Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
Department of Genetics, College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
PLoS One. 2021 Oct 26;16(10):e0258873. doi: 10.1371/journal.pone.0258873. eCollection 2021.
Traumatic brain injury (TBI) is a common neurological disorder whose outcomes vary widely depending on a variety of environmental factors, including diet. Using a Drosophila melanogaster TBI model that reproduces key aspects of TBI in humans, we previously found that the diet consumed immediately following a primary brain injury has a substantial effect on the incidence of mortality within 24 h (early mortality). Flies that receive equivalent primary injuries have a higher incidence of early mortality when fed high-carbohydrate diets versus water. Here, we report that flies fed high-fat ketogenic diet (KD) following TBI exhibited early mortality that was equivalent to that of flies fed water and that flies protected from early mortality by KD continued to show survival benefits weeks later. KD also has beneficial effects in mammalian TBI models, indicating that the mechanism of action of KD is evolutionarily conserved. To probe the mechanism, we examined the effect of KD in flies mutant for Eip75B, an ortholog of the transcription factor PPARγ (peroxisome proliferator-activated receptor gamma) that contributes to the mechanism of action of KD and has neuroprotective effects in mammalian TBI models. We found that the incidence of early mortality of Eip75B mutant flies was higher when they were fed KD than when they were fed water following TBI. These data indicate that Eip75B/PPARγ is necessary for the beneficial effects of KD following TBI. In summary, this work provides the first evidence that KD activates PPARγ to reduce deleterious outcomes of TBI and it demonstrates the utility of the fly TBI model for dissecting molecular pathways that contribute to heterogeneity in TBI outcomes.
创伤性脑损伤 (TBI) 是一种常见的神经疾病，其结果因多种环境因素（包括饮食）而异。我们之前使用一种能重现人类 TBI 关键方面的黑腹果蝇 TBI 模型发现，原发性脑损伤后立即摄入的饮食对 24 小时内（早期死亡率）的死亡率发生率有很大影响。与水相比，接受同等原发性损伤的果蝇在摄入高碳水化合物饮食时，早期死亡率更高。在这里，我们报告称，TBI 后接受高脂肪生酮饮食 (KD) 的果蝇表现出与饮水果蝇相当的早期死亡率，并且通过 KD 预防早期死亡率的果蝇在数周后仍表现出生存获益。KD 在哺乳动物 TBI 模型中也有有益的作用，表明 KD 的作用机制在进化上是保守的。为了探究其机制，我们研究了 KD 对 Eip75B 突变果蝇的影响，Eip75B 是转录因子 PPARγ（过氧化物酶体增殖物激活受体 γ）的同源物，它有助于 KD 的作用机制，并在哺乳动物 TBI 模型中具有神经保护作用。我们发现，与 TBI 后接受水喂养相比，Eip75B 突变果蝇在接受 KD 喂养时，早期死亡率更高。这些数据表明，Eip75B/PPARγ 是 KD 对 TBI 有益作用所必需的。总之，这项工作首次提供了 KD 通过激活 PPARγ 来减轻 TBI 不良后果的证据，并证明了果蝇 TBI 模型在剖析导致 TBI 结果异质性的分子途径方面的效用。
