A single day of excessive dietary fat intake reduces whole-body insulin sensitivity: the metabolic consequence of binge eating

Consuming excessive amounts of energy as dietary fat for several days or weeks can impair glycemic control and reduce insulin sensitivity in healthy adults. However, individuals who demonstrate binge eating behavior overconsume for much shorter periods of time; the metabolic consequences of such behavior remain unknown. The aim of this study was to determine the effect of a single day of high-fat overfeeding on whole-body insulin sensitivity. Fifteen young, healthy adults underwent an oral glucose tolerance test before and after consuming a high-fat (68% of total energy), high-energy (78% greater than daily requirements) diet for one day. Fasting and postprandial plasma concentrations of glucose, insulin, non-esterified fatty acids, and triglyceride were measured and the Matsuda insulin sensitivity index was calculated. One day of high-fat overfeeding increased postprandial glucose area under the curve (AUC) by 17.1% (p < 0.0001) and insulin AUC by 16.4% (p = 0.007). Whole-body insulin sensitivity decreased by 28% (p = 0.001). In conclusion, a single day of high-fat, overfeeding impaired whole-body insulin sensitivity in young, healthy adults. This highlights the rapidity with which excessive consumption of calories through high-fat food can impair glucose metabolism, and suggests that acute binge eating may have immediate metabolic health consequences for the individual

Short-term, high-fat overfeeding impairs glycaemic control but does not alter gut hormone responses to a mixed meal tolerance test in healthy, normal-weight individuals

Obesity is undoubtedly caused by a chronic positive energy balance. However, the early metabolic and hormonal responses to overeating are poorly described. This study determined glycaemic control and selected gut hormone responses to nutrient intake before and after seven days of high-fat overfeeding. Nine healthy individuals (5 males, 4 females) performed a mixed meal tolerance test (MTT) before and after consuming a high-fat (65%) high-energy (+50%) diet for seven days. Measurements of plasma glucose, NEFA, acylated ghrelin, GLP-1, GIP and serum insulin were taken before (fasting) and at 30 minutes intervals throughout the 180 min MTT (postprandial). Body mass increased by 0.79 ± 0.14 kg after high-fat overfeeding (p < 0.0001), and BMI increased by 0.27 ± 0.05 kg/m2 (p = 0.002). High-fat overfeeding also resulted in an 11.6% increase in postprandial glucose AUC (p = 0.007) and a 25.9% increase in postprandial insulin AUC (p = 0.005). Acylated ghrelin, GLP-1 and GIP responses to the MTT were all unaffected by the high-fat, high-energy diet. These findings demonstrate that even brief periods of overeating are sufficient to disrupt glycaemic control. However, as the postprandial orexigenic (ghrelin) and anorexigenic/insulintropic (GLP-1 and GIP) hormone responses were unaffected by the diet intervention, it appears that these hormones are resistant to short-term changes in energy balance, and that they do not play a role in the rapid reduction in glycaemic control

Influence of hyper-energetic, high-fat feeding on circulating hepatokines in healthy men: a randomised crossover study [Abstract]

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Neutrophil microvesicles drive atherosclerosis by delivering <i>miR-155</i> to atheroprone endothelium

Neutrophils are implicated in the pathogenesis of atherosclerosis but are seldom detected in atherosclerotic plaques. We investigated whether neutrophil-derived microvesicles may influence arterial pathophysiology. Here we report that levels of circulating neutrophil microvesicles are enhanced by exposure to a high fat diet, a known risk factor for atherosclerosis. Neutrophil microvesicles accumulate at disease-prone regions of arteries exposed to disturbed flow patterns, and promote vascular inflammation and atherosclerosis in a murine model. Using cultured endothelial cells exposed to disturbed flow, we demonstrate that neutrophil microvesicles promote inflammatory gene expression by delivering miR-155, enhancing NF-κB activation. Similarly, neutrophil microvesicles increase miR-155 and enhance NF-κB at disease-prone sites of disturbed flow in vivo. Enhancement of atherosclerotic plaque formation and increase in macrophage content by neutrophil microvesicles is dependent on miR-155. We conclude that neutrophils contribute to vascular inflammation and atherogenesis through delivery of microvesicles carrying miR-155 to disease-prone regions

Impact of high-fat overfeeding on white adipose tissue and systemic metabolic and inflammatory responses [Abstract]

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Short-term high-fat overfeeding does not induce NF-κB inflammatory signaling in subcutaneous white adipose tissue

Context It is unclear how white adipose tissue (WAT) inflammatory signaling proteins respond during the early stages of overnutrition. Objective To investigate the effect of short-term, high-fat overfeeding on fasting abdominal subcutaneous WAT total content and phosphorylation of proteins involved in nuclear factor-κB (NF-κB) inflammatory signaling, systemic metabolic measures and inflammatory biomarkers. Design Individuals consumed a high-fat (65% total energy total fat), high-energy (50% above estimated energy requirements) diet for 7 days. Results Fifteen participants (age 27 ± 1 y; BMI 24.4 ± 0.6 kg/m2) completed the study. Body mass increased following high-fat overfeeding (+1.2 ± 0.2 kg; P Conclusion Acute lipid oversupply did not impact on total content or phosphorylation of proteins involved in WAT NF-κB inflammatory signaling, despite modest weight gain and metabolic alterations. Systemic LBP, which is implicated in the progression of low-grade inflammation during the development of obesity, increased in response to a 7-day high-fat overfeeding period.</div

A 7‐day high‐fat, high‐calorie diet induces fibre‐specific increases in intramuscular triglyceride and perilipin protein expression in human skeletal muscle

KEY POINTS: We have recently shown that a high-fat high-calorie (HFHC) diet decreases whole body glucose clearance without impairing skeletal muscle insulin signalling, in healthy lean individuals. These diets are also known to increase skeletal muscle IMTG stores, but the effect on lipid metabolites leading to skeletal muscle insulin resistance has not been investigated. This study measured the effect of 7 days HFHC diet on: 1) skeletal muscle concentration of lipid metabolites, and 2) potential changes in the perilipin (PLIN) content of the lipid droplets (LD) storing IMTG. The HFHC diet increased PLIN3 protein expression and redistributed PLIN2 to LD stores in type I fibres. The HFHC diet increased IMTG content in type I fibres, while lipid metabolite concentrations remained the same. The data suggest that the increases in IMTG stores assists reducing the accumulation of lipid metabolites known to contribute to skeletal muscle insulin resistance. ABSTRACT: A HFHC diet reduces whole body glucose clearance without impairing skeletal muscle insulin signalling in healthy lean individuals. HFHC diets also increase skeletal muscle lipid stores. However, unlike certain lipid metabolites, intramuscular triglyceride (IMTG) stored within lipid droplets (LD) does not directly contribute to skeletal muscle insulin resistance. Increased expression of perilipin (PLIN) proteins and colocalisation to LD has been shown to assist in IMTG storage. We aimed to test the hypothesis that 7 days on a HFHC diet increases IMTG content while minimising accumulation of lipid metabolites known to disrupt skeletal muscle insulin signalling in sedentary and obese individuals. We also aimed to identify changes in expression and subcellular distribution of proteins involved in IMTG storage. Muscle biopsies were obtained from the m. vastus lateralis of 13 (n = 11 males, n = 2 females) healthy lean individuals (age: 23 ± 2.5 y, BMI: 24.5 ± 2.4 kg m-2 ), following an overnight fast, before and after consuming a high-fat (64% energy) high-calorie (+47% kcal) diet for 7 days. After the HFHC diet, IMTG content increased in type I fibres only (+10%; P < 0.001), whereas there was no change in the concentration of either total diacylglycerol (P = 0.123) or total ceramides (P = 0.150). Of the PLINs investigated, only PLIN3 content increased (+50%; P < 0.01) solely in type I fibres. LDs labelled with PLIN2 increased (80%; P < 0.01), also in type I fibres only. We propose that these adaptations to LD support IMTG storage and minimise accumulation of lipid metabolites to protect skeletal muscle insulin signalling following 7 days HFHC diet

High-fat overfeeding impairs peripheral glucose metabolism and muscle microvascular eNOS Ser1177 phosphorylation

Abstract Context The mechanisms responsible for dietary fat-induced insulin resistance of skeletal muscle and its microvasculature are only partially understood. Objective To determine the impact of high-fat overfeeding on postprandial glucose fluxes, muscle insulin signaling, and muscle microvascular eNOS content and activation. Design Fifteen non-obese volunteers consumed a high-fat (64%) high-energy (+47%) diet for 7 days. Experiments were performed before and after the diet. Stable isotope tracers were used to determine glucose fluxes in response to carbohydrate plus protein ingestion. Muscle insulin signaling was determined as well as the content and activation state of muscle microvascular eNOS. Results High-fat overfeeding impaired postprandial glycemic control as demonstrated by higher concentrations of glucose (+11%; P = 0.004) and insulin (+19%; P = 0.035). Carbohydrate plus protein ingestion suppressed endogenous glucose production to a similar extent before and after the diet. Conversely, high-fat overfeeding reduced whole body glucose clearance (-16%; P = 0.021) and peripheral insulin sensitivity (-26%; P = 0.006). This occurred despite only minor alterations in skeletal muscle insulin signaling. High-fat overfeeding reduced eNOS content in terminal arterioles (P = 0.017) and abolished the increase in eNOS Ser1177 phosphorylation that was seen after carbohydrate plus protein ingestion. Conclusion High-fat overfeeding impaired whole-body glycemic control due to reduced glucose clearance, not elevated endogenous glucose production. The finding that high-fat overfeeding abolished insulin-mediated eNOS Ser1177 phosphorylation in the terminal arterioles suggests that impairments in the vasodilatory capacity of the skeletal muscle microvasculature may contribute to early dietary fat-induced impairments in glycemic control

Acute hyper-energetic, high-fat feeding increases circulating FGF21, LECT2 and fetuin-A in healthy men

Background: Hepatokines such as fibroblast growth factor 21 (FGF21), leukocyte cell-derived chemotaxin 2 (LECT2), fetuin-A, fetuin-B and selenoprotein P (SeP) are liver-derived proteins which are modulated by chronic energy status and metabolic disease. Emerging data from rodent and cell models indicate that hepatokines may be sensitive to acute nutritional manipulation; however, data in humans are lacking. Objective: To investigate the influence of hyper-energetic, high-fat feeding on circulating hepatokine concentrations, including the time-course of responses. Methods: In a randomised, crossover design, 12 healthy men (mean ± SD: age, 24 ± 4 years; BMI, 24.1 ± 1.5 kg∙m-2) consumed a seven-day hyper-energetic, high-fat diet (HE-HFD; +50% energy, 65% total energy as fat [32% saturated, 26% monounsaturated, 8% polyunsaturated]) and control diet (36% total energy as fat), separated by three weeks. Whole-body insulin sensitivity was assessed before and after each diet using oral glucose tolerance tests. Fasting plasma concentrations of FGF21 (primary outcome), LECT2, fetuin-A, fetuin-B, SeP, and related metabolites were measured after 1, 3 and 7 d of each diet. Hepatokine responses were analysed using two-way repeated-measures ANOVA and subsequent pairwise comparisons. Results: Compared with control, the HE-HFD increased circulating FGF21 at 1 (105%) and 3 d (121%; P 0.040); LECT2 at 3 (17%) and 7 d (32%; P 0.004); and fetuin A at 7 d (7%, P = 0.028). Plasma fetuin-B and SeP did not respond to the HE-HFD. Whole-body insulin sensitivity was reduced after the HE-HFD by 31% (P = 0.021). Conclusions: Acute high-fat overfeeding augments circulating levels of FGF21, LECT2 and fetuin A in healthy men. Notably, the time-course of response varies between proteins and is transient for FGF21. These findings provide further insight into the nutritional regulation of hepatokines in humans and their interaction with metabolic homeostasis. This study was registered at clinicaltrials.gov as NCT03369145