Days Of High-fat Diet Research Articles

Abstract 17311: Molecular Memory and the Epigenetic Regulation of Cardiac Intracellular Matrix Metalloproteinase-2

Introduction: We have identified an intracellular isoform of MMP-2 generated by oxidative stress activation of a promoter in the first intron of the MMP-2 gene. This generates a N-terminal truncated isoform of MMP-2 (NTT-MMP-2) which is enzymatically active and found in mitochondria. NTT-MMP-2 triggers the mitochondrial permeability transition leading to myocyte regulated necrosis and inflammation. We hypothesized that transient oxidative stress induces durable epigenetic changes in the NTT-MMP-2 alternate promoter resulting in enhanced injury in subsequent episodes of stress (molecular memory). Methods: The intronic promoter was mapped using a combination of PCR-based and intronic/luciferase constructs. In vivo studies used the hypomorphic ApoER61h/h SR-B1-/- murine model (HypoE mice) of diet-induced coronary atherogenesis and myocardial infarction. Chromatin immunopreciptation (ChIP) probed the RNA Pol II, H3K4Me1 and H3K27Me3 epigenetic marks. NTT-MMP-2 was measured by qPCR. Results: NTT-MMP-2 transcription start sites were mapped to two stress-activated basal promoters along with a stress-activated NF-κB enhancer element. HypoE mice were fed a high fat diet (HFD) for 20 days, followed by gene repair of the hypomorphic ApoE alleles and returned to normal diet for 6-15 weeks. NTT-MMP-2 expression at 20 days of HFD was elevated two-three fold as compared to controls, remained elevated after 6 weeks of normal diet and returned to baseline at 15 weeks. ChIP of the intronic promoter revealed association of RNA Pol II at 6 weeks of normal diet and was not detectable at 15 weeks. In contrast, the pro-transcriptional mark H3K4Me1 remained elevated out to 15 weeks; the inhibitory H3K27Me3 mark returned to baseline at 15 weeks. A brief return to HFD (7 days) at 6 weeks increased NTT-MMP-2 expression resulting in myocyte inflammation and necrosis relative to controls exposed to only 7 days of HFD. Conclusions: Transient periods of oxidative stress lead to durable epigenetic changes in the NTT-MMP-2 promoter that facilitate exaggerated responses to otherwise minor levels of oxidative stress. Our findings may provide an explanation for the enhanced injury susceptibility to relatively minor stresses of patients with pre-existing cardiac disease.

Effects Of 3 Days Of High Fat Diet On Exercise-induced Growth Hormone Response In Men

Effects Of 3 Days Of High Fat Diet On Exercise-induced Growth Hormone Response In Men

Hypothalamic 2-Arachidonoylglycerol Regulates Multistage Process of High-Fat Diet Preferences

BackgroundIn this study, we examined alterations in the hypothalamic reward system related to high-fat diet (HFD) preferences. We previously reported that hypothalamic 2-arachidonoylglycerol (2-AG) and glial fibrillary acid protein (GFAP) were increased after conditioning to the rewarding properties of a HFD. Here, we hypothesized that increased 2-AG influences the hypothalamic reward system.MethodsThe conditioned place preference test (CPP test) was used to evaluate HFD preferences. Hypothalamic 2-AG was quantified by gas chromatography-mass spectrometry. The expression of GFAP was examined by immunostaining and western blotting.ResultsConsumption of a HFD over either 3 or 7 days increased HFD preferences and transiently increased hypothalamic 2-AG levels. HFD consumption over 14 days similarly increased HFD preferences but elicited a long-lasting increase in hypothalamic 2-AG and GFAP levels. The cannabinoid 1 receptor antagonist O-2050 reduced preferences for HFDs after 3, 7, or 14 days of HFD consumption and reduced expression of GFAP after 14 days of HFD consumption. The astrocyte metabolic inhibitor Fluorocitrate blocked HFD preferences after 14 days of HFD consumption.ConclusionsHigh levels of 2-AG appear to induce HFD preferences, and activate hypothalamic astrocytes via the cannabinoid system. We propose that there may be two distinct stages in the development of HFD preferences. The induction stage involves a transient increase in 2-AG, whereas the maintenance stage involves a long lasting increase in 2-AG levels and activation of astrocytes. Accordingly, hypothalamic 2-AG may influence the development of HFD preferences.

Inflammation Is Necessary for Long-Term but Not Short-Term High-Fat Diet–Induced Insulin Resistance

OBJECTIVETissue inflammation is a key factor underlying insulin resistance in established obesity. Several models of immuno-compromised mice are protected from obesity-induced insulin resistance. However, it is unanswered whether inflammation triggers systemic insulin resistance or vice versa in obesity. The purpose of this study was to assess these questions.RESEARCH DESIGN AND METHODSWe fed a high-fat diet (HFD) to wild-type mice and three different immuno-compromised mouse models (lymphocyte-deficient Rag1 knockout, macrophage-depleted, and hematopoietic cell-specific Jun NH2-terminal kinase–deficient mice) and measured the time course of changes in macrophage content, inflammatory markers, and lipid accumulation in adipose tissue, liver, and skeletal muscle along with systemic insulin sensitivity.RESULTSIn wild-type mice, body weight and adipose tissue mass, as well as insulin resistance, were clearly increased by 3 days of HFD. Concurrently, in the short-term HFD period inflammation was selectively elevated in adipose tissue. Interestingly, however, all three immuno-compromised mouse models were not protected from insulin resistance induced by the short-term HFD. On the other hand, lipid content was markedly increased in liver and skeletal muscle at day 3 of HFD.CONCLUSIONSThese data suggest that the initial stage of HFD-induced insulin resistance is independent of inflammation, whereas the more chronic state of insulin resistance in established obesity is largely mediated by macrophage-induced proinflammatory actions. The early-onset insulin resistance during HFD feeding is more likely related to acute tissue lipid overload.

High-fat feeding stimulates endocrine, glucose-dependent insulinotropic polypeptide (GIP)-expressing cell hyperplasia in the duodenum of Wistar rats

Incretins are hormones released by enteroendocrine cells in response to meals, depending upon absorption of nutrients. The present study aimed to elucidate the mechanisms through which a high-fat diet (HFD) induces insulin resistance and insulin hypersecretion by focusing on the effects on enteroendocrine cells, especially those secreting glucose-dependent insulinotropic polypeptide (GIP). Forty male Wistar rats, 4 months old, were randomised into two groups; one group received a chow diet and the other one received a purified tripalmitin-based HFD ad libitum. An OGTT was performed every 10 days and histological and immunofluorescence evaluations of the duodenum were obtained at 60 days from the beginning of the diets. Plasma glucose, insulin, GIP and glucagon-like peptide-1 (GLP-1) levels were measured. Immunofluorescence analysis of duodenal sections for pancreatic duodenal homeobox-1 (PDX-1), KI67, GLP-1, GIP and insulin were performed. Compared with chow diet, HFD induced a progressive significant increase of the glucose, insulin and GIP responses to OGTT, whereas GLP-1 circulating levels were reduced over time. After 60 days of HFD, cellular agglomerates of KI67 and PDX-1 positive cells, negative for insulin and GLP-1 but positive for GIP staining, were found inside the duodenal mucosa, and apoptosis was significantly increased. With the limitation that we could not establish a causal relationship between events, our study shows that HFD stimulates duodenal proliferation of endocrine cells differentiating towards K cells and oversecreting GIP. The progressive increment of GIP levels might represent the stimulus for insulin hypersecretion and insulin resistance.

Short-term adaptation of postprandial lipoprotein secretion and intestinal gene expression to a high-fat diet

Western diet is characterized by a hypercaloric and hyperlipidic intake, enriched in saturated fats, that is associated with the increased occurrence of metabolic diseases. To cope with this overload of dietary lipids, the intestine, which delivers dietary lipids to the body, has to adapt its capacity in lipid absorption and lipoprotein synthesis. We have studied the early effects of a high-fat diet (HFD) on intestinal lipid metabolism in mice. After 7 days of HFD, mice displayed normal fasting triglyceridemia but postprandial hypertriglyceridemia. HFD induced a decreased number of secreted chylomicrons with increased associated triglycerides. Secretion of larger chylomicrons was correlated with increased intestinal microsomal triglyceride transfer protein (MTP) content and activity. Seven days of HFD induced a repression of genes involved in fatty acid synthesis (FAS, ACC) and an increased expression of genes involved in lipoprotein assembly (apoB, MTP, and apoA-IV), suggesting a coordinated control of intestinal lipid metabolism to manage a high-fat loading. Of note, the mature form of the transcription factor SREBP-1c was increased and translocated to the nucleus, suggesting that it could be involved in the coordinated control of gene transcription. Activation of SREBP-1c was partly independent of LXR. Moreover, HFD induced hepatic insulin resistance whereas intestine remained insulin sensitive. Altogether, these results demonstrate that a short-term HFD is sufficient to impact intestinal lipid metabolism, which might participate in the development of dyslipidemia and metabolic diseases.

High-Fat Diet Exposure Increases Dopamine D2 Receptor and Decreases Dopamine Transporter Receptor Binding Density in the Nucleus Accumbens and Caudate Putamen of Mice

This experiment examined dopamine D2 receptor and its transporter (DAT) density in mice fed a high-fat or low-fat diet for twenty days as well as fed twenty days of high-fat diet then changed to low-fat diet for one and seven days. Quantitative autoradiography revealed that twenty days of high-fat diet consumption significantly increased D2 receptor and decreased DAT density in the dorsal and ventral parts of the caudal caudate putamen (D2: 32% and 35% respectively, DAT: 33.3% and 28.8% respectively) compared with low-fat diet. High-fat feeding also increased D2 binding in the nucleus accumbens shell (36%). D2 receptor and DAT density remained unchanged following reversal of the diets from high-fat to low-fat diet. The high-fat diet induced increase of D2 receptor and decrease of DAT binding may have occurred due to defensive control over dopaminergic activity in response to a positive energy balance.

Chronological Approach of Diet‐induced Alterations in Muscle Mitochondrial Functions in Rats

Mitochondrial dysfunction might predispose individuals to develop insulin resistance. Our objective was to determine whether mitochondrial dysfunction or insulin resistance was the primary event during high-fat (HF) diet. Rats were fed an HF diet for 0, 3, 6, 9, 14, 20, or 40 days and compared with control. Soleus and tibialis muscle mitochondrial activity were assessed using permeabilized fiber technique. Insulin [area under the curve for insulin (AUC(I))] and glucose [area under the curve for glucose (AUC(G))] responses to intraperitoneal glucose tolerance test as well as fasting plasma non-esterified fatty acids (NEFAs), triglyceride, and glycerol concentrations were determined. AUC(I) and AUC(G) were altered from Day 6 (p < 0.01 vs. Day 0). In soleus, oxidative phosphorylation (OXPHOS) activity was transiently enhanced by 26% after 14 days of HF diet (p < 0.05 vs. Day 0) conjointly with 62% increase in NEFA concentration (p < 0.05 vs. Day 0). This was associated with normalized AUC(G) at Day 14 and with a decline of plasma NEFA concentration together with stabilization of intra-abdominal adiposity at Day 20. Prolongation of HF diet again caused an increase in plasma NEFA concentration, intra-abdominal adiposity, AUC(I), and AUC(G). At Day 40, significant decrease in OXPHOS activity was observed in soleus. Mitochondria first adapt to overfeeding in oxidative muscle limiting excess fat deposition. This potentially contributes to maintain glucose homeostasis. Persistent overfeeding causes insulin resistance and results in a slow decline in oxidative muscle OXPHOS activity. This shows that the involvement of mitochondria in the predisposition to insulin resistance is mainly due to an inability to face prolonged excess fat delivery.

Oligofructose Promotes Satiety in Rats Fed a High‐Fat Diet: Involvement of Glucagon‐Like Peptide‐1

To analyze the putative interest of oligofructose (OFS) in the modulation of food intake after high-fat diet in rats and to question the relevance of the expression and secretion of intestinal peptides in that context. Male Wistar rats were pretreated with standard diet or OFS-enriched (10%) standard diet for 35 days followed by 15 days of high-fat diet enriched or not with OFS (10%) treatment. Body weight, food intake, triglycerides, and plasma ghrelin levels were monitored during the treatment. On day 50, rats were food-deprived 8 hours and anesthetized for blood and intestinal tissue sampling for further proglucagon mRNA, glucagon-like peptide (GLP)-1, and GLP-2 quantification. The addition of OFS in the diet protects against the promotion of energy intake, body weight gain, fat mass development, and serum triglyceride accumulation induced by a high-fat diet. OFS fermentation leads to an increase in proglucagon mRNA in the cecum and the colon and in GLP-1 and GLP-2 contents in the proximal colon, with consequences on the portal concentration of GLP-1 (increase). A lower ghrelin level is observed only when OFS is added to the standard diet of rats. In rats exposed to high-fat diet, OFS is, thus, able to modulate endogenous production of gut peptides involved in appetite and body weight regulation. Because several approaches are currently used to treat type 2 diabetes and obesity with limited effectiveness, dietary fibers such as OFS, which promote the endogenous production of gut peptides like GLP-1, could be proposed as interesting nutrients to consider in the management of fat intake and associated metabolic disorders.

Increase in fat oxidation on a high-fat diet is accompanied by an increase in triglyceride-derived fatty acid oxidation.

The aim of this study is to investigate the mechanism behind the slow increase in fat oxidation on a high-fat diet. Therefore, we determined 24-h substrate oxidation using respiration chambers and the rate of appearance and oxidation of plasma-derived fatty acids in seven healthy nonobese men (age 23 +/- 2 years, height 1.85 +/- 0.03 m, weight 70.4 +/- 2.3 kg, % body fat 13 +/- 1). Before testing, they consumed a low-fat diet (30% fat, 55% carbohydrate) at home for 3 days. Measurements were performed after 1 day consumption of either a low-fat diet (LF), a high-fat diet (HF1, 60% fat, 25% carbohydrate), or a high-fat diet preceded by a glycogen-lowering exercise test (HF1+EX), and after 7 days on a high-fat diet (HF7). After an overnight fast, an infusion of [U-13C]palmitate (0.00806 micromol x min(-1) x kg(-1)) was started and continued for 2 h at rest followed by 1 h of exercise at 50% of maximal power output (Wmax). Whole-body fat oxidation was measured using indirect calorimetry, and plasma-derived fatty acid oxidation was evaluated by measuring breath 13CO2 enrichment and corrected with the acetate recovery factor. Twenty-four-hour fat oxidation gradually increased on the high-fat diet. Both at rest and during exercise, there was no change in rate of appearance of fatty acids and plasma-derived fatty acid oxidation. Triglyceride-derived fatty acid oxidation tended to be higher after 7 days of high-fat diet at rest (P < 0.07). This difference was significant during exercise (P < 0.05). In conclusion, the results from this study suggest that triglyceride-derived fatty acid oxidation (VLDL or intramuscular triglycerides) plays a role in the increase in fat oxidation on a high-fat diet, but plasma-derived fatty acids remain the major source for fat oxidation.