皮质激素（ACTH）诱导的脂肪分解（P<0.05）。由于黑皮质素受体（MCR）参与了刺鼠蛋白的某些作用，我们接下来确定刺鼠蛋白的抗脂肪分解作用是否通过对ACTH受体（MCR-2）的竞争性拮抗作用来发挥。福斯可林（1 microM），一种腺苷酸环化酶激活剂，可使人类脂肪细胞的脂肪分解增加48%（P<0.05）；100 nM的刺鼠蛋白可逆转这种作用（P<0.05），表明刺鼠蛋白的抗脂肪分解作用发生在ACTH受体的下游。为了确定[Ca2+]i在刺鼠蛋白抗脂肪分解作用中的作用，分别用氯化钾或精氨酸加压素处理人类脂肪细胞，以刺激电压依赖性和受体依赖性的钙离子内流。这两种试剂都导致福斯可林诱导的脂肪分解受到抑制（P<0.005）。此外，刺鼠蛋白的抗脂肪分解作用也被钙离子通道阻滞剂尼群地平所阻断。这些数据表明，刺鼠蛋白通过一种钙离子依赖性机制在人类脂肪细胞中发挥强大的抗脂肪分解作用。这种作用，与刺鼠蛋白诱导的脂肪生成相结合，代表了对脂肪细胞脂质代谢的协同控制，这可能导致刺鼠蛋白诱导的肥胖综合征。
