Long-term High Fat Ketogenic Diet Promotes Renal Tumor Growth in a Rat Model of Tuberous Sclerosis

Abstract

Nutritional imbalance underlies many disease processes but can be very beneficial in certain cases; for instance, the antiepileptic action of a high fat and low carbohydrate ketogenic diet. Besides this therapeutic feature it is not clear how this abundant fat supply may affect homeostasis, leading to side effects. A ketogenic diet is used as anti-seizure therapy i.a. in tuberous sclerosis patients, but its impact on concomitant tumor growth is not known. To examine this we have evaluated the growth of renal lesions in Eker rats (Tsc2+/−) subjected to a ketogenic diet for 4, 6 and 8 months. In spite of existing opinions about the anticancer actions of a ketogenic diet, we have shown that this anti-seizure therapy, especially in its long term usage, leads to excessive tumor growth. Prolonged feeding of a ketogenic diet promotes the growth of renal tumors by recruiting ERK1/2 and mTOR which are associated with the accumulation of oleic acid and the overproduction of growth hormone. Simultaneously, we observed that Nrf2, p53 and 8-oxoguanine glycosylase α dependent antitumor mechanisms were launched by the ketogenic diet. However, the pro-cancerous mechanisms finally took the ascendency by boosting tumor growth.

Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics

“…While epidemiological associations among obesity, cancer, and ketogenic diets are debated (Liskiewicz et al, 2016; Wright and Simone, 2016), a meta-analysis using ketogenic diets in animal models and in human studies suggested a salutary impact on survival, with benefits prospectively linked to the magnitude of ketosis, time of diet initiation, and tumor location (Klement et al, 2016; Woolf et al, 2016). Treatment of pancreatic cancer cells with ketone bodies ( d -βOHB or AcAc) inhibited growth, proliferation and glycolysis, and a ketogenic diet (81% kcal fat, 18% protein, 1% carbohydrate) reduced in vivo tumor weight, glycemia, and increased muscle and body weight in animals with implanted cancer (Shukla et al, 2014).…”

Beneficial Effects of Ketogenic Diets for Cancer Patients – A Realist Review With Focus on Evidence and Confirmation

“…In total, 72% (21/29) of the animal studies provided evidence for anti-tumor effects of the KD, while in only one study evidence for pro-tumor effects was found. Noteworthy, this study [64] provided evidence for both anti-and pro-tumor effects, depending on the length of the KD feeding period. The two meta-analyses concluded that there is overall evidence for anti-tumor effects of KDs in mice [70,71].…”

Roles of Lipids in Cancer

“…A second aspect to the role of lipids in promoting cancer is the influence of exogenous sources of lipids in facilitating tumorigenesis and metastasis. Numerous studies have experimented with high lipid content diets using mouse models and reported increases in tumour growth and/or metastasis, implicating high fat ketogenic diets [34][35][36] or specific lipids such as cholesterol [37] or palmitic acid [38] in promoting cancer. There is a variety of mechanisms by which high concentrations of dietary lipids can exert a tumorigenic effect.…”

“…There is a variety of mechanisms by which high concentrations of dietary lipids can exert a tumorigenic effect. According to Liśkiewicz and colleagues, their high fat ketogenic diet administered ad libitum to mice led to activation of ERK1/2 which controls cell proliferation, differentiation and survival [39], as well as elevated mTOR signalling in renal tumours [34]. In a different study, high fat diets caused acetoacetate levels in the serum of recipient mice to increase, subsequently leading to enhanced tumour growth of xenograft human melanoma cells with a V600E mutation in the BRAF gene [35].…”