Feasible diet and circadian interventions reduce in vivo progression of FLT3-ITD-positive acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) with an internal tandem duplication in the fms-like tyrosine kinase receptor 3 gene (FLT3-ITD) is associated with poor survival, and few studies have examined the impact of modifiable behaviors, such as nutrient quality and timing, in this subset of acute leukemia. METHODS: The influence of diet composition (low-sucrose and/or low-fat diets) and timing of diet were tested in tandem with anthracycline treatment in orthotopic xenograft mouse models. A pilot clinical study to test receptivity of pediatric leukemia patients to macronutrient matched foods was conducted. A role for the circadian protein, BMAL1 (brain and muscle ARNT-like 1), in effects of diet timing was studied by overexpression in FLT3-ITD-bearing AML cells. RESULTS: Reduced tumor burden in FLT3-ITD AML-bearing mice was observed with interventions utilizing low-sucrose and/or low-fat diets, or time-restricted feeding (TRF) compared to mice fed normal chow ad libitum. In a tasting study, macronutrient matched low-sucrose and low-fat meals were offered to pediatric acute leukemia patients who largely reported liking the meals. Expression of the circadian protein, BMAL1, was heightened with TRF and the low-sucrose diet. BMAL1 overexpression and treatment with a pharmacological inducer of BMAL1 was cytotoxic to FLT3-ITD AML cells. CONCLUSIONS: Mouse models for FLT3-ITD AML show that diet composition and timing slows progression of FLT3-ITD AML growth in vivo, potentially mediated by BMAL1. These interventions to enhance therapy efficacy show preliminary feasibility, as pediatric leukemia patients responded favorable to preparation of macronutrient matched meals.

The Effect of Low-Carbohydrate Diet on Macrovascular and Microvascular Endothelial Function is Not Affected by the Provision of Caloric Restriction in Women with Obesity: A Randomized Study.

Obesity impairs both macro- and microvascular endothelial function due to decreased bioavailability of nitric oxide. Current evidence on the effect of low-carbohydrate (LC) diet on endothelial function is conflicting and confounded by the provision of caloric restriction (CR). We tested the hypothesis that LC without CR diet, but not LC with CR diet, would improve macro- and microvascular endothelial function in women with obesity. Twenty-one healthy women with obesity (age: 33 ± 2 years, body mass index: 33.0 ± 0.6 kg/m2; mean ± SEM) were randomly assigned to receive either a LC diet (~10% carbohydrate calories) with CR (n = 12; 500 calorie/day deficit) or a LC diet without CR (n = 9) and completed the 6-week diet intervention. After the intervention, macrovascular endothelial function, measured as brachial artery flow-mediated dilation did not change (7.3 ± 0.9% to 8.0 ± 1.1%, p = 0.7). On the other hand, following the LC diet intervention, regardless of CR, blocking nitric oxide production decreased microvascular endothelial function, measured by arteriolar flow-induced dilation (p ≤ 0.02 for both diets) and the magnitude was more than baseline (p ≤ 0.04). These data suggest improved NO contributions following the intervention. In conclusion, a 6-week LC diet, regardless of CR, may improve microvascular, but not macrovascular endothelial function, via increasing bioavailability of nitric oxide in women with obesity.

Low-Fat Diet Designed for Weight Loss But Not Weight Maintenance Improves Nitric Oxide-Dependent Arteriolar Vasodilation in Obese Adults.

Obesity is associated with microvascular dysfunction. While low-fat diet improves cardiovascular risk, its contributions on microvascular function, independent of weight loss, is unknown. We tested the hypothesis that nitric oxide (NO)-dependent vasodilation in microvessels is improved by low-fat diets designed for weight loss (LFWL) compared to low-fat weight maintenance (LFWM) diet. Obese adults were randomly assigned to either a LFWL diet (n = 11) or LFWM diet (n = 10) for six weeks. Microvessels were obtained from gluteal subcutaneous fat biopsies before and after the intervention for vascular reactivity measurements to acetylcholine (Ach) and flow, with and without L-NAME or indomethacin. Vascular and serum NO and C-reactive protein (CRP) were also measured. LFWL diet increased flow-induced (FID) and ACh-induced dilation (AChID); an effect that was inhibited by L-NAME. Conversely, LFWM diet did not affect FID or AChID. Indomethacin improved FID and AChID in the baseline and this effect was minimized in response to both diets. Serum NO or CRP did not change in response to either diet. In conclusion, LFWL diet improves microvascular reactivity compared to LFWM diet and increased vascular NO contribution to the improved microvascular dilation. These data suggest that weight reduction on low fat diet is critical for microvascular health.