Specific knockout of p85α in brown adipose tissue induces resistance to high-fat diet-induced obesity and its metabolic complications in male mice.,Molecular Metabolism

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Specific knockout of p85α in brown adipose tissue induces resistance to high-fat diet-induced obesity and its metabolic complications in male mice.
Molecular Metabolism ( IF 7.0 ) Pub Date : 2019-11-09 , DOI: 10.1016/j.molmet.2019.10.010
Almudena Gomez-Hernandez ₁ , Andrea R Lopez-Pastor ₂ , Carlota Rubio-Longas ₃ , Patrik Majewski ₃ , Nuria Beneit ₂ , Vanesa Viana-Huete ₂ , Gema García-Gómez ₄ , Silvia Fernandez ₄ , Marta Letizia Hribal ₅ , Giorgio Sesti ₅ , Oscar Escribano ₁ , Manuel Benito ₁

Affiliation

Objective

An increase in mass and/or brown adipose tissue (BAT) functionality leads to an increase in energy expenditure, which may be beneficial for the prevention and treatment of obesity. Moreover, distinct class I PI3K isoforms can participate in metabolic control as well as in systemic dysfunctions associated with obesity. In this regard, we analyzed in vivo whether the lack of p85α in BAT (BATp85αKO) could modulate the activity and insulin signaling of this tissue, thereby improving diet-induced obesity and its associated metabolic complications.

Methods

We generated BATp85αKO mice using Cre-LoxP technology, specifically deleting p85α in a conditional manner. To characterize this new mouse model, we used mice of 6 and 12 months of age. In addition, BATp85αKO mice were submitted to a high-fat diet (HFD) to challenge BAT functionality.

Results

Our results suggest that the loss of p85α in BAT improves its thermogenic functionality, high-fat diet–induced adiposity and body weight, insulin resistance, and liver steatosis. The potential mechanisms involved in the improvement of obesity include (1) increased insulin signaling and lower activation of JNK in BAT, (2) enhanced insulin receptor isoform B (IRB) expression and association with IRS-1 in BAT, (3) lower production of proinflammatory cytokines by the adipose organ, (4) increased iWAT browning, and (5) improved liver steatosis.

Conclusions

Our results provide new mechanisms involved in the resistance to obesity development, supporting the hypothesis that the gain of BAT activity induced by the lack of p85α has a direct impact on the prevention of diet-induced obesity and its associated metabolic complications.

中文翻译：

棕色脂肪组织中p85α的特异敲除可诱导对高脂饮食诱发的肥胖的抵抗，并引起雄性小鼠的代谢并发症。

客观的

质量和/或棕色脂肪组织（BAT）功能的增加导致能量消耗的增加，这可能对预防和治疗肥胖病有益。此外，不同的I类PI3K亚型可以参与代谢控制以及与肥胖相关的全身功能障碍。在这方面，我们在体内分析了BAT中缺少p85α（BATp85αKO）是否可以调节该组织的活性和胰岛素信号传导，从而改善饮食引起的肥胖症及其相关的代谢并发症。

方法

我们使用Cre-LoxP技术生成了BATp85αKO小鼠，特别是有条件地删除了p85α。为了表征这种新的小鼠模型，我们使用了6个月和12个月大的小鼠。此外，将BATp85αKO小鼠接受高脂饮食（HFD）挑战BAT功能。

结果

我们的结果表明，BAT中p85α的缺失改善了其产热功能，高脂饮食诱导的肥胖和体重，胰岛素抵抗和肝脂肪变性。肥胖症改善的潜在机制包括（1）BAT中胰岛素信号增强和JNK活化降低;（2）BAT中胰岛素受体同工型B（IRB）表达增强和与IRS-1相关;（3）产量降低脂肪器官促炎性细胞因子的释放，（4）iWAT褐变增加，（5）改善肝脂肪变性。