Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, 70210, Kuopio, Finland.
Diabetologia. 2014 Feb;57(2):347-51. doi: 10.1007/s00125-013-3097-4. Epub 2013 Nov 7.
AIMS/HYPOTHESIS: The insulin receptor (INSR) has two protein isoforms based on alternative splicing of exon 11. INSR-A promotes cell growth whereas INSR-B predominantly regulates glucose homeostasis. In this study we investigated whether weight loss regulates INSR alternative splicing and the expression of splicing factors in adipose tissue.
To determine the relative ratio of the INSR splice variants, we implemented the PCR-capillary electrophoresis method with adipose tissue samples from two weight-loss-intervention studies, the Kuopio Obesity Surgery study (KOBS, n = 108) and a very low calorie diet (VLCD) intervention (n = 32), and from the population-based Metabolic Syndrome in Men study (METSIM, n = 49).
Expression of INSR-B mRNA variant increased in response to weight loss induced by both bariatric surgery (p = 1 × 10(-5)) and the VLCD (p = 1 × 10(-4)). The adipose tissue expression of INSR-B correlated negatively with fasting insulin levels in the pooled data of the three studies (p = 3 × 10(-22)). Finally, expression of several splicing factors correlated negatively with the expression of the INSR-B variant. The strongest correlation was with HNRNPA1 (p = 1 × 10(-5)), a known regulator of INSR exon 11 splicing.
CONCLUSIONS/INTERPRETATION: INSR splicing is regulated by weight loss and associates with insulin levels. The effect of weight loss on INSR splicing could be mediated by changes in the expression of splicing factors.
目的/假设：胰岛素受体（INSR）有两种蛋白异构体，基于外显子 11 的选择性剪接。INSR-A 促进细胞生长，而 INSR-B 主要调节葡萄糖稳态。在这项研究中，我们研究了体重减轻是否调节脂肪组织中的 INSR 选择性剪接和剪接因子的表达。
为了确定 INSR 剪接变体的相对比率，我们使用来自两个体重减轻干预研究的脂肪组织样本，即库奥皮奥肥胖手术研究（KOBS，n=108）和极低卡路里饮食（VLCD）干预（n=32），以及来自基于人群的代谢综合征男性研究（METSIM，n=49），实施了 PCR-毛细管电泳法。
两种减重手术（手术组 p=1×10(-5)）和极低卡路里饮食（VLCD 组 p=1×10(-4))均可诱导 INSR-B mRNA 变体的表达增加。在这三项研究的汇总数据中，脂肪组织中 INSR-B 的表达与空腹胰岛素水平呈负相关（p=3×10(-22))。最后，几种剪接因子的表达与 INSR-B 变体的表达呈负相关。与 INSR 外显子 11 剪接相关的已知调节因子 HNRNPA1（p=1×10(-5))的相关性最强。
结论/解释：INSR 剪接受体重减轻调节，并与胰岛素水平相关。体重减轻对 INSR 剪接的影响可能是通过剪接因子表达的变化介导的。
