Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
PLoS One. 2010 Jun 23;5(6):e11286. doi: 10.1371/journal.pone.0011286.
Syndecans are a family of type-I transmembrane proteins that are involved in cell-matrix adhesion, migration, neuronal development, and inflammation. Previous quantitative genetic studies pinpointed Drosophila Syndecan (dSdc) as a positional candidate gene affecting variation in fat storage between two Drosophila melanogaster strains. Here, we first used quantitative complementation tests with dSdc mutants to confirm that natural variation in this gene affects variability in Drosophila fat storage. Next, we examined the effects of a viable dSdc mutant on Drosophila whole-body energy metabolism and associated traits. We observed that young flies homozygous for the dSdc mutation had reduced fat storage and slept longer than homozygous wild-type flies. They also displayed significantly reduced metabolic rate, lower expression of spargel (the Drosophila homologue of PGC-1), and reduced mitochondrial respiration. Compared to control flies, dSdc mutants had lower expression of brain insulin-like peptides, were less fecund, more sensitive to starvation, and had reduced life span. Finally, we tested for association between single nucleotide polymorphisms (SNPs) in the human SDC4 gene and variation in body composition, metabolism, glucose homeostasis, and sleep traits in a cohort of healthy early pubertal children. We found that SNP rs4599 was significantly associated with resting energy expenditure (P = 0.001 after Bonferroni correction) and nominally associated with fasting glucose levels (P = 0.01) and sleep duration (P = 0.044). On average, children homozygous for the minor allele had lower levels of glucose, higher resting energy expenditure, and slept shorter than children homozygous for the common allele. We also observed that SNP rs1981429 was nominally associated with lean tissue mass (P = 0.035) and intra-abdominal fat (P = 0.049), and SNP rs2267871 with insulin sensitivity (P = 0.037). Collectively, our results in Drosophila and humans argue that syndecan family members play a key role in the regulation of body metabolism.
黏附素是一类Ⅰ型跨膜蛋白，参与细胞-基质黏附、迁移、神经元发育和炎症反应。先前的定量遗传研究将果蝇黏附素（dSdc）确定为影响两个黑腹果蝇品系间脂肪储存差异的位置候选基因。在这里，我们首先使用 dSdc 突变体的定量互补测试来确认该基因的自然变异会影响果蝇脂肪储存的变异性。接下来，我们检查了一个可行的 dSdc 突变对果蝇全身能量代谢和相关特征的影响。我们观察到，dSdc 突变纯合子的年轻果蝇脂肪储存减少，睡眠时间比纯合野生型果蝇长。它们还表现出明显降低的代谢率、较低的 spargel（PGC-1 的果蝇同源物）表达和减少的线粒体呼吸。与对照果蝇相比，dSdc 突变体的脑胰岛素样肽表达较低，繁殖力较低，对饥饿更敏感，寿命缩短。最后，我们在一个健康的早期青春期儿童队列中测试了人类 SDC4 基因的单核苷酸多态性（SNP）与身体成分、代谢、葡萄糖稳态和睡眠特征的变异之间的关联。我们发现 SNP rs4599 与静息能量消耗显著相关（经 Bonferroni 校正后 P = 0.001），与空腹血糖水平（P = 0.01）和睡眠时间（P = 0.044）呈名义相关。平均而言，携带次要等位基因的儿童的葡萄糖水平较低，静息能量消耗较高，睡眠时间较短。我们还观察到 SNP rs1981429 与瘦组织质量（P = 0.035）和腹内脂肪（P = 0.049）呈名义相关，SNP rs2267871 与胰岛素敏感性（P = 0.037）相关。总之，我们在果蝇和人类中的研究结果表明，黏附素家族成员在调节身体代谢中起着关键作用。
