Objective

Insulin signalling via phosphoinositide 3-kinase (PI3K) requires PIK3R1-encoded regulatory subunits. C-terminal PIK3R1 mutations cause SHORT syndrome, as well as lipodystrophy and insulin resistance (IR), surprisingly without fatty liver or metabolic dyslipidaemia. We sought to investigate this discordance.

Methods

The human pathogenic Pik3r1 Y657^∗ mutation was knocked into mice by homologous recombination. Growth, body composition, bioenergetic and metabolic profiles were investigated on chow and high-fat diet (HFD). We examined adipose and liver histology, and assessed liver responses to fasting and refeeding transcriptomically.

Results

Like humans with SHORT syndrome, Pik3r1^WT/Y657∗ mice were small with severe IR, and adipose expansion on HFD was markedly reduced. Also as in humans, plasma lipid concentrations were low, and insulin-stimulated hepatic lipogenesis was not increased despite hyperinsulinemia. At odds with lipodystrophy, however, no adipocyte hypertrophy nor adipose inflammation was found. Liver lipogenic gene expression was not significantly altered, and unbiased transcriptomics showed only minor changes, including evidence of reduced endoplasmic reticulum stress in the fed state and diminished Rictor-dependent transcription on fasting. Increased energy expenditure, which was not explained by hyperglycaemia nor intestinal malabsorption, provided an alternative explanation for the uncoupling of IR from dyslipidaemia.

Conclusions

Pik3r1 dysfunction in mice phenocopies the IR and reduced adiposity without lipotoxicity of human SHORT syndrome. Decreased adiposity may not reflect bona fide lipodystrophy, but rather, increased energy expenditure, and we suggest that further study of brown adipose tissue in both humans and mice is warranted.

中文翻译：

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Pik3r1 的截短会导致严重的胰岛素抵抗，而这与能量消耗增加而导致的肥胖和血脂异常无关。

客观的

通过磷酸肌醇 3-激酶 (PI3K) 的胰岛素信号传导需要PIK3R1编码的调节亚基。C 端PIK3R1突变会导致 SHORT 综合征、脂肪营养不良和胰岛素抵抗 (IR)，但令人惊讶的是，却没有脂肪肝或代谢性血脂异常。我们试图调查这种不一致。

方法

通过同源重组将人类致病性Pik3r1 Y657 ^*突变敲入小鼠体内。研究了食物和高脂饮食 (HFD) 的生长、身体成分、生物能和代谢特征。我们检查了脂肪和肝脏组织学，并通过转录组评估了肝脏对禁食和重新进食的反应。

结果

与患有 SHORT 综合征的人类一样，Pik3r1 ^WT/Y657*小鼠体型较小，IR 严重，并且 HFD 下的脂肪膨胀显着减少。与人类一样，血浆脂质浓度较低，尽管存在高胰岛素血症，但胰岛素刺激的肝脏脂肪生成并未增加。然而，与脂肪营养不良不同的是，没有发现脂肪细胞肥大或脂肪炎症。肝脏脂肪生成基因表达没有显着改变，无偏转录组学仅显示出微小的变化，包括进食状态下内质网应激减少和禁食时 Rictor 依赖性转录减少的证据。能量消耗增加（不能用高血糖或肠道吸收不良来解释）为 IR 与血脂异常的解耦提供了另一种解释。

结论

小鼠中的Pik3r1功能障碍可模拟 IR 并减少肥胖，而不会产生人类短路综合征的脂毒性。肥胖减少可能并不反映真正的脂肪营养不良，而是反映能量消耗增加，我们建议对人类和小鼠的棕色脂肪组织进行进一步研究。