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Intermittent energy restriction in overweight women at increased risk of breast cancer

ABSTRACT: Lymphocyte and breast tissue samples from overweight woman at increased risk of breast cancer before and after 1 month of intermittant energy restriction Introduction Observational studies indicate that weight loss and energy restriction reduce breast cancer risk. Intermittent energy restriction (IER) reduces weight as well as, or more than continuous energy restriction (CER), but its effect on the breast and systemic metabolism as indicators of breast cancer risk are not known. Methods We assessed the effect of IER ( 2 days of 65% energy restriction) for one menstrual cycle on the breast (breast gene expression and fat cell size) and systemic metabolism (insulin resistance, lipids, serum and urine metabolites) in 23 overweight premenopausal women at high risk of breast cancer. Unsupervised hierarchical analysis selected 100 genes with the highest variance between pre and post IER biopsies in 20 subjects, whilst mass spectrometry was used to assess corresponding changes in serum (LCMS) and urine metabolites (GCMS) in 23 subjects in the restricted and unrestricted days of the IER. Results Women lost on average 4.8% (± 2.0) of body weight and 8.0% (± 5.0) of body fat. Insulin resistance (HOMA) was reduced by 29.8% (±17.8) on the restricted days and by 11%(±34) on the unrestricted days of the IER. Over 250 serum and urine metabolites significantly increased or decreased during the two restricted days and most returned to normal after the subsequent five day period . In the breast tissue, approximately half (In 11) of the subjects displayed down regulation of several metabolic pathways including lipid synthesis, growth factors and hormones, whilst epithelial genes including milk proteins, secretoglobulins and mucins were up-regulated and several metabolic pathways down-regulated including lipid synthesis, growth factors and hormones. In the other nine subjects there was no appreciable effect of IER on the breast. CorrespondingThe gene changes were not seen in peripheral blood lymphocytes, and there was no reduction in breast fat cell size. The two groups defined by change in gene expression or lack of it did not differ in the degree of weight or fat loss, other systemic metabolic markers, or histological assessment of the biopsies. Conclusion We conclude that breasts vary in response to short-term IER, the mechanism of which requires further investigation. Trial registration ISRCTN77916487

ORGANISM(S): Homo sapiens

PROVIDER: GSE66161 | GEO | 2016/07/13

SECONDARY ACCESSION(S): PRJNA275991

REPOSITORIES: GEO

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Project description:Background: Despite the established relation between energy restriction and metabolic health, the most beneficial nutrient composition of a weight-loss diet is still subject of debate. Objectives: The aim of the study was to examine the additional effects of nutrient quality on top of energy restriction(ER). Methods: A parallel-designed 12-week 25%ER dietary intervention study was conducted. Participants aged 40-70 years with abdominal obesity were randomized over three groups: a 25%ER high nutrient quality diet (n = 40); a 25%ER low nutrient quality diet (n = 40); or a habitual diet (n = 30). Both ER diets were nutritionally adequate, the high nutrient quality ER diet was enriched in monounsaturated and n-3 polyunsaturated fatty acids, fiber, and plant protein and reduced in fructose. Before and after the intervention intra-hepatic lipids, body fat distribution, fasting and postprandial responses to a mixed meal shake challenge test of cardio-metabolic risk factors, lipoproteins, vascular measurements, and adipose tissue transcriptome were assessed. Results: The high quality ER diet (-8.4 ± 3.2) induced 2.1 kg more weight loss (P = 0.007) than the low quality ER diet (-6.3 ± 3.9), reduced fasting serum total cholesterol (P = 0.014) and plasma triglycerides (P < 0.001), promoted an anti-atherogenic lipoprotein profile and induced a more pronounced decrease in adipose tissue gene expression of energy metabolism pathways than the low quality ER diet. Explorative analyses showed that the difference in weight loss between both ER diets were specifically present in insulin sensitive subjects (HOMA-IR ≤ 2.5), in whom the high nutrient quality diet induced 3.9 kg more weight loss than the low nutrient quality diet. Conclusion: A high nutrient quality 25%ER diet is more beneficial for cardiometabolic health than a low nutrient quality 25%ER diet. Overweight insulin sensitive subjects may benefit more from a high than a low nutrient quality ER diet with respect to weight loss, due to potential attenuation of glucose-induced lipid synthesis in adipose tissue. Trial registration: ClinicalTrials.gov NCT02194504.

Project description:We investigated the regulation of adipose tissue (AT) gene expression during different phases of a dietary weight loss program and its relationship with insulin sensitivity. Obese women followed a weight reduction program composed of an energy restriction phase (ER) with a 4-week very-low-calorie diet and a weight stabilization period (WS) composed of a 2-month low-calorie diet followed by 3 to 4 months of a weight maintenance diet. At each time point, body composition, plasma parameters and glucose disposal rate were assessed and subcutaneous AT biopsies were performed. Variations in mRNA levels were determined using DNA microarrays and reverse transcription-quantitative PCR. Distinct sets of AT genes are regulated during calorie restriction and weight stabilization revealing an unexpected temporal pattern in the link between AT and insulin sensitivity during weight loss. Experiment Overall Design: Fifteen obese premenopausal women were recruited at the Third Faculty of Medicine of Charles University and at the Institute for Mother and Child Care in Prague, Czech Republic. During the first four weeks of the dietary intervention program, the subjects received an energy restricted diet of 800 kcal/day (liquid formula diet, Redita, Promil). During the next two months, a low-calorie diet was designed to provide 600 kcal/day less than the individually estimated energy requirement based on an initial resting metabolic rate multiplied by 1.3. Following this, subjects entered a weight maintenance phase for a period of 3 to 4 months, during which the patients were instructed to keep their weight stable. A complete clinical investigation in the fasting state was realized before and at the end of each phase. Needle microbiopsy of subcutaneous AT was performed under local anesthesia (1% Xylocaine) from the abdominal region (14â20 cm lateral to the umbilicus). Total RNA were isolated from AT samples with Qiagen RNeasy kit. RNA quantity and quality were checked with the Experion automated electrophoresis system (BioRad laboratories). We performed a whole transcriptome analysis comparing 1) before vs. after the initial 4 weeks severe energy restriction (ER), 2) after energy restriction vs. after weight stabilization (WS) and 3) before dietary intervention vs. after weight stabilization (DI). Eight subjects representative of the cohort were selected, matched for high quality of total RNA samples, insulin sensitivity and weight changes during the study. Targets for microarray experiments were generated from 500 ng of total RNA with Agilent low RNA input amplification kit (Agilent Technologies) and hybridized to whole genome 44k oligonucleotide arrays (Agilent Technologies). Each combination of samples was analyzed twice using a dye swap design (i.e., a total of 48 hybridizations). Data acquisition from microarrays was obtained with a GenePix 4000B scanner (Axon instruments) and image processing was performed with Feature Extraction 8.5 (Agilent Technologies). Raw data were normalized with a global Lowess procedure and filtered with R package LIMMA (Bioconductor). Outlier replicates and spots with a signal to noise ratio lesser than 2 on both red and green channel were eliminated from our analyses. Mean log ratios were calculated from paired duplicates before normalization. Differentially expressed genes were identified with Significance Analysis of Microarray (SAM) procedure.

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Intermittent energy restriction in overweight women at increased risk of breast cancer

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