Role of IGFBP-3 in the Regulation of ß-Cell Mass during Obesity: Adipose Tissue/ ß-Cell Cross Talk

In obesity an increase in ß-cell mass occurs to cope with the rise in insulin demand. This ß -cell plasticity is essential to avoid the onset of hyperglycemia, although the molecular mechanisms that regulate this process remain unclear. This study analyzed the role of adipose tissue in the control of ß -cell replication. Using a diet-induced model of obesity, we obtained conditioned media from three different white adipose tissue depots. Only in the adipose tissue depot surrounding the pancreas did the diet induce changes that led to an increase in INS1E cells and the islet replication rate. To identify the factors responsible for this proliferative effect, adipose tissue gene expression analysis was conducted by microarrays and quantitative RT-PCR. Of all the differentially expressed proteins, only the secreted ones were studied. IGF binding protein 3 (Igfbp3) was identified as the candidate for this effect. Furthermore, in the conditioned media, although the blockage of IGFBP3 led to an increase in the proliferation rate, the blockage of IGF-I receptor decreased it. Taken together, these data show that obesity induces specific changes in the expression profile of the adipose tissue depot surrounding the pancreas, leading to a decrease in IGFBP3 secretion. This decrease acts in a paracrine manner, stimulating the ß -cell proliferation rate, probably through an IGF-I-dependent mechanism. This cross talk between the visceral-pancreatic adipose tissue and ß -cells is a novel mechanism that participates in the control of ß -cell plasticity. (Endocrinology 153: 177–187, 2012)肥胖状态下，机体β细胞（β-cell）团会发生增殖，以应对升高的胰岛素需求。尽管调控这一过程的分子机制尚未明确，但这种β细胞可塑性对于避免高血糖症的发生至关重要。本研究探讨了脂肪组织在调控β细胞增殖中的作用。借助饮食诱导的肥胖模型，研究团队从三种不同的白色脂肪组织分区中获取了条件培养基。仅在胰周脂肪组织分区中，致肥胖饮食诱导的变化可使INS1E细胞数量增加，并提升胰岛增殖速率。为明确介导此种增殖效应的因子，研究团队通过基因芯片与定量逆转录聚合酶链反应开展了脂肪组织基因表达分析。在所有差异表达蛋白中，仅对分泌型蛋白进行了研究。胰岛素样生长因子结合蛋白3（IGF binding protein 3，Igfbp3）被确定为该效应的候选介导因子。此外，在条件培养基中，尽管阻断IGFBP3可提升β细胞增殖速率，但阻断胰岛素样生长因子I受体（IGF-I receptor）则会降低β细胞增殖速率。综合以上数据可知，肥胖可使胰周脂肪组织分区的基因表达谱发生特异性变化，进而降低IGFBP3的分泌水平。这种分泌水平的降低以旁分泌方式发挥作用，通过胰岛素样生长因子I依赖的信号通路，提升β细胞增殖速率。胰周内脏脂肪组织与β细胞之间的此种细胞串扰，是调控β细胞可塑性的全新机制。（《内分泌学》，153卷：177–187，2012年）