Wolfram syndrome is a rare autosomal recessive disorder caused by mutations in the wolframin ER transmembrane glycoprotein (WFS1) gene and characterized by diabetes mellitus, diabetes insipidus, optic atrophy and deafness. In experimental models the homozygous Wfs1 mutant mice have a full penetrance and clearly expressed phenotype, whereas heterozygous mutants have a less-pronounced phenotype between the wild-type and homozygous mutant mice. Heterozygous WFS1 mutations have been shown to be significant risk factors for diabetes and metabolic disorders in humans. In the present study we analyzed the response of heterozygous Wfs1 mice to high fat diet (HFD) by exploring potential outcomes and molecular changes induced by this challenge. The HFD treatment increased the body weight (BW) similarly both in Wfs1 wild-type (WT) and heterozygous (HZ) mice, and therefore HFD also prevented the impaired BW gain found in Wfs1 mutant mice. In Wfs1HZ mutant mice, HFD impaired the normalized insulin secretion and the expression of ER stress genes in isolated pancreatic islets. These results suggest that Wfs1HZ mice have a decreased insulin response and pronounced cellular stress response due to a higher sensitivity to HFD as hypothesized. In Wfs1HZ mice, HFD increased the expression of Ire1α and Chop in pancreas and decreased that of Ire1α and Atf4 in liver. The present study shows that HFD can disturb insulin function with an increased ER stress in Wfs1HZ mice and only one functional Wfs1 gene copy is not sufficient to compensate this challenge. In conclusion, our study indicates that quantitative Wfs1 gene deficiency is sufficient to predispose the carriers of single functional Wfs1 copy to diabetes and metabolic syndrome and makes them susceptible to the environmental challenges such as HFD.

Wolfram 综合征是一种罕见的常染色体隐性遗传疾病，由 wolframin ER 跨膜糖蛋白 (WFS1) 基因突变引起，以糖尿病、尿崩症、视神经萎缩和耳聋为特征。在实验模型中，纯合Wfs1突变小鼠具有完全外显率和清晰表达的表型，而杂合突变体在野生型和纯合突变小鼠之间具有不太明显的表型。杂合的 WFS1突变已被证明是人类糖尿病和代谢紊乱的重要危险因素。在本研究中，我们分析了杂合Wfs1的反应通过探索这一挑战引起的潜在结果和分子变化，将小鼠改为高脂肪饮食 (HFD)。在Wfs1野生型 (WT) 和杂合子 (HZ) 小鼠中，HFD 治疗同样增加了体重 (BW) ，因此 HFD 还阻止了Wfs1突变小鼠中发现的体重增加受损。在 Wfs1HZ 突变小鼠中，HFD 损害了正常化的胰岛素分泌和孤立胰岛中 ER 应激基因的表达。这些结果表明，Wfs1HZ 小鼠的胰岛素反应降低，细胞应激反应明显，这是由于假设的对 HFD 的敏感性更高。在 Wfs1HZ 小鼠中，HFD 增加了Ire1α和Chop在胰腺中的表达，并降低了Ire1α和肝脏中的Atf4。本研究表明，HFD 可以扰乱胰岛素功能，增加 Wfs1HZ 小鼠的 ER 应激，只有一个功能性Wfs1基因拷贝不足以弥补这一挑战。总之，我们的研究表明，定量Wfs1基因缺陷足以使单功能Wfs1拷贝的携带者易患糖尿病和代谢综合征，并使他们容易受到 HFD 等环境挑战的影响。