Calorie-restricted Ketogenic Diet Research Articles

Significance of Calorie-Restricted Ketogenic Diet for Lung Cancer with Brain Metastases and Hepatoma with Pulmonary Metastases: Two Case Reports

Background: Cancer cells have altered metabolism that is characterized by an enhanced uptake and utilization of glucose. These increased glucose dependence alterations, present potential vulnerabilities that could be targeted for cancer therapy. The calorie-restricted ketogenic diet (KD) may meet the requirement. Case presentation: We present two cases of patients diagnosed with aggressive forms of cancer, lung cancer with brain metastatic tomours and primary liver cancer with pulmonary metastases. The patients began KD intervention after exhausting the other treatment options. Both of them responded to KD and demonstrated a beneficial effect. The tomour size from serial imaging and serum tumour markers were significantly reduced after KD in both subjects without any adverse effects. Both patients had tumour remission even after stopping the ketogenic diet, indicating that KD is a safe, effective treatment for aggressive cancers with metastases when used with conventional therapies. Conclusion: This study demonstrated the significant beneficial effect of a calorie-restricted ketogenic diet for two types of aggressive cancers with metastases. Even a brief KD intervention has a profound effect, implicating the significant therapeutic potential for the ketogenic diet as adjuvant therapy for cancer treatment.

Significance of Calorie-Restricted Ketogenic Diet for Lung Cancer with Brain Metastases and Hepatoma with Pulmonary Metastases: Two Case Reports

Background: Cancer cells have altered metabolism that is characterized by an enhanced uptake and utilization of glucose. These increased glucose dependence alterations, present potential vulnerabilities that could be targeted for cancer therapy. The calorie-restricted ketogenic diet (KD) may meet the requirement.

Recurrent acute pancreatitis during a ketogenic diet\u2014a case report and literature review

BackgroundThe ketogenic (“keto”) diet has been gaining more attention lately in the medical literature and the lay media as a potentially effective method for weight control and management of type 2 diabetes. Though rare, there have been case reports of serious side effects. Here, we present a peculiar case of pancreatitis presumably associated with the ketogenic diet.Case presentationA 35-year-old man on a calorie-restricted ketogenic diet presented to the emergency department with weekly abdominal pain on Monday mornings, each time after dietary indiscretions (“cheat days”) on the weekend. It was found that he had a clinical presentation consistent with acute pancreatitis with no associated alcohol use, hypertriglyceridemia, pancreatic obstruction, or other anatomic abnormalities. The patient’s symptoms resolved with conservative management and progressive reintroduction of a standard diet.ConclusionThis case indicates that the ketogenic diet could lower the threshold for acute pancreatitis, and that an episodic stressor may trigger an acute attack in the absence of traditional risk factors.

OS05.9.A Short-term fasting in glioma patients - Analysis of diet diaries and metabolic parameters of the ERGO2 trial

Abstract BACKGROUND The prospective, randomized ERGO2 trial investigated the effect of fasting / calorie restricted ketogenic diet (KD-IF) on re-irradiation for recurrent brain tumors (Clinicaltrials.gov number: NCT01754350). The study did not meet its primary endpoint of improved progression-free survival in comparison to a standard diet (SD). We here report the results of the quality of life questionnaire, neurocognition testing, detailed analysis of the diet diaries and the alterations of metabolic parameters. MATERIAL AND METHODS 50 Patients were randomized 1:1 to re-irradiation combined with either SD or KD-IF. The KD-IF schedule included 3 days of ketogenic diet (KD: 21–23 kcal/kg/d, carbohydrate intake limited to 50 g/d), followed by 3 days of fasting and again 3 days of KD. Follow-up included examination of cognition, quality of life and serum samples. RESULTS The 20 patients who completed KD-IF met the prespecified goals for calorie and carbohydrate restriction. In these, a decrease in leptin and insulin and an increase in uric acid was observed. The SD group had a lower calorie intake of 21 kcal/kg/d than the expected 30 kcal/kg/d. Neither quality of life nor cognition were affected by the diet. Low glucose emerged as a significant prognostic parameter in a best responder analysis. CONCLUSION The strict caloric goals of the ERGO2 trial could be achieved by patients with recurrent brain tumor. The unexpected lower calorie intake of the SD group might have hampered the interpretation of the trial. However, the short diet schedule already led to significant metabolic alterations, suggesting that short-term dietary interventions might be therapeutically useful, possibly combined with other modalities.

Short-term fasting in glioma patients: analysis of diet diaries and metabolic parameters of the ERGO2 trial

PurposeThe prospective, randomized ERGO2 trial investigated the effect of calorie-restricted ketogenic diet and intermittent fasting (KD-IF) on re-irradiation for recurrent brain tumors. The study did not meet its primary endpoint of improved progression-free survival in comparison to standard diet (SD). We here report the results of the quality of life/neurocognition and a detailed analysis of the diet diaries.Methods50 patients were randomized 1:1 to re-irradiation combined with either SD or KD-IF. The KD-IF schedule included 3 days of ketogenic diet (KD: 21–23 kcal/kg/d, carbohydrate intake limited to 50 g/d), followed by 3 days of fasting and again 3 days of KD. Follow-up included examination of cognition, quality of life and serum samples.ResultsThe 20 patients who completed KD-IF met the prespecified goals for calorie and carbohydrate restriction. Substantial decreases in leptin and insulin and an increase in uric acid were observed. The SD group, of note, had a lower calorie intake than expected (21 kcal/kg/d instead of 30 kcal/kg/d). Neither quality of life nor cognition were affected by the diet. Low glucose emerged as a significant prognostic parameter in a best responder analysis.ConclusionThe strict caloric goals of the ERGO2 trial were tolerated well by patients with recurrent brain cancer. The short diet schedule led to significant metabolic changes with low glucose emerging as a candidate marker of better prognosis. The unexpected lower calorie intake of the control group complicates the interpretation of the results.Clinicaltrials.gov number: NCT01754350; Registration: 21.12.2012.

ERGO2: A Prospective, Randomized Trial of Calorie-Restricted Ketogenic Diet and Fasting in Addition to Reirradiation for Malignant Glioma

ERGO2 is the first randomized clinical trial on a calorically restricted ketogenic diet (KD) and intermittent fasting (KD-IF) in addition to reirradiation for recurrent malignant gliomas. Fifty patients were randomized 1:1 to reirradiation combined with either a calorically unrestricted diet or KD-IF. The KD-IF schedule included 3 days of KD (21-23 kcal/kg/d), followed by 3 days of fasting and again 3 days of KD. Primary endpoint was progression-free survival (PFS) at 6 months (PFS6). Secondary endpoints were PFS, local PFS, overall survival (OS), frequency of epileptic seizures, rate of ketosis and quality of life. Four patients quit the trial before treatment and 3 patients stopped KD-IF prematurely. Of the 20 patients who completed KD-IF, 17 patients developed ketosis at day 6 and glucose levels declined significantly. KD-IF was well-tolerated with a modest weight loss of -2.1 ± 1.8 kg. No severe adverse events attributable to the diet occurred. PFS6 was not significantly different between the 2 groups (KD-IF: 20%; calorically unrestricted diet: 16%). Similarly, no difference in PFS, local PFS6, or OS was observable. Explorative analysis revealed that patients in the KD-IF group who had a glucose level of less than the median (83.5 mg/dL) on day 6 had significantly longer PFS and OS compared with those above the median (P < .05). KD-IF is feasible and effective in inducing ketosis in heavily pretreated patients with recurrent glioma. However, the short schedule reported here failed to increase the efficacy of reirradiation. CLINICALTRIALS. NCT01754350.

A Calorie-Restricted Ketogenic Diet Reduces Cerebral Cortex Vascularization in Prepubertal Rats.

The antiepileptic effect of ketogenic diets is acknowledged but its mechanism of action is poorly understood. The present work aimed to evaluate possible effects of a calorie-restricted ketogenic diet (CRKD) on brain growth and angiogenesis in normal prepubertal rats. Two groups of prepubertal rats were fed with a standard diet (group 1) or a CRKD (group 2) for ten weeks. Then, rats were sacrificed and the thickness for the following structures was evaluated by histology: (1) cerebral cortex, (2) deep cerebral white matter, and (3) substantia nigra. The capillary density was also evaluated within: (1) cerebral cortex, (2) dentate gyrus of the hippocampus, (3) periaqueductal grey matter, and (4) substantia nigra. The results showed a smaller thickness of all the areas examined and a reduced capillary density within the cerebral cortex in the CRKD-treated group compared to the control group. These findings suggest an association between reduced angiogenesis within the cerebral cortex and the antiepileptic effects of CRKD.

Combination of metronomic cyclophosphamide and dietary intervention inhibits neuroblastoma growth in a CD1-nu mouse model.

BackgroundMYCN-amplification in high-grade Neuroblastoma (NB) tumors correlates with increased vascularization and therapy resistance. This study combines an anti-angiogenic approach with targeting NB metabolism for treatment.Methods and ResultsMetronomic cyclophosphamide (MCP) monotherapy significantly inhibited NB growth and prolonged host survival. Growth inhibition was more pronounced in MYCN-amplified xenografts. Immunohistochemical evaluation of this subtype showed significant decrease in blood vessel density and intratumoral hemorrhage accompanied by blood vessel maturation and perivascular fibrosis. Up-regulation of VEGFA was not sufficient to compensate for the effects of the MCP regimen. Reduced Bcl-2 expression and increased caspase-3 cleavage were evident. In contrast non MYCN-amplified tumors developed resistance, which was accompanied by Bcl-2-up-regulation. Combining MCP with a ketogenic diet and/or calorie-restriction significantly enhanced the anti-tumor effect. Calorie-restricted ketogenic diet in combination with MCP resulted in tumor regression in all cases.ConclusionsOur data show efficacy of combining an anti-angiogenic cyclophosphamide dosing regimen with dietary intervention in a preclinical NB model. These findings might open a new front in NB treatment.

Inhibition of Neuroblastoma Tumor Growth by Ketogenic Diet and/or Calorie Restriction in a CD1-Nu Mouse Model.

IntroductionNeuroblastoma is a malignant pediatric cancer derived from neural crest cells. It is characterized by a generalized reduction of mitochondrial oxidative phosphorylation. The goal of the present study was to investigate the effects of calorie restriction and ketogenic diet on neuroblastoma tumor growth and monitor potential adaptive mechanisms of the cancer’s oxidative phosphorylation system.MethodsXenografts were established in CD-1 nude mice by subcutaneous injection of two neuroblastoma cell lines having distinct genetic characteristics and therapeutic sensitivity [SH-SY5Y and SK-N-BE(2)]. Mice were randomized to four treatment groups receiving standard diet, calorie-restricted standard diet, long chain fatty acid based ketogenic diet or calorie-restricted ketogenic diet. Tumor growth, survival, metabolic parameters and weight of the mice were monitored. Cancer tissue was evaluated for diet-induced changes of proliferation indices and multiple oxidative phosphorylation system parameters (respiratory chain enzyme activities, western blot analysis, immunohistochemistry and mitochondrial DNA content).ResultsKetogenic diet and/or calorie restriction significantly reduced tumor growth and prolonged survival in the xenograft model. Neuroblastoma growth reduction correlated with decreased blood glucose concentrations and was characterized by a significant decrease in Ki-67 and phospho-histone H3 levels in the diet groups with low tumor growth. As in human tumor tissue, neuroblastoma xenografts showed distinctly low mitochondrial complex II activity in combination with a generalized low level of mitochondrial oxidative phosphorylation, validating the tumor model. Neuroblastoma showed no ability to adapt its mitochondrial oxidative phosphorylation activity to the change in nutrient supply induced by dietary intervention.ConclusionsOur data suggest that targeting the metabolic characteristics of neuroblastoma could open a new front in supporting standard therapy regimens. Therefore, we propose that a ketogenic diet and/or calorie restriction should be further evaluated as a possible adjuvant therapy for patients undergoing treatment for neuroblastoma.

The role of metabolic therapy in treating glioblastoma multiforme.

Glioblastoma multiforme (GBM) is an aggressive and nearly uniformly fatal malignancy of the central nervous system. Despite extensive research and clinical trials over the past 50 years, very little progress has been made to significantly alter its lethal prognosis. The current standard of care (SOC) includes maximal surgical resection, radiation therapy and chemotherapy and temozolomide (TMZ), including the selective use of glucocorticoids for symptom control. These same treatments, however, have the potential to create an environment that may actually facilitate tumor growth and survival. Research investigating the unique metabolic needs of tumor cells has led to the proposal of a new metabolic treatment for various cancers including GBMs that may enhance the effectiveness of the SOC. The goal of metabolic cancer therapy is to restrict GBM cells of glucose, their main energy substrate. By recognizing the underlying energy production requirements of cancer cells, newly proposed metabolic therapy is being used as an adjunct to standard GBM therapies. This review will discuss the calorie restricted ketogenic diet (CR-KD) as a promising potential adjunctive metabolic therapy for patients with GBMs. The effectiveness of the CR-KD is based on the “Warburg Effect” of cancer metabolism and the microenvironment of GBM tumors. We will review recent case reports, clinical studies, review articles, and animal model research using the CR-KD and explain the principles of the Warburg Effect as it relates to CR-KD and GBMs.

Metabolic therapy: A new paradigm for managing malignant brain cancer

Little progress has been made in the long-term management of glioblastoma multiforme (GBM), considered among the most lethal of brain cancers. Cytotoxic chemotherapy, steroids, and high-dose radiation are generally used as the standard of care for GBM. These procedures can create a tumor microenvironment rich in glucose and glutamine. Glucose and glutamine are suggested to facilitate tumor progression. Recent evidence suggests that many GBMs are infected with cytomegalovirus, which could further enhance glucose and glutamine metabolism in the tumor cells. Emerging evidence also suggests that neoplastic macrophages/microglia, arising through possible fusion hybridization, can comprise an invasive cell subpopulation within GBM. Glucose and glutamine are major fuels for myeloid cells, as well as for the more rapidly proliferating cancer stem cells. Therapies that increase inflammation and energy metabolites in the GBM microenvironment can enhance tumor progression. In contrast to current GBM therapies, metabolic therapy is designed to target the metabolic malady common to all tumor cells (aerobic fermentation), while enhancing the health and vitality of normal brain cells and the entire body. The calorie restricted ketogenic diet (KD-R) is an anti-angiogenic, anti-inflammatory and pro-apoptotic metabolic therapy that also reduces fermentable fuels in the tumor microenvironment. Metabolic therapy, as an alternative to the standard of care, has the potential to improve outcome for patients with GBM and other malignant brain cancers.

Metabolic management of glioblastoma multiforme using standard therapy together with a restricted ketogenic diet: Case Report

BackgroundManagement of glioblastoma multiforme (GBM) has been difficult using standard therapy (radiation with temozolomide chemotherapy). The ketogenic diet is used commonly to treat refractory epilepsy in children and, when administered in restricted amounts, can also target energy metabolism in brain tumors. We report the case of a 65-year-old woman who presented with progressive memory loss, chronic headaches, nausea, and a right hemisphere multi-centric tumor seen with magnetic resonance imaging (MRI). Following incomplete surgical resection, the patient was diagnosed with glioblastoma multiforme expressing hypermethylation of the MGMT gene promoter.MethodsPrior to initiation of the standard therapy, the patient conducted water-only therapeutic fasting and a restricted 4:1 (fat: carbohydrate + protein) ketogenic diet that delivered about 600 kcal/day. The patient also received the restricted ketogenic diet concomitantly during the standard treatment period. The diet was supplemented with vitamins and minerals. Steroid medication (dexamethasone) was removed during the course of the treatment. The patient was followed using MRI and positron emission tomography with fluoro-deoxy-glucose (FDG-PET).ResultsAfter two months treatment, the patient's body weight was reduced by about 20% and no discernable brain tumor tissue was detected using either FDG-PET or MRI imaging. Biomarker changes showed reduced levels of blood glucose and elevated levels of urinary ketones. MRI evidence of tumor recurrence was found 10 weeks after suspension of strict diet therapy.ConclusionThis is the first report of confirmed GBM treated with standard therapy together with a restricted ketogenic diet. As rapid regression of GBM is rare in older patients following incomplete surgical resection and standard therapy alone, the response observed in this case could result in part from the action of the calorie restricted ketogenic diet. Further studies are needed to evaluate the efficacy of restricted ketogenic diets, administered alone or together with standard treatment, as a therapy for GBM and possibly other malignant brain tumors.

Caloric restriction augments brain glutamic acid decarboxylase-65 and -67 expression.

The ketogenic diet is a very low-carbohydrate, high-fat diet used to treat refractory epilepsy. We hypothesized that this diet may act by increasing expression of glutamic acid decarboxylase (GAD), the rate-limiting enzyme in gamma-aminobutyric acid (GABA) synthesis. Thus, we evaluated brain GAD levels in a well-established, seizure-suppressing, rodent model of the ketogenic diet. Because the diet is most effective when administered with a modest ( approximately 10%) calorie restriction, we studied three groups of animals: rats fed ad libitum standard rat chow (Ad lib-Std); calorie-restricted standard chow (CR-Std); and an isocaloric, calorie-restricted ketogenic diet (CR-Ket). We found that GAD67 mRNA was significantly increased in the inferior and superior colliculi and cerebellar cortex in both CR diet groups compared with control (e.g., by 45% in the superior colliculus and by 71% in the cerebellar cortex; P <.001). GAD65 mRNA was selectively increased in the superior colliculus and temporal cortex in both CR-Std and CR-Ket diet groups compared with ad lib controls. The only apparent CR-Ket-specific effect was a 30% increase in GAD67 mRNA in the striatum (P =.03). Enhanced GAD immunoreactivity was detected in parallel with the mRNA changes. These data clearly show that calorie restriction increases brain GAD65 and -67 expression in several brain regions, independent of ketogenic effects. These observations may explain why caloric restriction improves the efficacy of the ketogenic diet in treating epilepsy and suggest that diet modification might be useful in treatment of a number of brain disorders characterized by impaired GAD or GABA activity.

A ketogenic diet increases brain insulin-like growth factor receptor and glucose transporter gene expression.

A ketogenic diet suppresses seizure activity in children and in juvenile rats. To investigate whether alteration in brain IGF activity could be involved in the beneficial effects of the ketogenic diet, we examined the effects of this diet on IGF system gene expression in the rat brain. Juvenile rats were fed one of three different diets for 7 d: ad libitum standard rat chow (AL-Std), calorie-restricted standard chow (CR-Std), or a calorie-restricted ketogenic diet (CR-Ket). The calorie-restricted diets contained 90% of the rats' calculated energy requirements. The AL-Std diet group increased in weight, whereas the two CR groups merely maintained their weight during the 7-d diet. Glucose levels were significantly reduced in both CR groups compared with the AL-Std group, but only the CR-Ket group developed ketonemia. IGF1 mRNA levels were reduced by 30-50% in most brain regions in both CR groups. IGF1 receptor (IGF1R) mRNA levels were decreased in the CR-Std group but were increased in the CR-Ket diet group. Brain IGF binding protein (IGFBP)-2 and -5 mRNA levels were not altered by diet, but IGFBP-3 mRNA levels were markedly increased by the ketogenic diet while not altered by calorie restriction alone. Brain glucose transporter expression was also investigated in this study. Glucose transporter (GLUT) 4 mRNA levels were quite low and not appreciably altered by the different diets. Parenchymal GLUT1 mRNA levels were increased by the CR-Ket diet, but endothelial GLUT1 mRNA levels were not affected. Neuronal GLUT3 expression was decreased with the CR-Std diet and increased with the CR-Ket diet, in parallel with the IGF1R pattern. These observations reveal divergent effects of dietary caloric content and macronutrient composition on brain IGF system and GLUT expression. In addition, the data may be consistent with a role for enhanced IGF1R and GLUT expression in ketogenic diet-induced seizure suppression.

Effects of acute inhibition of fatty acid oxidation on latency to seizure and concentrations of β hydroxybutyrate in plasma of rats maintained on calorie restriction and/or the ketogenic diet

The present study was designed to evaluate the effects of acute inhibition of fatty acid oxidation on plasma levels of β hydroxybutyrate and latency to PTZ-induced seizures in ad libitum- (AL), calorie-restricted normal rodent chow- (CR), and calorie-restricted ketogenic diet (KD)-fed young rats. Young (day 23) Sprague–Dawley rats were fasted for 8 h and then fed their respective diets for 21 days. On day 21 of the diet rats in each group received either saline or the fatty acid oxidation inhibitor mercaptoacetate (MA; 46 mg/kg intraperitoneally (i.p.). Two hours later, all rats received pentylenetetrazole (PTZ; 10 mg/kg; i.p.) every 10 min until seizure onset. Results demonstrated that KD-fed rats had the longest ( P<0.05) latency to PTZ-induced seizures. KD-fed rats administered an acute dose of MA had lower ( P<0.01) levels of β hydroxybutyrate in plasma and shorter latency to PTZ-induced seizures compared with control KD-fed rats. However, there was not a significant positive correlation ( P>0.10) between plasma β hydroxybutyrate and latency to seizure, suggesting that β hydroxybutyrate may be indirectly involved in the antiseizure effects of the KD. Fatty acid oxidation inhibition represents an experimental manipulation that may allow for more precise establishment and evaluation of levels of β hydroxybutyrate in plasma necessary for antiseizure effects of the KD.

The ketogenic diet upregulates expression of the gene encoding the key ketogenic enzyme mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in rat brain

The ketogenic diet is a clinically and experimentally effective anti-epileptic treatment whose molecular mechanism(s) of action remain to be elucidated. As a first step in defining its effects on regulation of fatty acid oxidation and ketogenesis at the genetic level, we have administered to rats: (1) a calorie-restricted ketogenic diet (KCR); (2) a calorie-restricted normal diet (NCR); or (3) a normal diet ad libitum (NAL). We have used RNase protection to co-assay diet-induced changes in abundance of the mRNA encoding the critical enzyme of ketogenesis from acetyl-CoA namely mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHS) in liver and brain, together with mRNAs encoding three other key enzymes of fatty acid oxidation. We demonstrate that NCR-fed rats exhibit a significant 2-fold increase in liver mHS mRNA compared to NAL-fed rats, and that KCR-fed rats exhibit a significant 2-fold increase in both liver and brain mHS mRNA compared to NAL-fed rats. Our results demonstrate, for the first time, the effect of a ketogenic diet on gene expression in brain, and suggest possible anti-epileptic mechanisms for future investigation.

A ketogenic diet has different effects upon seizures induced by maximal electroshock and by pentylenetetrazole infusion

The purpose of these experiments was to determine whether a ketogenic diet previously shown to elevate seizure threshold also reduced seizure severity. Seizure threshold was tested by intravenous infusion of pentylenetetrazole (PTZ) whereas seizure severity was determined from measuring the hindlimb extension to flexion (E/F) ratio after seizures were evoked by maximal electroshock stimulation (MES). Surprisingly, seizures evoked by MES were more severe in animals fed a calorie-restricted ketogenic diet. Controls fed an isocaloric, calorie-restricted normal diet also exhibited more severe seizures than did animals fed the same diet ad libitum. When seizure threshold was evaluated in the same animals, those animals fed a calorie-restricted ketogenic diet exhibited a significant increase in seizure resistance compared to animals fed a ketogenic diet ad libitum, a calorie-restricted normal diet or a normal diet ad libitum. These findings suggest that both the amount and type of food affect seizures in rats and show that diet-related seizure protection depends upon the method by which seizures are provoked.

Seizure resistance is dependent upon age and calorie restriction in rats fed a ketogenic diet.

The present study was designed to evaluate the effects of age on the efficacy of the ketogenic diet in suppressing seizures evoked by tail-vein infusion of pentylenetetrazole (PTZ). Male rats of various ages were divided into three groups and fed one of three diets: (1) a calorie-restricted ketogenic diet, (2) a calorie-restricted normal (rodent chow) diet, or (3) a normal diet, ad libitum. After animals had been on experimental or control diets for more than 20 days, seizure threshold and blood levels of beta-hydroxybutyrate (beta-OHB) were determined. Animals fed a ketogenic diet exhibited significant elevations in levels of beta-OHB and seizure resistance compared to animals fed either a calorie-restricted normal diet or a normal diet, ad libitum. The levels of beta-OHB and seizure resistance were greatest for young pups. A surprising finding was that young animals fed a calorie-restricted rodent chow diet exhibited a significantly increased resistance to seizures compared to those fed the same diet, ad libitum. Results presented here demonstrate that the ketogenic diet produces the highest levels of ketonemia and seizure threshold in young animals. Collectively, these data suggest that age and caloric restriction are important considerations for implementing the ketogenic diet.

Prior Carbohydrate Consumption Affects the Amount of Carbohydrate that Rats Choose to Eat

Consumption of protein-rich, carbohydrate-restricted reducing diets has been associated anecdotally with an increased appetite for carbohydrate. We have tested the effect of such a diet on carbohydrate intake by rats. Rats were given either a calorie-restricted ketogenic diet containing protein and fat or a control diet containing carbohydrate along with the protein and fat. When allowed to choose from a pair of isocaloric, isonitrogenous diets containing 25 or 75% dextrin, ketotic rats ate significantly more carbohydrate and total food than control animals during the first 30 minutes of feeding, apparently requiring more of the carbohydrate to obtain an increase in brain tryptophan similar to controls. Ketotic rats ate a significantly higher proportion of total calories as carbohydrate. Similar results were obtained when sucrose replaced dextrin. When ketotic and control rats chose between two diets differing in proportions of fat or protein, no differences were observed between the groups in total food intake nor in the amounts or proportions of fat or protein eaten. We also compared the effects of a small, isocaloric premeal containing only carbohydrate (1.4 g dextrose) or mixed nutrients on subsequent carbohydrate consumption in otherwise untreated rats allowed to choose from 25 and 75% dextrin diets. Rats eating the carbohydrate premeal subsequently ate as much total food as the mixed-nutrient controls, but significantly less carbohydrate. These observations suggest that carbohydrate intake is influenced by prior nutrient consumption and that prolonged deprivation of carbohydrate can lead to over-consumption of this nutrient when it is reintroduced into the diet.