Systemic Ketone Replacement Does Not Improve Survival or Cancer Cachexia in Mice With Lung Cancer

Abstract

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.

Hepatic signal transducer and activator of transcription‐3 signalling drives early‐stage pancreatic cancer cachexia via suppressed ketogenesis

“… 33 Our results contradict recent reports showing that KD did not prevent cachexia in a KRAS‐driven murine lung cancer model, a heterotopic C26 colon cancer model or the autochthonous genetically engineered KPC PDAC model. 16 , 34 , 35 Furthermore, KD delayed tumour growth in the latter two models, yet we observed no effect of KD on tumour size. These discrepant results could be explained by differences in the KD interventions or duration of KD feeding.…”

“… 12 , S2 , S3 This is potentially because most studies evaluating cancer cachexia compare patients or mice with fully developed cachexia against healthy control populations. 13 , 14 , 15 , 16 , 17 , 18 Thus, the early biology driving initial wasting, which may differ from the inflammation‐driven biology defined in more advanced cachexia, is not well characterized. 6 Indeed, a recent study of early murine PDAC cachexia, using the autochthonous KPC model, showed no elevations in cachexia‐associated cytokines and was unable to discriminate cachexia from pure undernutrition.…”

Anti-tumor effects of ketogenic diets and their synergism with other treatments in mice: Bayesian evidence synthesis of 1755 individual mouse survival data

“…The primary PubMed search resulted in 184 hits of which 156 were discarded after title, abstract, or full-text screening, resulting in 28 articles for inclusion [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] , [54] , [55] , [56] , [57] , [58] , [59] , [60] , [61] , [62] . An additional 15 articles were retrieved from my personal library [20] , [63] , [64] , [65] , [66] , [67] , [68] , [69] , [70] , [71] , [72] , [73] , [74] , [75] , [76] .…”

IL-6/STAT3 signaling drives early-stage pancreatic cancer cachexia via suppressed ketogenesis

“…Furthermore, Thomsen et al present human data showing that infusion with BHB reduces muscle protein catabolism, which supports our in vitro observations (Thomsen et al, 2018). However, a separate, recent study in NSCLC showed that ketogenic diet was not sufficient to prevent tumor progression and cachexia development (Langer et al ., 2022). These apparently contradictory responses to ketogenic diet highlight the likelihood that cachexia can result from different underlying mechanisms, which may be susceptible to unique therapeutic approaches.…”

“…Cachexia is clinically defined by certain thresholds of weight and muscle loss (Fearon et al ., 2011), and most studies evaluating cancer cachexia compare mice with fully developed cachexia against healthy control populations (Arneson-Wissink et al, 2020; Langer et al, 2022; Michaelis et al, 2017; Talbert et al, 2019). Because of the focus on advanced disease, the pre-cachectic state remains poorly defined.…”