High-carbohydrate Low-fat Diet Research Articles

Development of hepatocellular cancer induced by long term low fat-high carbohydrate diet in a NAFLD/NASH mouse model.

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease. It can progress to nonalcoholic steatohepatitis (NASH) and, in a percentage of cases, to hepatocarcinogenesis. The strong incidence in western countries of obesity and metabolic syndrome, whose NAFLD is the hepatic expression, is thought to be correlated to consumption of diets characterized by processed food and sweet beverages. Previous studies described high-fat diet-induced liver tumors. Conversely, the involvement of low-fat/high-carbohydrate diet in the progression of liver disease or cancer initiation has not been described yet. Here we show for the first time hepatic cancer formation in low-fat/high-carbohydrate diet fed NAFLD/NASH mouse model. Animals were long term high-fat, low-fat/high-carbohydrate or standard diet fed. We observed progressive liver damage in low-fat/high-carbohydrate and high-fat animals after 12 and, more, 18 months. Tumors were detected in 20% and 50% of high-fat diet fed mice after 12 and 18 months and, interestingly, in 30% of low-fat/high-carbohydrate fed animals after 18 months. No tumors were detected in standard diet fed mice. Global increase of hepatic interleukin-1β, interleukin-6, tumor necrosis factor-α and hepatocyte growth factor was detected in low-fat/high-carbohydrate and high-fat with respect to standard diet fed mice as well as in tumor with respect to non-tumor bearing mice. A panel of 15 microRNAs was analyzed: some of them revealed differential expression in low-fat/high-carbohydrate with respect to high-fat diet fed groups and in tumors. Data here shown provide the first evidence of the involvement of low-fat/high-carbohydrate diet in hepatic damage leading to tumorigenesis.

Dietary sugars, not lipids, drive hypothalamic inflammation

ObjectiveThe hypothalamus of hypercaloric diet-induced obese animals is featured by a significant increase of microglial reactivity and its associated cytokine production. However, the role of dietary components, in particular fat and carbohydrate, with respect to the hypothalamic inflammatory response and the consequent impact on hypothalamic control of energy homeostasis is yet not clear. MethodsWe dissected the different effects of high-carbohydrate high-fat (HCHF) diets and low-carbohydrate high-fat (LCHF) diets on hypothalamic inflammatory responses in neurons and non-neuronal cells and tested the hypothesis that HCHF diets induce hypothalamic inflammation via advanced glycation end-products (AGEs) using mice lacking advanced glycation end-products (AGEs) receptor (RAGE) and/or the activated leukocyte cell-adhesion molecule (ALCAM). ResultsWe found that consumption of HCHF diets, but not of LCHF diets, increases microgliosis as well as the presence of N(ε)-(Carboxymethyl)-Lysine (CML), a major AGE, in POMC and NPY neurons of the arcuate nucleus. Neuron-secreted CML binds to both RAGE and ALCAM, which are expressed on endothelial cells, microglia, and pericytes. On a HCHF diet, mice lacking the RAGE and ALCAM genes displayed less microglial reactivity and less neovasculature formation in the hypothalamic ARC, and this was associated with significant improvements of metabolic disorders induced by the HCHF diet. ConclusionsCombined overconsumption of fat and sugar, but not the overconsumption of fat per se, leads to excessive CML production in hypothalamic neurons, which, in turn, stimulates hypothalamic inflammatory responses such as microgliosis and eventually leads to neuronal dysfunction in the control of energy metabolism.

Effects Of A Low-carbohydrate Diet And Walking Exercise On Inflammation In Type 2 Diabetes.

Low-carbohydrate high-fat (LCHF) diets are regaining popularity for improving glucose control in patients with type 2 diabetes (T2D). However, largely based on studies in rodents and findings from cell culture models, concern still remains over the possible pro-inflammatory and cardiovascular risk consequences of consuming a diet high in fat. The well-recognized anti-inflammatory and cardioprotective properties of exercise makes it a potential adjuvant to therapeutic LCHF diets. PURPOSE: To determine the impact of a short-term 1) LCHF diet, 2) LCHF diet with daily post-meal walking (LCHF+PW) and 3) low-fat, low glycemic index “guidelines” (G) diet on glucose control, markers of cellular inflammation, and cardiovascular risk factors in patients with T2D. METHODS: Nine individuals with T2D (age: 63±9, HbA1c: 6.7±0.9, means±SD) completed three isocaloric 4-day controlled diet conditions in a randomized crossover design. The LCHF+PW diet included three daily 15-min post meal walks at a light-to-moderate intensity. Glucose profiles were assessed by continuous glucose monitoring. Fasting blood samples were obtained before and after each intervention to measure glucose and lipids. Cellular markers implicated in the pro-inflammatory effects of excess lipids, including monocyte toll-like receptor 2 (TLR2) and 4 (TLR4) and platelet-monocyte aggregates (PMA), were measured by flow cytometry. RESULTS: When compared to G (7.3±1.2 mmol/l), both the LCHF (6.6±1.3 mmol/l) and LCHF+PW (6.4±1.1 mmol/l) diets decreased the 4-day mean glucose concentrations (p<0.001). PMA count per ml increased significantly after G (+27±16%, p=0.02) but was not significantly altered after LCHF (+21±68%, p=0.06) or LCHF+PW (-0.1±42.5%; p=0.99). Median fluorescence intensity of TLR4 on CD16+ monocytes decreased by ~4.3% (p= 0.05) after the LCHF diet. No other significant changes were seen in monocyte TLR2 or TLR4 (all p≥0.106). CONCLUSIONS: As compared to a G diet, four days of a LCHF diet reduced hyperglycemia and improved some inflammatory markers in people with T2D. The addition of three daily post meal walks did not appear to further improve glycemic or inflammatory status. Funding from Canadian Institutes of Health Research (MSH-141980) and Medtronic Diabetes.

Lipid And Glucose Profiles Of Middle-aged Male Runners After 3-week High Fat-low Carbohydrate Diet

PURPOSE: High fat-very low carbohydrate diets (HFLC) have become increasingly popular in the endurance community, but there is little data concerning the effects of HFLC on markers of cardiovascular disease risk. The aim of this study was to examine glucose and lipid marker responses following a prolonged HFLC. METHODS: Eight middle-aged (39.5 ± 9.9 y), trained but non-elite (VO2 peak = 48.5 ± 4.5 ml/kg/min) runners (1.77 ± 0.08 m; 81.7 ± 7.0 kg; 19.3 ± 6% body fat) served as participants. Venous blood was drawn from an antecubital vein after an overnight fast with standardized evening fluid intake on 4 occasions. During the first phase, runners simply consumed their habitual high carbohydrate diet (HC). Blood was collected around 0600 following ~48 h of restriction from any intense exercise. A 50-min run in the heat followed by a 5-km time trial was implemented following blood collection to induce significant heat and exercise stress. A fasted blood sample was acquired the subsequent morning to further delineate the influence of exercise stress. This protocol was repeated after 3 weeks during which time runners continued normal training but consumed <50 g of carbohydrate/day with ~70% of daily calories derived from fat. RESULTS: Diet intervention approached (p = 0.07) but did not reach significance for glucose. Triacylglycerol did not differ between treatments (pre-exercise HC = 65 ± 17; HFLC = 67 ± 35 mg/dL) but decreased (p < 0.05) for both treatments 24-h after exercise (HC = 42 ± 16; HFLC = 35 ± 21 mg/dL). There was a main effect for diet on HDL-C (pre-exercise: HC = 48 ± 10 and 50 ± 11; post-exercise: HFLC = 57 ± 13 and 60 ± 13 mg/dL). There was also a main effect (p = 0.02) for diet on LDL-C with HFLC exceeding HC at both collection points by ~20 mg/dL. Total cholesterol was approximately 30 mg/dL higher for HFLC both before and 24-h after exercise (p < 0.05). There was no change in VLDL-C and Lp(a). CONCLUSION: Implementing a HFLC does not appear to elicit significant negative cardiovascular disease risk in male runners 30-50 years of age with desirable pre-intervention lipid and glucose marker status.

Characterization of fat metabolism in the fatty liver caused by a high-fat, low-carbohydrate diet: A study under equal energy conditions

The pathology of fatty liver due to increased percentage of calories derived from fat without increased overall caloric intake is largely unclear. In this study, we aimed to characterize fat metabolism in rats with fatty liver resulting from consumption of a high-fat, low-carbohydrate (HFLC) diet without increased caloric intake. Four-week-old male Sprague-Dawley rats were randomly assigned to the control (Con) and HFLC groups, and rats were fed the corresponding diets ad libitum. Significant decreases in food intake per gram body weight were observed in the HFLC group compared with that in the Con group. Thus, there were no significant differences in body weights or caloric intake per gram body weight between the two groups. Marked progressive fat accumulation was observed in the livers of rats in the HFLC group, accompanied by suppression of de novo lipogenesis (DNL)-related proteins in the liver and increased leptin concentrations in the blood. In addition, electron microscopic observations revealed that many lipid droplets had accumulated within the hepatocytes, and mitochondrial numbers were reduced in the hepatocytes of rats in the HFLC group. Our findings confirmed that consumption of the HFLC diet induced fatty liver, even without increased caloric intake. Furthermore, DNL was not likely to be a crucial factor inducing fatty liver with standard energy intake. Instead, ultrastructural abnormalities found in mitochondria, which may cause a decline in β-oxidation, could contribute to the development of fatty liver.

Association between a High-fat Low-carbohydrate Diet and Non-alcoholic Fatty Liver Disease: Truth or Myth?

Reducing caloric intake is important for weight loss and obesity; a reduction of ~500-700 kcal/day has been recommended previously. However, only a minority of individuals can successfully sustain such a reduced caloric intake. Therefore, many specialized diet programs have been proposed. Until now, many experts have recommended low-fat diets in various countries, but very-low-carbohydrate diets have recently garnered attention in Korea. The various effects of changing the dietary compositions of macro- and micronutrients have been debated. The majority of large-scale studies have demonstrated that total caloric intake, rather than the composition of macronutrients or the consumption of a specialized diet, is important for successful weight loss. While many cross-sectional studies have investigated specialized diet programs for patients with non-alcoholic liver disease, no randomized controlled studies have been performed, except for some that investigated the effect of high consumption of unsaturated fatty acids as part of the Mediterranean diet. Keywords: Carbohydrate; Fat; Diet; Non-alcoholic fatty liver disease; Nutrition 중심 단어: 탄수화물; 지방; 식이요법; 비알코올지방간질환; 영양분

Low-Carbohydrate-High-Fat Diet: Can it Help Exercise Performance?

Low-carbohydrate-high-fat (LCHF) diets have been used as a means of weight loss and control of symptoms in several clinical conditions. There is emerging evidence that the metabolic changes induced by LCHF diets enhance endurance performance. The aims of this review are to examine the evidence of LCHF diets in improving various aspects of athletic performance. Long-term LCHF dietary intake may help control body weight and fat mass while maintaining lean body mass in athletes in weight-sensitive sports. LCHF-adapted endurance athletes can reach the maximal fat oxidation rate of approximately 1.5 g/min, with a lower carbohydrate oxidation rate and similar muscle glycogen content and a resynthesis rate compared to their counterparts consuming high-carbohydrate-low-fat (HCLF) diets. The elevated fat oxidation rate and glycogen sparing effect may improve performance in ultra-endurance events. These metabolic changes may also prevent the decline in performance in later stages of repeated high-intensity movements, in which the aerobic metabolism becomes more important. However, elevated blood concentrations of non-esterified fatty acids and ammonia during exercise after LCHF diets may lead to early development of central fatigue. It appears that at least several months of adaptation to a LCHF diet are required for the metabolic changes and restoration of muscle glycogen to occur. Further investigations on LCHF diets are needed regarding (1) performance after weight loss in weight-categorized sports; (2) repeated high-intensity exercise performance; (3) development of central fatigue during endurance events; (4) perceptual-motor performance during prolonged intermittent sports; and (5) ideal dietary fatty acid compositions.

Muscle PGC-1α is required for long-term systemic and local adaptations to a ketogenic diet in mice.

Low-carbohydrate/high-fat (LCHF) diets are increasingly popular dietary interventions for body weight control and as treatment for different pathological conditions. However, the mechanisms of action are still poorly understood, in particular, in long-term administration. Besides liver, brain, and heart, skeletal muscle is one of the major organs involved in the regulation of physiological and pathophysiological ketosis. We assessed the role of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in skeletal muscle of male wild-type control and PGC-1α muscle-specific knockout mice upon 12 wk of LCHF diet feeding. Interestingly, LCHF diet administration increased oxygen consumption in a muscle PGC-1α-dependent manner, concomitant with a blunted transcriptional induction of genes involved in fatty acid oxidation and impairment in exercise performance. These data reveal a new role for muscle PGC-1α in regulating the physiological adaptation to long-term LCHF diet administration.

Low carbohydrate, high fat diet impairs exercise economy and negates the performance benefit from intensified training in elite race walkers.

Key points Three weeks of intensified training and mild energy deficit in elite race walkers increases peak aerobic capacity independent of dietary support.Adaptation to a ketogenic low carbohydrate, high fat (LCHF) diet markedly increases rates of whole‐body fat oxidation during exercise in race walkers over a range of exercise intensities.The increased rates of fat oxidation result in reduced economy (increased oxygen demand for a given speed) at velocities that translate to real‐life race performance in elite race walkers.In contrast to training with diets providing chronic or periodised high carbohydrate availability, adaptation to an LCHF diet impairs performance in elite endurance athletes despite a significant improvement in peak aerobic capacity. We investigated the effects of adaptation to a ketogenic low carbohydrate (CHO), high fat diet (LCHF) during 3 weeks of intensified training on metabolism and performance of world‐class endurance athletes. We controlled three isoenergetic diets in elite race walkers: high CHO availability (g kg−1 day−1: 8.6 CHO, 2.1 protein, 1.2 fat) consumed before, during and after training (HCHO, n = 9); identical macronutrient intake, periodised within or between days to alternate between low and high CHO availability (PCHO, n = 10); LCHF (< 50 g day−1 CHO; 78% energy as fat; 2.1 g kg−1 day−1 protein; LCHF, n = 10). Post‐intervention, V˙O2 peak during race walking increased in all groups (P < 0.001, 90% CI: 2.55, 5.20%). LCHF was associated with markedly increased rates of whole‐body fat oxidation, attaining peak rates of 1.57 ± 0.32 g min−1 during 2 h of walking at ∼80% V˙O2 peak . However, LCHF also increased the oxygen (O2) cost of race walking at velocities relevant to real‐life race performance: O2 uptake (expressed as a percentage of new V˙O2 peak ) at a speed approximating 20 km race pace was reduced in HCHO and PCHO (90% CI: −7.047, −2.55 and −5.18, −0.86, respectively), but was maintained at pre‐intervention levels in LCHF. HCHO and PCHO groups improved times for 10 km race walk: 6.6% (90% CI: 4.1, 9.1%) and 5.3% (3.4, 7.2%), with no improvement (−1.6% (−8.5, 5.3%)) for the LCHF group. In contrast to training with diets providing chronic or periodised high‐CHO availability, and despite a significant improvement in V˙O2 peak , adaptation to the topical LCHF diet negated performance benefits in elite endurance athletes, in part due to reduced exercise economy.

Evidence that supports the prescription of low-carbohydrate high-fat diets: a narrative review

Low-carbohydrate high-fat (LCHF) diets are a highly contentious current topic in nutrition. This narrative review aims to provide clinicians with a broad overview of the effects of LCHF diets on...

A Moderate Zinc Deficiency Does Not Alter Lipid and Fatty Acid Composition in the Liver of Weanling Rats Fed Diets Rich in Cocoa Butter or Safflower Oil.

The aim of the study was to examine whether a moderate zinc deficiency alters hepatic lipid composition. Male weanling rats, assigned to five groups (8 animals each), were fed low-carbohydrate high-fat diets supplemented with 7 or 50 mg Zn/kg (LZ or HZ) and 22% cocoa butter (CB) or 22% safflower oil (SF) for four weeks. One group each had free access to the LZ-CB and LZ-SF diets, one group each was restrictedly fed the HZ-CB and HZ-SF diets in matching amounts, and one group had free access to the HZ-SF diet (ad libitum control). The rats fed the LZ diets had significantly lower energy intakes and final body weights than the ad libitum control group, and lower plasma and femur Zn concentrations than the animals consuming the HZ diets. Hepatic cholesterol, triacylglycerol and phospholipid concentrations, and fatty acid composition of hepatic triacylglycerols and phospholipids did not significantly differ between the LZ and their respective HZ groups, but were greatly affected by dietary fat source. In conclusion, the moderate Zn deficiency did not significantly alter liver lipid concentrations and fatty acid composition.

Consumer Acceptability of Intramuscular Fat.

Fat in meat greatly improves eating quality, yet many consumers avoid visible fat, mainly because of health concerns. Generations of consumers, especially in the English-speaking world, have been convinced by health authorities that animal fat, particularly saturated or solid fat, should be reduced or avoided to maintain a healthy diet. Decades of negative messages regarding animal fats has resulted in general avoidance of fatty cuts of meat. Paradoxically, low fat or lean meat tends to have poor eating quality and flavor and low consumer acceptability. The failure of low-fat high-carbohydrate diets to curb “globesity” has prompted many experts to re-evaluate of the place of fat in human diets, including animal fat. Attitudes towards fat vary dramatically between and within cultures. Previous generations of humans sought out fatty cuts of meat for their superior sensory properties. Many consumers in East and Southeast Asia have traditionally valued more fatty meat cuts. As nutritional messages around dietary fat change, there is evidence that attitudes towards animal fat are changing and many consumers are rediscovering and embracing fattier cuts of meat, including marbled beef. The present work provides a short overview of the unique sensory characteristics of marbled beef and changing consumer preferences for fat in meat in general.

A low-carbohydrate high-fat diet decreases lean mass and impairs cardiac function in pair-fed female C57BL/6J mice

BackgroundExcess body fat is a major health issue and a risk factor for the development of numerous chronic diseases. Low-carbohydrate diets like the Atkins Diet are popular for rapid weight loss, but the long-term consequences remain the subject of debate. The Scandinavian low-carbohydrate high-fat (LCHF) diet, which has been popular in Scandinavian countries for about a decade, has very low carbohydrate content (~5 E %) but is rich in fat and includes a high proportion of saturated fatty acids. Here we investigated the metabolic and physiological consequences of a diet with a macronutrient composition similar to the Scandinavian LCHF diet and its effects on the organs, tissues, and metabolism of weight stable mice.MethodsFemale C57BL/6J mice were iso-energetically pair-fed for 4 weeks with standard chow or a LCHF diet. We measured body composition using echo MRI and the aerobic capacity before and after 2 and 4 weeks on diet. Cardiac function was assessed by echocardiography before and after 4 weeks on diet. The metabolic rate was measured by indirect calorimetry the fourth week of the diet. Mice were sacrificed after 4 weeks and the organ weight, triglyceride levels, and blood chemistry were analyzed, and the expression of key ketogenic, metabolic, hormonal, and inflammation genes were measured in the heart, liver, and adipose tissue depots of the mice using real-time PCR.ResultsThe increase in body weight of mice fed a LCHF diet was similar to that in controls. However, while control mice maintained their body composition throughout the study, LCHF mice gained fat mass at the expense of lean mass after 2 weeks. The LCHF diet increased cardiac triglyceride content, impaired cardiac function, and reduced aerobic capacity. It also induced pronounced alterations in gene expression and substrate metabolism, indicating a unique metabolic state.ConclusionsPair-fed mice eating LCHF increased their percentage of body fat at the expense of lean mass already after 2 weeks, and after 4 weeks the function of the heart deteriorated. These findings highlight the urgent need to investigate the effects of a LCHF diet on health parameters in humans.

Metformin Reduces Lipogenesis Markers in Obese Mice Fed a Low-Carbohydrate and High-Fat Diet.

Lipogenesis is the process by which fatty acids are synthesized. In metabolic syndrome, an insulin resistant state along with high plasma levels of free fatty acids (FFA) and hyperglycemia may contribute to the lipogenic process. The aim of the present study was to investigate the effects of oral administration of metformin on the expression of lipogenic genes and glycemic profile in mice fed with low-carbohydrate high-fat diet by evaluating their metabolic profile. SWISS male mice were divided into 4 groups (N=7) that were fed with standard (ST), standard plus metformin (ST+MET), low-carbohydrate high-fat diet (LCHFD) and low-carbohydrate high-fat diet plus metformin (LCHFD+MET) (100mgkg-1 diet) diets respectively. Food intake, body weight and blood parameters, such as glucose tolerance, insulin sensitivity, glucose, HDL-c, total cholesterol, triglycerides, ASL and ALT levels were assessed. Histological analyses were performed on hematoxylin and eosin-stained epididymal adipose tissue histological specimens. The expression levels of peroxisome proliferator-activated receptor (PPARγ), sterol regulatory element-binding protein 1 (SREBP1), fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC), were assessed by RT-PCR. This study showed that metformin decreased adipocyte area, body weight and food consumption in obese animals when compared to the standard group. Furthermore, the expression of lipogenic markers in adipose tissue were diminished in obese animals treated with metformin. This data showed that oral administration of metformin improved glucose and lipid metabolic parameters in white adipose tissue by reducing the expression of lipogenesis markers, suggesting an important clinical application of MET in treating obesity-related diseases in metabolic syndrome.

Gluconeogenesis during endurance exercise in cyclists habituated to a long-term low carbohydrate high-fat diet.

Blood glucose is an important fuel for endurance exercise. It can be derived from ingested carbohydrate, stored liver glycogen and newly synthesized glucose (gluconeogenesis). We hypothesized that athletes habitually following a low carbohydrate high fat (LCHF) diet would have higher rates of gluconeogenesis during exercise compared to those who follow a mixed macronutrient diet. We used stable isotope tracers to study glucose production kinetics during a 2h ride in cyclists habituated to either a LCHF or mixed macronutrient diet. The LCHF cyclists had lower rates of total glucose production and hepatic glycogenolysis but similar rates of gluconeogenesis compared to those on the mixed diet. The LCHF cyclists did not compensate for reduced dietary carbohydrate availability by increasing glucose synthesis during exercise but rather adapted by altering whole body substrate utilization. Endogenous glucose production (EGP) occurs via hepatic glycogenolysis (GLY) and gluconeogenesis (GNG) and plays an important role in maintaining euglycaemia. Rates of GLY and GNG increase during exercise in athletes following a mixed macronutrient diet; however, these processes have not been investigated in athletes following a low carbohydrate high fat (LCHF) diet. Therefore, we studied seven well-trained male cyclists that were habituated to either a LCHF (7% carbohydrate, 72% fat, 21% protein) or a mixed diet (51% carbohydrate, 33% fat, 16% protein) for longer than 8months. After an overnight fast, participants performed a 2h laboratory ride at 72% of maximal oxygen consumption. Glucose kinetics were measured at rest and during the final 30min of exercise by infusion of [6,6-(2) H2 ]-glucose and the ingestion of (2) H2 O tracers. Rates of EGP and GLY both at rest and during exercise were significantly lower in the LCHF group than the mixed diet group (Exercise EGP: LCHF, 6.0±0.9mgkg(-1) min(-1) , Mixed, 7.8±1.1mgkg(-1) min(-1) , P<0.01; Exercise GLY: LCHF, 3.2±0.7mgkg(-1) min(-1) , Mixed, 5.3±0.9mgkg(-1) min(-1) , P<0.01). Conversely, no difference was detected in rates of GNG between groups at rest or during exercise (Exercise: LCHF, 2.8±0.4mgkg(-1) min(-1) , Mixed, 2.5±0.3mgkg(-1) min(-1) , P=0.15). We conclude that athletes on a LCHF diet do not compensate for reduced glucose availability via higher rates of glucose synthesis compared to athletes on a mixed diet. Instead, GNG remains relatively stable, whereas glucose oxidation and GLY are influenced by dietary factors.

Methodological problems with the test of the Paleo diet by Lamont et al. (2016).

Some studies of the twentieth-century hunter–gatherer diets have found them to be low in carbohydrates and high in fat, relative to the Department of Agriculture's dietary guidelines.1, 2, 3 Although there is a disagreement regarding the carbohydrate content of the ancestral human diet,4 advocates of Paleolithic diets who hold that high-carbohydrate foods were not frequently eaten by our pre-agricultural ancestors have recommended low-carbohydrate high-fat diets (LCHFDs) as a way to possibly prevent obesity and ameliorate some diseases, including diabetes.1, 2 Lamont et al.5 recently attempted to test this version (that is, the LCHF version) of the Paleo diet. They fed prediabetic New Zealand obese mice either LCHFDs (carbohydrates comprising 6% of energy, 81% of fat) or standard rodent chow (carbohydrates comprising 70% of energy, 10% of fat). Mice in the former (that is, the experimental) condition experienced ‘greater weight gain and insulin resistance.' Although Lamont et al. do not mention the Paleo diet by name in the paper, in an interview with ABC News the lead author (Andrikopoulos) claims that the study suggests that ‘The Paleo diet may not necessarily be good for everybody.' He was paraphrased as saying that ‘the results of [the] study were a cautionary tale about fad diets.'6 A YouTube video released by the authors' university is titled simply ‘Paleo diets=weight gain.'7 But Lamont et al.'s results do not undermine the theory behind the Paleo diet. Their results are exactly what would be predicted by the theory. Why is that? The theory behind the Paleo diet is that each species is genetically adapted to thrive on the diet eaten by its ancestors throughout most of the species' evolutionary history.8 Consequently (according to the theory) members of a species will have the best health outcomes when they eat a diet that resembles the ancestral one in terms of its basic properties (the ratio of macronutrients, amounts of various vitamins and so on). They will have poorer health outcomes if they eat a diet with radically different properties—on the view that the human ancestral diet was LCHF, Homo sapiens will have poorer health outcomes on diets high in carbohydrates and low in fat. Paleo theory predicts that mice will flourish most on their ancestral diet. Mice (Mus musculus) are omnivores, but studies of the stomach contents of mice in the wild suggest that, though their diet varies by region and time of year, it is composed largely of seeds and other plant material high in carbohydrates, and does not contain any high-fat food sources.9 The rodent chow fed to the mice in Lamont et al.'s control condition was high in carbohydrates and low in fat—in this respect it was similar to the mouse ancestral diet. Therefore, it was the mice in the control condition that were actually fed something close to a (mouse) Paleo diet. Mice in the experimental condition were fed something loosely based on a version of the human Paleo diet, which for mice is not Paleo. Although the results of Lamont et al. do not say anything about health outcomes for humans on a (human) Paleo diet, their results are consistent with Paleo theory in that they confirm one of its predictions: they demonstrate that mice put on a diet deviating significantly from their ancestral one experienced worse health outcomes. Studies on humans, however, suggest that for that species LCHFDs are beneficial in diabetes management.10

CREBH-FGF21 axis improves hepatic steatosis by suppressing adipose tissue lipolysis.

Adipose tissue lipolysis produces glycerol and nonesterified fatty acids (NEFA) that serve as energy sources during nutrient scarcity. Adipose tissue lipolysis is tightly regulated and excessive lipolysis causes hepatic steatosis, as NEFA released from adipose tissue constitutes a major source of TG in the liver of patients with nonalcoholic fatty liver diseases. Here we show that the liver-enriched transcription factor CREBH is activated by TG accumulation and induces FGF21, which suppresses adipose tissue lipolysis, ameliorating hepatic steatosis. CREBH-deficient mice developed severe hepatic steatosis due to increased adipose tissue lipolysis, when fasted or fed a high-fat low-carbohydrate ketogenic diet. FGF21 production was impaired in CREBH-deficient mice, and adenoviral overexpression of FGF21 suppressed adipose tissue lipolysis and improved hepatic steatosis in these mice. Thus, our results uncover a negative feedback loop in which CREBH regulates NEFA flux from adipose tissue to the liver via FGF21.

A Supplemented High-Fat Low-Carbohydrate Diet for the Treatment of Glioblastoma

Dysregulated energetics coupled with uncontrolled proliferation has become a hallmark of cancer, leading to increased interest in metabolic therapies. Glioblastoma (GB) is highly malignant, very metabolically active, and typically resistant to current therapies. Dietary treatment options based on glucose deprivation have been explored using a restrictive ketogenic diet (KD), with positive anticancer reports. However, negative side effects and a lack of palatability make the KD difficult to implement in an adult population. Hence, we developed a less stringent, supplemented high-fat low-carbohydrate (sHFLC) diet that mimics the metabolic and antitumor effects of the KD, maintains a stable nutritional profile, and presents an alternative clinical option for diverse patient populations. The dietary paradigm was tested in vitro and in vivo, utilizing multiple patient-derived gliomasphere lines. Cellular proliferation, clonogenic frequency, and tumor stem cell population effects were determined in vitro using the neurosphere assay (NSA). Antitumor efficacy was tested in vivo in preclinical xenograft models and mechanistic regulation via the mTOR pathway was explored. Reducing glucose in vitro to physiologic levels, coupled with ketone supplementation, inhibits proliferation of GB cells and reduces tumor stem cell expansion. In vivo, while maintaining animal health, the sHFLC diet significantly reduces the growth of tumor cells in a subcutaneous model of tumor progression and increases survival in an orthotopic xenograft model. Dietary-mediated anticancer effects correlate with the reduction of mTOR effector expression. We demonstrate that the sHFLC diet is a viable treatment alternative to the KD, and should be considered for clinical testing. Clin Cancer Res; 22(10); 2482-95. ©2015 AACR.

Impact of high-fat, low-carbohydrate diet on myocardial substrate oxidation, insulin sensitivity, and cardiac function after ischemia-reperfusion.

High-fat, low-carbohydrate Diet (HFLCD) impairs the myocardial response to ischemia-reperfusion, but the underlying mechanisms remain elusive. We sought to determine the magnitude of diet-induced alterations in intrinsic properties of the myocardium (including insulin sensitivity and substrate oxidation) and circulating substrate and insulin differences resulting from diet, leading to this impaired response. Rats were fed HFLCD (60% kcal from fat/30% protein/10% carbohydrate) or control diet (CONT) (16%/19%/65%) for 2 wk. Isolated hearts underwent global low-flow ischemia followed by reperfusion (I/R). Carbon-13 NMR spectroscopy was used to determine myocardial substrate TCA cycle entry. Myocardial insulin sensitivity was assessed as dose-response of Akt phosphorylation. There was a significant effect of HFLCD and I/R with both these factors leading to an increase in free fatty acid (FFA) oxidation and a decrease in carbohydrate or ketone oxidation. Following I/R, HFLCD led to decreased ketone and increased FFA oxidation; the recovery of left ventricular (LV) function was decreased in HFLCD and was negatively correlated with FFA oxidation and positively associated with ketone oxidation. HFLCD also resulted in reduced insulin sensitivity. Under physiologic ranges, there were no direct effects of buffer insulin and ketone levels on oxidation of any substrate and recovery of cardiac function after I/R. An insulin-ketone interaction exists for myocardial substrate oxidation characteristics. We conclude that the impaired recovery of function after ischemia-reperfusion with HFLCD is largely due to intrinsic diet effects on myocardial properties, rather than to diet effect on circulating insulin or substrate levels.

Macronutrient Balance and Dietary Glycemic Index in Pregnancy Predict Neonatal Body Composition.

The influence of maternal macronutrient balance and dietary glycemic index (GI) on neonatal body composition has received little study. We hypothesized that the overall quantity and quality of macronutrients, particularly carbohydrate, in the maternal diet could have trimester-specific effects on neonatal growth and body composition in women at risk of gestational diabetes. Maternal diet was assessed using 3-day food records in mid (n = 96) and late (n = 88) pregnancy as part of the GI Baby 3 study. Neonatal body composition was assessed by air-displacement plethysmography within 48 h of birth, adjusted for length, and expressed as fat mass index (FMI) and fat-free mass index (FFMI). In mid pregnancy, higher maternal intake of carbohydrate energy was negatively correlated with infant FFMI (p = 0.037). In late pregnancy, higher dietary GI was associated with lower FFMI (p = 0.010) and higher carbohydrate energy predicted lower FMI (p = 0.034). Higher fat intake (%E) and saturated fat, but not protein, also predicted neonatal body composition (higher FFMI in mid pregnancy and higher FMI in late pregnancy). Depending on pregnancy stage, a high carbohydrate-low fat diet, particularly from high glycemic sources, may reduce neonatal indices of both lean mass and adiposity.