Induction of ketosis in rats fed low-carbohydrate, high-fat diets depends on the relative abundance of dietary fat and protein

Bielohuby, Maximilian; Menhofer, Dominik; Kirchner, Henriette; Stoehr, Barbara J. M.; Müller, Timo; Stock, Peggy; Hempel, M; Stemmer, Kerstin; Pfluger, Paul T.; Kienzle, Ellen; Christ, Bruno; Tschöp, Matthias H.; Bidlingmaier, Martin

doi:10.1152/ajpendo.00478.2010

Cited by 81 publications

(71 citation statements)

References 48 publications

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“…27,30). This is consistent with very recent studies showing that ketosis requires high dietary fat (31) and suggests that ketosis does not contribute to the slower tumor growth we observe with our low CHO diets.…”

Section: % Chosupporting

confidence: 93%

A Low Carbohydrate, High Protein Diet Slows Tumor Growth and Prevents Cancer Initiation

et al. 2011

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Since cancer cells depend on glucose more than normal cells, we compared the effects of low carbohydrate (CHO) diets to a Western diet on the growth rate of tumors in mice. To avoid caloric restriction-induced effects, we designed the low CHO diets isocaloric with the Western diet by increasing protein rather than fat levels because of the reported tumor-promoting effects of high fat and the immune-stimulating effects of high protein.We found that both murine and human carcinomas grew slower in mice on diets containing low amylose CHO and high protein compared with a Western diet characterized by relatively high CHO and low protein. There was no weight difference between the tumor-bearing mice on the low CHO or Western diets.Additionally, the low CHO-fed mice exhibited lower blood glucose, insulin, and lactate levels. Additive antitumor effects with the low CHO diets were observed with the mTOR inhibitor CCI-779 and especially with the COX-2 inhibitor Celebrex, a potent anti-inflammatory drug. Strikingly, in a genetically engineered mouse model of HER-2/neu-induced mammary cancer, tumor penetrance in mice on a Western diet was nearly 50% by the age of 1 year whereas no tumors were detected in mice on the low CHO diet. This difference was associated with weight gains in mice on the Western diet not observed in mice on the low CHO diet. Moreover, whereas only 1 mouse on the Western diet achieved a normal life span, due to cancer-associated deaths, more than 50% of the mice on the low CHO diet reached or exceeded the normal life span. Taken together, our findings offer a compelling preclinical illustration of the ability of a low CHO diet in not only restricting weight gain but also cancer development and progression. Cancer Res; 71(13); 4484-93. Ó2011 AACR.

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Section: % Chosupporting

confidence: 93%

A Low Carbohydrate, High Protein Diet Slows Tumor Growth and Prevents Cancer Initiation

et al. 2011

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“…Notably, carbohydrate supplementation in animals on a ketogenic diet had no effect on FGF21 levels, confirming that dietary protein restriction underlies the increased levels of circulating FGF21 typically observed after feeding with a ketogenic diet. These data confirm and extend the findings of a previous study by Bielohuby and colleagues, in which they demonstrated that circulating FGF21 levels are increased in rats fed a ketogenic diet limited to 10% protein, but not in rats fed an isocaloric ketogenic diet comprising 20% or 30% protein (10).…”

Section: A Low-protein Diet Induces Fgf21 Expressionsupporting

confidence: 92%

Play down protein to play up metabolism?

Müller¹,

Tschöp²

2014

J. Clin. Invest.

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C o m m e n t a r y FGF21 production benefits energy metabolismAfter an exhausting day and when craving dinner, not many of us appreciate that over the course of the day, various signaling molecules have been delivered into the bloodstream in order to cope with continually changing energy demands without a sacrifice in optimal function. One of the key players in fine-tuning the endocrine machinery is FGF21, which has widely been considered a fasting-induced hormone. Primarily expressed in the liver and adipose tissue (1, 2), FGF21 exerts a number of beneficial effects on energy metabolism (Figure 1), making it a popular drug target for the pharmaceutical industry. In adipose tissue, FGF21 has been reported to promote glucose uptake in an insulinindependent fashion, and this FGF21-dependent glucose uptake appears to be mediated through modulation of glucose transporter GLUT1 expression and is additive to the glycemic action of insulin (3).In line with its participation in glycemic regulation, FGF21 enhances hepatic gluconeogenesis and helps maintain normoglycemia under conditions of increased glucose utilization. FGF21 also lowers body weight by increasing energy expenditure, an effect that seemingly involves FGF21 signaling in both the CNS (4) and the periphery (5). Based on its combined effects on both glucose homeostasis and energy expenditure, FGF21 is considered a potential weapon against the negative metabolic consequences associated with the metabolic syndrome. A low-protein diet induces FGF21 expressionCurrent thought is that FGF21 is a fasting hormone secreted from the liver into circulation in response to increased fatty acid oxidation, as occurs after fasting or exposure to a ketogenic diet (6-8). While numerous studies have established that levels of circulating FGF21 increase under conditions of nutrient deprivation, the exact physiologic stimulus that regulates FGF21 secretion has been elusive. In this issue, Laeger et al. provide an answer to this important problem and demonstrate that serum levels of FGF21 increase specifically upon exposure to low-protein (LP) diets, regardless of overall caloric intake, in both rodents and humans (9). Laeger et al. assessed hepatic FGF21 expression in rats following exposure to a diet either low in protein, low in energy, or low in both. In this feeding paradigm, rats restricted for dietary protein but not energy intake displayed a robust increase in hepatic FGF21 expression. In contrast, rats that were energy restricted but not protein restricted showed decreased levels of FGF21. Importantly, Laeger et al. corroborated this observation in humans by demonstrating increased FGF21 levels in participants of a clinical study that were fed a LP diet. Next, Laeger et al. assessed FGF21 levels upon fasting and refeeding and observed that the fasting-induced increase in FGF21 is potentiated by refeeding with an LP diet, but not a high-protein diet. To this end, protein supplementation in mice fed a ketogenic diet lowered FGF21 levels to approximately 50% of the level ob...

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“…This observation plus the striking effects of FGF21 on carbohydrate and lipid metabolism has prompted studies investigating the regulation of hepatic FGF21 expression in intact animals. Feeding mice a high fat, low carbohydrate (HF-LC) 2 ketogenic diet stimulates a 5-25-fold increase in hepatic FGF21 mRNA abundance (10,11), an effect * This work was supported by American Diabetes Association Basic Science that is associated with a 1.7-9-fold elevation in FGF21 levels in the blood (10,12,13). This finding has led to the proposal that alterations in hepatic FGF21 expression play a role in mediating changes in carbohydrate and lipid metabolism caused by HF-LC ketogenic diet consumption.…”

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confidence: 99%

Activation of the Farnesoid X Receptor Induces Hepatic Expression and Secretion of Fibroblast Growth Factor 21

Cyphert

Kohan

et al. 2012

Journal of Biological Chemistry

132

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Background:The hormone FGF21 is a potent regulator of carbohydrate and lipid metabolism and a promising drug for treating metabolic syndrome. Results: Farnesoid X receptor (FXR) agonists and FGF19 induce hepatic FGF21 secretion via a transcriptional mechanism and posttranscriptional mechanism, respectively. Conclusion: Activation of the FXR pathway stimulates FGF21 expression and secretion. Significance: Activation of FXR is a potential approach to enhance endogenous FGF21 production and reverse metabolic syndrome.

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Induction of ketosis in rats fed low-carbohydrate, high-fat diets depends on the relative abundance of dietary fat and protein

Cited by 81 publications

References 48 publications

A Low Carbohydrate, High Protein Diet Slows Tumor Growth and Prevents Cancer Initiation

A Low Carbohydrate, High Protein Diet Slows Tumor Growth and Prevents Cancer Initiation

Play down protein to play up metabolism?

Activation of the Farnesoid X Receptor Induces Hepatic Expression and Secretion of Fibroblast Growth Factor 21

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