Systemic Ketone Replacement Does Not Improve Survival or Cancer Cachexia in Mice With Lung Cancer.
Systemic Ketone Replacement Does Not Improve Survival or Cancer Cachexia in Mice With Lung Cancer.
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DOI：
10.3389/fonc.2022.903157
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发表时间：
2022
影响因子：
4.7
通讯作者：
Goncalves, Marcus DaSilva
中科院分区：
文献类型：
--
作者：
Langer, Henning Tim;Ramsamooj, Shakti;Liang, Roger J.;Grover, Rahul;Hwang, Seo-Kyoung;Goncalves, Marcus DaSilva
关键词：
恶病质是一种影响许多肺癌患者的衰弱性合并症。我们之前发现，患有肺癌的病毒性小鼠由于肝脏中PPARα活性低而降低了血清酮体水平。非诺贝特恢复肝脏PPARα活性增加循环酮和延迟肌肉和白色脂肪组织的消耗。我们假设循环酮的丧失在恶病质中起病理生理作用，并进行了两项饮食干预研究来验证这一假设。在第一项研究中，雄性和雌性小鼠在接受肿瘤诱导后随机食用低碳水化合物生酮饮食（KD）或正常食物（NC）。KD成功地恢复了恶病质小鼠的血清酮水平并降低了血糖，但没有改善体重维持或生存率。事实上，KD在雄性小鼠中有恶化生存的趋势，而在雌性小鼠中没有。在第二项研究中，我们在NC饮食中添加了酮酯补充剂（KE），并在肿瘤诱导后将荷瘤小鼠随机分为KE或NC。我们证实，与NC相比，KE能够急性和慢性地增加血清中的酮体丰度。然而，恢复循环中的酮类并不能改善患有肺癌的雄性或雌性小鼠的体重维持或生存。最后，我们研究了饲喂KE和NC的小鼠肝脏中PPARα的活性，发现补充酮酯的小鼠肝脏中几种PPARα靶点的mRNA表达显著增加。这些数据否定了我们最初的假设，并表明恢复肺癌小鼠循环中的酮体可用性不会改变恶病质的发展或改善生存，尽管增加了肝脏PPARα活性。
Cachexia is a debilitating comorbidity affecting many lung cancer patients. We have previously found that cachectic mice with lung cancer have reduced serum ketone body levels due to low PPARα activity in the liver. Restoring hepatic PPARα activity with fenofibrate increased circulating ketones and delayed muscle and white adipose tissue wasting. We hypothesized that the loss of circulating ketones plays a pathophysiologic role in cachexia and performed two dietary intervention studies to test this hypothesis. In the first study, male and female mice were randomized to consume either a very low carbohydrate, ketogenic diet (KD) or normal chow (NC) after undergoing tumor induction. The KD successfully restored serum ketone levels and decreased blood glucose in cachectic mice but did not improve body weight maintenance or survival. In fact, there was a trend for the KD to worsen survival in male but not in female mice. In the second study, we compounded a ketone ester supplement into the NC diet (KE) and randomized tumor-bearing mice to KE or NC after tumor induction. We confirmed that KE was able to acutely and chronically increase ketone body abundance in the serum compared to NC. However, the restoration of ketones in the circulation was not able to improve body weight maintenance or survival in male or female mice with lung cancer. Finally, we investigated PPARα activity in the liver of mice fed KE and NC and found that animals fed a ketone ester supplement showed a significant increase in mRNA expression of several PPARα targets. These data negate our initial hypothesis and suggest that restoring ketone body availability in the circulation of mice with lung cancer does not alter cachexia development or improve survival, despite increasing hepatic PPARα activity.
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