High Saturated Fat Diet Research Articles

Influence of dietary fatty acid composition and exercise on changes in fat oxidation from a high-fat diet

Acute high-fat (HF) diets can lead to short-term positive fat balances until the body increases fat oxidation to match intake. The purpose of this study was to examine the effects of a HF diet, rich in either mono-unsaturated or saturated fatty acids (FAs) and exercise, on the rate at which the body adapts to a HF diet.(13)C-labeled oleate and (2)H-labeled palmitate were also given to determine the contribution of exogenous vs. global fat oxidation. Eight healthy men (age of 18-45 yr; body mass index of 22 ± 3 kg/m(2)) were randomized in a 2 × 2 crossover design. The four treatments were a high saturated fat diet with exercise (SE) or sedentary (SS) conditions and a high monounsaturated fat diet with exercise (UE) or sedentary (US) conditions. Subjects stayed for 5 days in a metabolic chamber. All meals were provided. On day 1, 30% of energy intake was from fat, whereas days 2-5 had 50% of energy as fat. Subjects exercised on a stationary cycle at 45% of maximal oxygen uptake for 2 h each day. Respiratory gases and urinary nitrogen were collected to calculate fat oxidation. Change from day 1 to day 5 showed both exercise treatments increased fat oxidation (SE: 76 ± 30 g, P = 0.001; UE: 118 ± 31 g, P < 0.001), whereas neither sedentary condition changed fat oxidation (SS: -10 ± 33 g, P = not significant; US: 41 ± 14 g, P = 0.07). No differences for dietary FA composition were found. Exercise led to a faster adaptation to a HF diet by increasing fat oxidation and achieving fat balance by day 5. Dietary FA composition did not differentially affect 24-h fat oxidation.

Long‐term effects of weight loss with a very low carbohydrate and low fat diet on vascular function in overweight and obese patients

To compare the effects of an energy reduced very low carbohydrate, high saturated fat diet (LC) and an isocaloric high carbohydrate, low fat diet (LF) on endothelial function after 12 months. Forty-nine overweight or obese patients (age 50.0 +/- 1.1 years, BMI 33.7 +/- 0.6 kg m(-2)) were randomized to either an energy restricted ( approximately 6-7 MJ), planned isocaloric LC or LF for 52 weeks. Body weight, endothelium-derived factors, flow-mediated dilatation (FMD), adiponectin, augmentation index (AIx) and pulse wave velocity (PWV) were assessed. All data are mean +/- SEM. Weight loss was similar in both groups (LC -14.9 +/- 2.1 kg, LF -11.5 +/- 1.5 kg; P = 0.20). There was a significant time x diet effect for FMD (P = 0.045); FMD decreased in LC (5.7 +/- 0.7% to 3.7 +/- 0.5%) but remained unchanged in LF (5.9 +/- 0.5% to 5.5 +/- 0.7%). PWV improved in both groups (LC -1.4 +/- 0.6 m s(-1), LF -1.5 +/- 0.6 m s(-1); P = 0.001 for time) with no diet effect (P = 0.80). AIx and VCAM-1 did not change in either group. Adiponectin, eSelectin, tPA and PAI-1 improved similarly in both groups (P < 0.01 for time). Both LC and LF hypoenergetic diets achieved similar reductions in body weight and were associated with improvements in PWV and a number of endothelium-derived factors. However, the LC diet impaired FMD suggesting chronic consumption of a LC diet may have detrimental effects on endothelial function.

The role of calcium handling in the improved contractile function associated with high‐fat feeding in heart failure

Heart failure (HF) is characterized by deteriorating left ventricular (LV) function. High saturated fat diets (SAT) are associated with increased risks for lipotoxicity &amp; contractile dysfunction. However, HF animals fed SAT exhibit improved in vivo LV contractility versus HF animals fed normal chow (NC) as assessed by LV +dP/dt max. Ca2+ handling properties are known to be altered &amp; contribute to HF. Therefore, we hypothesize that LV contractile dysfunction associated with alterations in Ca2+ handling properties in HF are improved with SAT. Male rats underwent coronary ligation or sham surgery (SH) &amp; fed NC or SAT for 8 weeks. Cardiomyocytes were isolated, followed by measurements of cell shortening, Ca2+ transients, sarcoplasmic reticulum (SR) Ca2+ content, &amp; L‐type Ca2+ current. Myocytes from both HF groups were hypertrophied &amp; their Ca2+ decay (τ1/2) prolonged versus SH. HF+NC myocytes exhibited decreased cell shortening at 1Hz but increased Ca2+ transients despite decreased SR Ca2+ content versus SH+NC. HF+NC myocytes had depressed L‐type Ca2+ currents &amp; a diminished response to β‐adrenergic stimulation versus SH+NC which may contribute to the decrease in cell shortening. However, cell shortening, L‐type ca2+ currents at baseline and in response to β‐adrenergic stimulation were not decreased in HF animals fed high fat and thus, may account for in vivo differences in contractility. (Grant: NHLBI HL‐081857)

Insulin resistance as a mechanism of preserved myocardial function in heart failure animals fed a high fat diet

Heart failure (HF) rats fed a high saturated fat diet (SAT) have improved left ventricular contractile function compared to HF animals fed normal chow (NC) diets. Both HF and SAT are individually associated with the development of insulin resistance (IR), but the role of IR in HF+SAT is unknown. We hypothesize that the cardioprotective effect seen in HF+SAT results from defects in insulin signaling that decrease glucose uptake in IR myocardium. Rats underwent coronary ligation or sham (SH) surgery &amp; were fed NC or SAT for 8 weeks. Cardiac contractility (peak positive dP/dt) was preserved in HF+SAT animals versus HF+NC. SH+SAT, HF+NC &amp; HF+SAT animals have abnormal glucose tolerance tests &amp; elevated insulin levels compared to SH+NC, indicating peripheral IR. MicroPET data shows HF+SAT animals have myocardial IR relative to all other groups. Protein targets of insulin signaling (IRS‐1, Akt, pAkt, GLUT4) are currently being analyzed. HF+SAT animals are IR in both peripheral tissue &amp; the myocardium, while SH+SAT &amp; HF+NC animals are IR in the periphery only. This correlates to preserved contractile function in HF+SAT versus HF+NC. We predict that insulin signaling targets such as pAkt and GLUT4 are downregulated, which may be the mechanism by which myocardial insulin resistance preserves contractile function in HF+SAT animals. (Grant # NHLBI HL‐081857)

Exercise training increases hepatic endoplasmic reticulum (er) stress protein expression in MTP‐inhibited high‐fat fed rats

The purpose of the study was: (1) to determine the effects of microsomal triglyceride transfer protein (MTP) inhibition on endoplasmic reticulum (ER) stress in liver, and (2) to determine if this response is altered in exercise-trained rats. Female Sprague-Dawley rats (6 weeks) fed either a standard (SD) or a high-saturated fat (HF; 43% as energy) diet were trained (Tr) or kept sedentary (Sed) for 6 week. Exercise training consisted of continuous running on a motor-driven rodent treadmill 5 times/week. Ten days before the end of these interventions, rats were administrated (ip) daily a MTP inhibitor (MTPX) or a placebo (P). MTPX injection resulted in a large (p < 0.01) liver triacylglycerol (TAG) accumulation in SD and HF-fed rats (approximately 200 mg g(-1)), irrespective of the training status, while plasma TAG levels were largely (approximately 80%) decreased (p < 0.01). MTPX injection in HF but not in SD-fed animals resulted in an increase in BiP/GRP78, ATF6, PERK, and XBP-1 mRNA levels, (p < 0.01) indicating an increase in the unfolding protein response (UPR) to ER stress. Interestingly, exercise training in rats fed the HF diet resulted in a further increase in BiP/GRP78 and XBP-1 mRNA levels in MTPX animals (p < 0.01). It is concluded that: (1) ER stress induced by MTPX occurs only in HF-fed rats despite the fact that liver TAG levels were largely increased in both dietary models; (2) the increase in gene expression of UPR markers with training may constitute a protective mechanism against ER stress in liver.

De Novo Lipogenesis and Stearoyl-CoA Desaturase Are Coordinately Regulated in the Human Adipocyte and Protect against Palmitate-induced Cell Injury

De novo lipogenesis (DNL) is paradoxically up-regulated by its end product, saturated fatty acids (SAFAs). We tested the hypothesis that SAFA-induced up-regulation of DNL reflects coordinate up-regulation of elongation and desaturation pathways for disposal of SAFAs and production of monounsaturated fatty acids to protect cells from SAFA toxicity. Human preadipocytes were differentiated in vitro for 14 days with [U-(13)C]palmitate (0-200 microM) to distinguish exogenous fatty acids from those synthesized by DNL. Exogenous palmitate up-regulated DNL (p < 0.001) concomitantly with SCD and elongation (each p < 0.001). Adipocytes from some donors were intolerant to high palmitate concentrations (400 microM). Palmitate-intolerant cells showed lower TG accumulation. They had lower expression of SCD mRNA and less monounsaturated fatty acids in TG, emphasizing the importance of desaturation for dealing with exogenous SAFAs. There was greater [U-(13)C]palmitate incorporation in phospholipids. SCD knockdown with small interfering RNA caused down-regulation of DNL and of expression of DNL-related genes, with reduced membrane fluidity (p < 0.02) and insulin sensitivity (p < 0.01), compared with scrambled small interfering RNA controls. There was preferential channeling of DNL-derived versus exogenous palmitate into elongation and of DNL-derived versus exogenous stearate into desaturation. DNL may not act primarily to increase fat stores but may serve as a key regulator, in tandem with elongation and desaturation, to maintain cell membrane fluidity and insulin sensitivity within the human adipocyte.

The effect of dietary fat content on phospholipid fatty acid profile is muscle fiber type dependent

A high-saturated-fat diet (HFD) induces obesity and insulin resistance (IR). IR has been linked to alterations and increased saturation in the phospholipid composition of skeletal muscles. We aimed to determine whether HFD feeding affects fatty acid (FA) membrane profile in a muscle fiber type-specific manner. We measured phospholipid FAs and expression of FA synthesis genes in oxidative soleus (SOL) and glycolytic extensor digitorum longus (EDL) muscles from rats fed either standard chow (standard laboratory diet, SLD) or a HFD. The HFD increased fat mass, plasma insulin, and leptin levels. Compared with EDL, SOL muscles preferentially accumulated C18 over C16 FAs and n-6 over n-3 polyunsaturated FAs (PUFAs) on either diet. With the HFD, SOL muscles contained more n-9 monounsaturated FAs (MUFAs) and n-6 PUFAs and less n-7 MUFAs and n-3 PUFAs than EDL muscles and had lower unsaturation index, a pattern known to be associated with IR. Stearoyl-CoA desaturase-1 expression was approximately 13-fold greater in EDL than in SOL muscles but did not change with the HFD in either muscle. The expression of Elongase-5 was higher, and that of Elongase-6 (Elovl6) was lower in EDL compared with SOL muscles with both diets. In EDL muscles, the expression of Elovl6 was lower in the HFD than in the SLD. The pattern of FA uptake, expression, and diet-induced changes in FA desaturating and elongating enzymes maintained higher FA unsaturation in EDL muscles. Accordingly, the fiber type composition of skeletal muscles and their distribution may be important in the development and progression of obesity and IR.

Use of hamster as a model to study diet-induced atherosclerosis

Golden-Syrian hamsters have been used as an animal model to assess diet-induced atherosclerosis since the early 1980s. Advantages appeared to include a low rate of endogenous cholesterol synthesis, receptor-mediated uptake of LDL cholesterol, cholesteryl ester transfer protein activity, hepatic apoB-100 and intestinal apoB-48 secretion, and uptake of the majority of LDL cholesterol via the LDL receptor pathway. Early work suggested hamsters fed high cholesterol and saturated fat diets responded similarly to humans in terms of lipoprotein metabolism and aortic lesion morphology. Recent work has not consistently replicated these findings. Reviewed was the literature related to controlled hamster feeding studies that assessed the effect of strain, background diet (non-purified, semi-purified) and dietary perturbation (cholesterol and/or fat) on plasma lipoprotein profiles and atherosclerotic lesion formation. F1B hamsters fed a non-purified cholesterol/fat-supplemented diet had more atherogenic lipoprotein profiles (nHDL-C > HDL-C) than other hamster strains or hamsters fed cholesterol/fat-supplemented semi-purified diets. However, fat type; saturated (SFA), monounsaturated or n-6 polyunsaturated (PUFA) had less of an effect on plasma lipoprotein concentrations. Cholesterol- and fish oil-supplemented semi-purified diets yielded highly variable results when compared to SFA or n-6 PUFA, which were antithetical to responses observed in humans. Dietary cholesterol and fat resulted in inconsistent effects on aortic lipid accumulation. No hamster strain was reported to consistently develop lesions regardless of background diet, dietary cholesterol or dietary fat type amount. In conclusion, at this time the Golden-Syrian hamster does not appear to be a useful model to determine the mechanism(s) of diet-induced development of atherosclerotic lesions.

High–saturated-fat diet induces gestational diabetes and placental vasculopathy in C57BL/6 mice

Gestational diabetes mellitus (GDM) is a commonly encountered disorder of mid to late pregnancy that is characterized by hyperglycemia, hyperinsulinemia, and impaired glucose tolerance. Gestational diabetes mellitus is thought to be multifactorial in origin and derives from both genetic and environmental factors. However, the mechanisms underlying GDM are incompletely understood; and current GDM animal models do not appear to closely mimic the clinical situation in humans. The present study used environmental exposure to high–saturated-fat diet (HFD) in an effort to develop a GDM mouse model that closely simulates metabolic abnormalities seen in human GDM. This model was then used to determine the contributions of HFD-induced placental oxidative stress (OS) and vascular dysregulation, which are observed in GDM patients and are believed to contribute to the pathogenesis of the disease. Pathologic manifestations of the disease were quantified by evaluating the extent of placental lipid peroxidation and by determining protective effects of dietary antioxidant quercetin supplementation to reduce HFD-associated placental OS. In this study, female C57BL/6 mice were fed HFD for 1 month before conception and throughout gestation to mimic chronic maternal fast food consumption. Maternal body weight increased from gestation day (GD) 0 to GD19 by 41% with HFD, as compared with 23% in control dams; HFD dams also developed insulin resistance (66% increase in plasma insulin and 27% increase in plasma glucose levels by GD10) as compared with control dams. Placentas from HFD GD19 dams demonstrated loss of trophoblasts and OS-mediated labyrinthine endothelial cellular damage, the latter of which was prevented with quercetin supplementation. Our findings suggest that prenatal HFD alters glucose metabolism and elevates placental OS, which are believed to collectively relate to improper formation of the conceptus and impaired birth outcome.

Intrauterine exposure to high saturated fat diet elevates risk of adult‐onset chronic diseases in C57BL/6 mice

The developmental environment is thought to determine, in part, lifelong metabolic parameters and risk of adult disease. Effects of maternal malnutrition on fetal growth have been studied extensively, and the role of poor prenatal diet in elevating lifelong risk of cardiovascular and metabolic disease has been well characterized (www.thebarkertheory.com). However, the contribution of gestational high saturated fat diet (HFD) to adult-onset metabolic disease and skeletal dysfunction has only recently been recognized, and as such is incompletely understood. The present study evaluates the pathophysiologic mechanisms linking gestational HFD (approximating the macronutrient content of fast food) and elevated oxidative stress (OS) to adult-onset skeletal, cardiovascular, and metabolic dysfunction. Results of this study demonstrate that adult offspring of dams fed HFD during pregnancy exhibited adult hyperglycemia, insulin resistance, obesity, and hypertension, despite being fed healthy standard rodent chow throughout postnatal life. These offspring also showed significantly lower femoral epiphyseal average bone mineral density (ABMD) at 6 months of age, and dysregulation of distal femoral trabecular architecture at 12 months of age, characteristic of osteoporosis. Incidence of these adult-onset adverse skeletal and metabolic effects was reduced by supplementing the pregnant dam with the antioxidant (quercetin, Q) during pregnancy. Collectively, these data suggest that offspring of dams who consume a diet rich in saturated fats during pregnancy are at increased risk of adult-onset chronic disease. Additionally, these chronic diseases were determined to be in-part OS-mediated, and preventable by increasing a prenatal dietary antioxidant; this knowledge offers both a putative mechanism of disease pathogenesis and suggests a potential preventive strategy.

Pyruvate dehydrogenase kinase isoenzyme 4 (PDHK4) deficiency attenuates the long-term negative effects of a high-saturated fat diet

The hypothesis that PDHK4 (pyruvate dehydrogenase kinase isoenzyme 4) has potential as a target for the treatment of type 2 diabetes was tested by feeding wild-type and PDHK4 knockout mice a high saturated fat diet that induces hyperglycemia, hyperinsulinaemia, glucose intolerance, hepatic steatosis and obesity. Previous studies have shown that PDHK4 deficiency lowers blood glucose by limiting the supply of three carbon gluconeogenic substrates to the liver. There is concern, however, that the increase in glucose oxidation caused by less inhibition of the pyruvate dehydrogenase complex by phosphorylation will inhibit fatty acid oxidation, promote ectopic fat accumulation and worsen insulin sensitivity. This was examined by feeding wild-type and PDHK4 knockout mice a high saturated fat diet for 8 months. Fasting blood glucose levels increased gradually in both groups but remained significantly lower in the PDHK4 knockout mice. Hyperinsulinaemia developed in both groups, but glucose tolerance was better and body weight was lower in the PDHK4 knockout mice. At termination, less fat was present in the liver and skeletal muscle of the PDHK4 knockout mice. Higher amounts of PGC-1alpha [PPARgamma (peroxisome proliferator-activated receptor gamma) coactivator 1alpha] and PPARalpha and lower amounts of fatty acid synthase and acetyl-CoA carboxylase isoenzyme 1 were present in the liver of the PDHK4 knockout mice. These findings suggest PDHK4 deficiency creates conditions that alter upstream signalling components involved in the regulation of lipid metabolism. The findings support the hypothesis that PDHK4 is a viable target for the treatment of type 2 diabetes.

Effects of Fat-Enriched Diet on the Content of Sphingolipids in the Brain and on Cognitive Functions in Old Rats

It was demonstrated that levels of free fatty acids and radioactively labeled ([ 14 C]) ceramide in the liver, muscles, and brain of rats fed a saturated fat-enriched diet for 36 weeks (from 15 to 24 months) increased, as compared with the corresponding levels in control animals of the same age (24 months old). A high-saturated fat diet resulted in a rise in the content of sphingolipids synthesized de novo in the neocortex and hippocampus of 24-month-old rats. High levels of ceramide and sphingosine in the neocortex and hippocampus induced in these rats by the above diet correlated with considerable worsening of the conditioned reflex activity of animals (reflex of active avoidance in the shuttle chamber).

Ala54Thr polymorphism of the fatty acid binding protein 2 gene and saturated fat intake in relation to lipid levels and insulin resistance: the Coronary Artery Risk Development in Young Adults (CARDIA) study

The Thr54 allele of the intestinal fatty acid–binding protein Ala54Thr functional polymorphism (FABP2) is associated with increased fat oxidation and insulin resistance. We determined the cross-sectional associations of the FABP2 gene with lipid levels and insulin resistance in 2148 participants who completed the year-20 examination of the Coronary Artery Risk Development in Young Adults (CARDIA) study. No significant difference in total cholesterol, low-density or high-density lipoprotein cholesterol, triglycerides, high-density lipoprotein cholesterol to total cholesterol ratio, or homeostasis model assessment of insulin resistance (HOMA-IR) was found between FABP2 genotypes. However, in the presence of a high–saturated fat diet (≥53.2 g/d, the 90th percentile for the population), the AA/AG genotypes (carriers of the Thr54 allele) of FABP2 had statistically significantly higher levels of log(HOMA-IR) (P = .006) and a lower high-density lipoprotein cholesterol to total cholesterol ratio (P = .03), and borderline statistically significantly higher levels of total cholesterol, low-density lipoprotein cholesterol, and log(triglycerides) (P values = .08, .07, and .05, respectively) compared with those with the GG genotype (Ala54 homozygotes). Lipid levels and log(HOMA-IR) did not vary by genotype with saturated fat intake less than 53.2 g/d. Limiting dietary saturated fat intake may be particularly important among carriers of the A allele of FABP2.

Evaluation of Electrical Conductivity of Hemoglobin and Oxidative Stress in High Fat Diet Rabbits

Abstract: The aim of this study was to evaluate the effects of feeding hgh cholesterol and saturated fat diet for a period of 10 weeks on the antioxidant status and the electrical conductivity of hemoglobin in rabbits. Thus, twenty of 12 weeks old male New Zealand whte rabbits obtained from the Laborato~y Animal Centre (College of Pharmacy, King Saud University, Saudi Arabia) were used. The rabbits were indvidually caged and divided into control group and high fat diet group. Sem lipids were measured using standard techniques. The electrical conductivity of hemoglobin and oxidative stress were evaluated in both groups of rabbits. We found that the levels of Total Cholesterol (TC), Triglycerides (TG), Low Demity Lipoprotein (LDL), High Density Lipoprotein (HDL) and Malondaldehyde (MDA) were significantly increased in the hgh fat diet rabbits compared with the control rabbits, and a significant decrease in the activities of plasma antioxidant enzymes, such as Superoxide Dismutase (SOD) and Glutahone Proxidase (GPx), was obsenred in the high fat det rabbits compared with the control rabbits. The electrical conductivity of hemoglobin was significantly increased in the high fat det rabbits compared with the control rabbits. Furthermore, a significant increase in the oxidative stress was obsenred in the high fat diet rabbits compared with the control rabbits, which was concomitant with the increase in the electrical conductivity of hemoglobin. Our results suggest that feedng rabbits a high cholesterol and saturated fat diet for a period of 10 weeks induces significant changes in TC, TG, LDL, HDL, MDA, SOD, GPx, the electrical conductivity of hemoglobin and the oxidative stress. Indeed, SOD, GPx, the electrical conductivity of hemoglobin and the oxidative stress may help in diagnosing and monitoring the progression of atherosclerosis.

Effect of high saturated‐fat diets on bone mass and endochondral ossification in healthy growing rats

High‐fat diets can produce deleterious effects on bone metabolism in growing animals. Objective: To investigate in healthy growing rats the effect of high saturated‐fat diets on bone mass and endochondral ossification. Weaning male Wistar rats (n=20) were fed ad libitum one of the 2 diets, for 4 wks: control (C; fat=7% w/w) (AIN‐93G) or a high‐fat diet containing 20% w/w of beef‐tallow (BT). Then rats were sacrificed. Total skeleton bone mineral density (BMD) and bone mineral content (BMC) were evaluated by DXA (Lunar DPX‐L).The following histomorphometric parameters were evaluated: Bone volume (BV/TV)(%) and cartilage growth plate thickness (CGP.Th).Statistics: Student's t test &amp; Pearson's correlations coefficients were calculated. Results (as mean±SD): BMD(mg/cm2), C=245±13 vs BT=244±13 (p&gt;0.05); BMC(mg), C=1085±319 vs BT=689± 224; (BV/TV)(%), C=45±5 vs BT=38±3 (p&lt;0.03); total GPC.Th(mm), C=0.44±0.04 vs BT=0.43±0.03 (p&gt;0.05); proliferative zone GPC.Th(mm), C=0.21±0.01 vs BT=0.18± 0.01 (p&gt;0.001).The correlation between BMC vs proliferative zone CGP.Th was ‐0.881 (p&lt;0.05).ConclusionHigh saturated‐fat diets lead to a decreased in BMC associated with a significant increased in CGP.Th as well as a reduction in BV/TV. Based on these findings, we suggest that high saturated‐fat diets acts as a dependent risk factor for bone modeling interfering the acquired of bone mass. Awarded by UBACyT O 008 ‐ O015.

Role of insulin resistance in heart failure and high fat diet

Both heart failure (HF) and high saturated fat diets (SAT) are associated with the development of insulin resistance. Whether insulin resistance exists in a model that involves both HF+SAT has not been studied. Previous studies reported that HF+SAT rats have improved left ventricular contractile and mitochondrial function compared to HF animals fed normal chow (NC). We hypothesize that myocardial insulin resistance exists in HF+SAT rats and that it serves a cardioprotective role. Male Wistar rats underwent coronary ligation or sham surgery and were fed NC (10% kcal fat) or SAT (60% kcal saturated fat) for 8 weeks. Five weeks post ligation, a glucose tolerance test (GTT) was performed to determine peripheral insulin resistance via plasma glucose and insulin concentrations. Echocardiography was done at 7 weeks post ligation to assess cardiac function. Tissue was harvested 8 weeks post ligation to assess the insulin signaling pathway via targets such as AKT, mTOR, GSK3β, eIF‐2, and AMPK by protein and RNA analysis. Preliminary results indicate that HF+NC and Sham+SAT have abnormal GTTs compared to Sham+NC. However, HF+SAT animals do not have impaired GTT. Ongoing studies will assess whether differences in GTT result from alterations in insulin signaling and whether these alterations in HF+SAT serve in a cardioprotective function in heart failure. (Grant # NHLBI HL‐081857 &amp; AHA 0535361N)

Hepatic gene expression and proteomic profile of mice with nonalcoholic fatty liver disease due to high fat diet

IntroductionAlthough nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, the responsible molecular mechanisms are incompletely understood. Here, we performed hepatic gene expression and proteomic analysis in mice with NAFLD due to a high saturated fat diet. Materials and Methods: Male C57/BL6 mice were fed 60% lard or control diet for 8 weeks. Those on the high fat diet developed hepatic steatosis. Hepatic gene expression was analyzed by microarray technology, and the proteome was analyzed by two‐dimensional difference gel electrophoresis with mass spectrometry.ResultsCompared to control diet, high fat diet changed the expression of 473 genes (256 up‐ and 217 down‐regulated) by 2‐fold or greater. Multiple genes encoding proteins involved in fatty acid oxidation were up‐regulated. Several genes encoding extracellular matrix proteins, adhesion molecules, and xenobiotic metabolizing enzymes were down‐regulated. Proteomic analysis revealed eleven proteins which were differentially expressed. Of these, glutathione S‐transferase mu1 and pi, and selenium binding protein 2 were decreased on both gene chip and proteomic analysis.ConclusionNAFLD due to a high saturated fat diet in mice is associated with specific gene expression and proteomic changes. This work was supported by the NIH (IVD, CJM), the AASLD (MC) and the VA (CJM).

Liver Fatty Acid Binding Protein (L-FABP) as a Target for the Prevention of High Fat Diet Induced Obesity and Hepatic Steatosis

An epidemic of obesity, fueled in large part by increased consumption of diets enriched in saturated fat, has heightened interest in the pathways and mechanisms that modulate the uptake and utilization of individual dietary lipid components. Emerging evidence has implicated members of the intracellular fatty acid binding protein (FABP) multigene family as important metabolic sensors that may regulate substrate trafficking and metabolic compartmentalization. Among these, liver fatty acid binding protein (L-FABP, Fabp1) is an abundant cytosolic protein expressed in both mammalian small intestinal enterocytes and hepatocytes. L-Fabp -/- mice were protected against hepatic steatosis following a prolonged fast, suggesting a role in modulating hepatic FA trafficking in response to augmented lipid mobilization from adipose stores. In addition, L-Fabp -/- mice are protected against obesity and hepatic steatosis when fed a high saturated fat diet or a high saturated fat diet containing cholesterol (ie Western diet), but not when fed a high fat diet containing polyunsaturated fat. These findings imply substrate specificity in the lipid sensing functions of L-FABP. Together the data suggest that L-FABP regulates elements of both intestinal and hepatic FA trafficking as well as cholesterol metabolism and in turn exerts an important role in the pathogenesis of diet- induced obesity and hepatic steatosis through specific diet- gene interactions.

Myocardial Ischemic‐reperfusion Injury in a Rat Model of Metabolic Syndrome

Hearts of NaCl-induced hypertensive-glucose intolerant (HGI) rats develop reduced infarcts after ischemia-reperfusion injury (IRI) than their hypertensive (H) counterparts. Because high intake of saturated fat is a major risk factor for ischemic heart disease, we tested the hypothesis that chronic (18 weeks) consumption of a high saturated fat diet increases susceptibility to IRI, an effect more marked in the HGI rats than in the H rats. The fat-fed H (HFAT) rat displayed significantly higher body weight and plasma leptin content compared to the H, HGI, or fat-fed HGI (HGIFAT) rats which all showed similar values. In contrast, plasma triglyceride concentration was significantly higher in the HGIFAT rat than in the other three groups. Plasma insulin concentration was similar in the two H groups but higher than that of the two HGI groups. Compared to the H rat, the HGI rat was markedly glucose intolerant, with fat feeding causing comparable worsening of glucose intolerance in each group. The HGIFAT rats displayed a reduction in baseline myocardial contractility and relaxation and a higher end-diastolic pressure compared to the other three groups. Infarct size was significantly lower in the HGI rats than in the H rats. Although fat feeding did not affect infarct size of the H rat, it worsened that of the HGIFAT rat thereby abrogating the differential that existed between the H and HGI rats. In conclusion, excess fat feeding impairs myocardial function of HGI rats and increases their susceptibility to IRI. These findings are of relevance to the metabolic syndrome that manifests as a cluster of insulin resistance, dyslipidemia, and systemic hypertension.

Gestational high saturated fat diet alters C57BL/6 mouse skeletal formation

Gestational high saturated fat diet alters C57BL/6 mouse skeletal formation