Despite remarkable improvements in screening, diagnosis, and targeted therapies, cancer remains the second leading cause of death in the United States. It is increasingly clear that diet and lifestyle practices play a substantial role in cancer development and progression. As such, various dietary compositions have been proposed for reducing cancer risk and as potential adjuvant therapies. In this article, we critically assess the preclinical and human trials on the effects of the ketogenic diet (KD, i.e., high-fat, moderate-to-low protein, and very-low carbohydrate content) for cancer-related outcomes. The mechanisms underlying the hypothesized effects of KD, most notably the Warburg Effect, suggest that restricting carbohydrate content may impede cancer development and progression via several pathways (e.g., tumor metabolism, gene expression). Overall, although preclinical studies suggest that KD has antitumor effects, prolongs survival, and prevents cancer development, human clinical trials are equivocal. Because of the lack of high-quality clinical trials, the effects of KD on cancer and as an adjunctive therapy are essentially unknown. We propose a set of research recommendations for clinical studies examining the effects of KD on cancer development and progression.

Background: Brain‐derived neurotrophic factor (BDNF) increases neuronal viability and cognitive function, peripheral lipid metabolism and skeletal muscle repair. The primary purpose of this study was to determine the effect of short‐term high‐intensity interval training (HIIT) on serum BDNF concentrations in healthy young women. Methods: Seventeen women (age:22 ± 1 years); body mass index (BMI:24.2 ± 2.2 kg/m²), body fat percentage (% fat:25.8 ± 4.7) participated in the study. Participants were randomly assigned to a control (n = 8) or HIIT group (n = 9). All participants performed a graded exercise test (GXT) on an electronically‐braked cycle ergometer to determine maximal aerobic power (MAP, Watts). HIIT was performed three days per week for four weeks. Each HIIT session consisted of three to five cycling bouts of 30 s each at 80% MAP, followed by four‐minutes of recovery at 40% MAP. Forty‐eight hours after the last bout of exercise, both groups performed a follow‐up GXT. Non‐fasting blood samples were collected before and immediately after each GXT. Mixed factorial (2 groups x 4 measures, and 2 groups x 2 measures) ANOVA was used to assess BDNF concentrations, performance and anthropometric variables. Results: Serum BDNF concentrations in the HIIT group (21.9 ± 1.3 ng/mL) increased compared to control (19.2 ± 2.8 ng/mL) (∼12%, P < 0.05) following HIIT. In contrast, circulating BDNF concentrations were reduced following the GXT (P < 0.05). The MAP and % Fat did not change with HIIT. Conclusions: Twelve sessions of HIIT increases circulating BDNF concentrations in healthy young women despite no change in physical performance or % fat.

Calorie restriction (CR) decreases adiposity, but the magnitude and defense of weight loss is less than predicted due to reductions in total daily energy expenditure (TEE). The purpose of the current investigation was to determine whether high-intensity interval training (HIIT) would increase markers of sympathetic activation in white adipose tissue (WAT) and rescue CR-mediated reductions in EE to a greater extent than moderate-intensity aerobic exercise training (MIT). Thirty-two 5-wk-old male C57BL/6J mice were placed on ad libitum HFD for 11 wk, followed by randomization to one of four groups (n = 8/group) for an additional 15 wk: 1) CON (remain on HFD), 2) CR (25% lower energy intake), 3) CR + HIIT (25% energy deficit created by 12.5% CR and 12.5% EE through HIIT), and 4) CR + MIT (25% energy deficit created by 12.5% CR and 12.5% EE through MIT). Markers of adipose thermogenesis (Ucp1, Prdm16, Dio2, and Fgf21) were unchanged in either exercise group in inguinal or epididymal WAT, whereas CR + HIIT decreased Ucp1 expression in retroperitoneal WAT and brown adipose tissue. HIIT rescued CR-mediated reductions in lean body mass (LBM) and resting energy expenditure (REE), and both were associated with improvements in glucose/insulin tolerance. Improvements in glucose metabolism in the CR + HIIT group appear to be linked to a molecular signature that enhances glucose and lipid storage in skeletal muscle. Exercise performed at either moderate or high intensity does not increase markers of adipose thermogenesis when performed in the presence of CR but remodels skeletal muscle metabolic and thermogenic capacity.

Postprandial hyperlipemia produces long-term derangements in lipid/lipoprotein metabolism, vascular endothelial dysfunction, hypercoagulability, and sympathetic hyperactivity which are strongly linked to atherogenesis. The purpose of this review is to (1) provide a qualitative analysis of the available literature examining the dysregulation of postprandial lipid metabolism in the presence of obesity, (2) inspect the role of adiposity distribution and sex on postprandial lipid metabolism, and (3) examine the role of energy deficit (exercise- and/or energy restriction-mediated), isoenergetic low-carbohydrate diets, and omega-3 (n-3) fatty acid supplementation on postprandial lipid metabolism. We conclude from the literature that central adiposity primarily accounts for sex-related differences in postprandial lipemia and that aerobic exercise attenuates this response in obese or lean men and women to a similar extent through potentially unique mechanisms. In contrast, energy restriction produces only mild reductions in postprandial lipemia suggesting that exercise may be superior to energy restriction alone as a strategy for lowering postprandial lipemia. However, isoenergetic very low-carbohydrate diets and n-3 fatty acid supplementation reduce postprandial lipemia indicating that macronutrient manipulations reduce postprandial lipemia in the absence of energy restriction. Therefore, interactions between exercise/energy restriction and alterations in macronutrient content remain top priorities for the field to identify optimal behavioral treatments to reduce postprandial lipemia.

The dietary R ‐3‐hydroxybutyrate‐ R ‐1,3‐butanediol monoester increases resting energy expenditure (REE) and markers of brown and white adipose thermogenesis in lean mice. The purpose of this investigation was to determine whether the ketone ester, R,S ‐1,3‐butanediol diacetoacetate (BD‐AcAc ₂ ), increases energy expenditure and markers of adipose tissue thermogenesis in the context of high‐fat diet (HFD)‐induced obesity. Thirty‐five‐week‐old male C57BL/ 6J mice were placed on an ad libitum HFD (45% kcal) for 10 wk. The mice were then randomized to 1 of 3 groups (n = 10 per group) for an additional 12 wk: 1 ) control (Con), continuous HFD, 2) pair‐fed (PF) to ketone ester (KE); and 3) KE: HFD +30% energy from BD‐AcAc ₂ . Mean energy intake throughout the study was ∼26% lower in the KE compared to the Con group (8.2 ± 0.5 vs . 11.2 ± 0.7 kcal/d; P < 0.05). Final body weight (26.8 ± 3.6 vs . 34.9 ± 4.8 g; P < 0.001) and fat mass (5.2 ± 1.2 vs . 11.3 ± 4.5 g; P < 0.001) of the KE group was significantly lower than PF, despite being matched for energy provisions. Differences in body weight and adiposity were accompanied by higher REE and total energy expenditure in the KE group compared to PF after adjustment for lean body mass and fat‐mass ( P = 0.001 and 0.007, respectively). Coupled or uncoupled mitochondrial respiratory rates in skeletal muscle were not different among groups, but markers of mitochondrial uncoupling and thermogenesis (uncoupling protein‐1, deiodinase‐2, and peroxisome proliferator‐activated receptor y coactivator‐1α) were higher in interscapular brown adipose tissue (BAT) of mice receiving the KE diet. The absence of mitochondrial uncoupling in skeletal muscle and increased markers of mitochondrial uncoupling in BAT suggest that BD‐AcAc ₂ initiates a transcriptional signature consistent with BAT thermogenesis in the context of HFD‐induced obesity.—Davis, R. A. H., Deemer, S. E., Bergeron, J. M., Little, J. T., Warren, J. L., Fisher, G., Smith, D. L., Jr., Fontaine, K. R., Dickinson, S. L., Allison, D. B., Plaisance, E. P. Dietary R,S‐1,3‐butanediol diacetoacetate reduces body weight and adiposity in obese mice fed a high‐fat diet. FASEB J. 33, 2409–2421 (2019). www.fasebj.org