Regional specific effect of saturated vs unsaturated fat on leptin receptor signalling in mice brain areas regulating feeding.

Leptin receptors (LepR) are expressed in brain areas controlling food intake homeostasis, such as the hypothalamus, the hippocampus and the prefrontal cortex. In a previous study we reported that long-term intake of saturated and monounsaturated fat alters hypothalamic LepR signalling. The current study aims at investigating the effect of foods high in either saturated (SOLF) or monounsaturated fat (UOLF) on LepR functionality in the hippocampus and the prefrontal cortex. Male mice were placed on SOLF/UOLF (eight weeks), then treated with recombinant murine leptin (1 mg/kg). After 60 min, brain regions were dissected and processed for western blot of phosphorylated STAT3 (pSTAT3), Akt (pAkt) and AMPK (pAMPK). Levels of SOCS3 were also quantified. SOLF itself increased basal levels of pSTAT3, while UOLF impaired leptin-induced phosphorylation of both Akt and AMPK. SOCS3 levels were specifically increased by UOLF within the prefrontal cortex. Our results show that SOLF and UOLF differently affect LepR signalling within the hippocampus and the prefrontal cortex, which points to the complex effect of saturated and unsaturated fat on brain function, particularly in areas regulating food intake.

Reduced phasic dopamine release and slowed dopamine uptake occur in the nucleus accumbens after a diet high in saturated but not unsaturated fat.

High-fat diets are linked with obesity and changes in dopamine neurotransmission. Mounting evidence shows that saturated fat impacts dopamine neurons and their terminal fields, but little is known about the effect a diet high in unsaturated fat has on the dopamine system. This study sought to determine whether fat type, saturated vs. unsaturated, differentially affected body weight, blood glucose regulation, locomotor behavior, and control of dopamine release and uptake at dopamine neuron terminals in the nucleus accumbens (NAc). C57BL/6 mice were fed a control diet or a nutrient-matched diet high in saturated fat (SF), unsaturated flaxseed oil (Flax) or a blend of the two fats. After 6-weeks, mice from each high-fat diet group gained significantly more weight than Controls, but the group fed Flax gained less weight than the SF group and had fasting blood glucose levels similar to Controls. Ex-vivo fast scan cyclic voltammetry revealed the SF group also had significantly slower synaptic dopamine clearance and a reduced capacity for phasic dopamine release in the nucleus accumbens (NAc), but the Flax and Blend groups resembled Controls. These data show that different types of dietary fat have substantially different effects on metabolic phenotype and influence how dopamine terminals in the NAc regulate dopamine neurotransmission. Our data also suggests that a diet high in unsaturated fat may preserve normal metabolic and behavioral parameters as well as dopamine signaling in the NAc.

The therapeutic effect of PEGlated nanoliposome of pistachio unsaturated oils and its efficacy to attenuate inflammation in multiple sclerosis: A randomized, double-blind, placebo-controlled clinical trial phase I.

The aim of this study was to evaluate the therapeutic effect of PEGlated nanoliposome of pistachio unsaturated oils (PEGNLPUOs) and their efficacy to attenuate inflammation in multiple sclerosis (MS). This study was a randomized, double-blind, placebo-controlled clinical trial phase I. The level of docosahexaenoic and eicosapentaenoic acid was significantly increased and the level of matrix metallopeptidase-9 was significantly decreased in MS patients treated with PEGNLPUOs. The level of cytokine showed a Th2-biased response with attenuation of inflammation after treatment with PEGNLPUOs. The number of relapses, disability scores, and T2 lesions was significantly decreased after treatment with PEGNLPUOs.

Overfeeding Saturated Fat Increases LDL (Low-Density Lipoprotein) Aggregation Susceptibility While Overfeeding Unsaturated Fat Decreases Proteoglycan-Binding of Lipoproteins.

Objective: We recently showed that measurement of the susceptibility of LDL (low-density lipoprotein) to aggregation is an independent predictor of cardiovascular events. We now wished to compare effects of overfeeding different dietary macronutrients on LDL aggregation, proteoglycan-binding of plasma lipoproteins, and on the concentration of oxidized LDL in plasma, 3 in vitro parameters consistent with increased atherogenicity. Approach and Results: The participants (36 subjects; age, 48+/-10 years; body mass index, 30.9+/-6.2 kg/m2) were randomized to consume an extra 1000 kcal/day of either unsaturated fat, saturated fat, or simple sugars (CARB) for 3 weeks. We measured plasma proatherogenic properties (susceptibility of LDL to aggregation, proteoglycan-binding, oxidized LDL) and concentrations and composition of plasma lipoproteins using nuclear magnetic resonance spectroscopy, and in LDL using liquid chromatography mass spectrometry, before and after the overfeeding diets. LDL aggregation increased in the saturated fat but not the other groups. This change was associated with increased sphingolipid and saturated triacylglycerols in LDL and in plasma and reduction of clusterin on LDL particles. Proteoglycan binding of plasma lipoproteins decreased in the unsaturated fat group relative to the baseline diet. Lipoprotein properties remained unchanged in the CARB group. Conclusions: The type of fat during 3 weeks of overfeeding is an important determinant of the characteristics and functional properties of plasma lipoproteins in humans.

Impact of short-term overfeeding of saturated or unsaturated fat or sugars on the gut microbiota in relation to liver fat in obese and overweight adults.

BACKGROUNDS & AIMS: Intestinal microbiota may be causally involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). We aimed to study the effect of short-term overfeeding on human gut microbiota in relation to baseline and overfeeding-induced liver steatosis. We also asked whether the baseline microbiota composition is associated to the overfeeding-induced increase in liver fat. METHODS: In a randomized trial, 38 overweight and obese subjects were assigned to consume an excess of 1000 kcal/day of diets rich in either saturated fat, unsaturated fat, or simple sugars for 3 weeks. Fasting blood samples and 1H-MR spectroscopy were used for extensive clinical phenotyping as previously reported (PMID: 29844096). Fecal samples were collected for the analysis of the gut microbiota using 16S rRNA amplicon sequencing, imputed metagenomics and qPCR. Microbiota results were correlated with dietary intakes and clinical measurements before and during overfeeding. RESULTS: The overall community structure of the microbiota remained highly stable and personalized during overfeeding based on between-sample Bray-Curtis dissimilarity, but the relative abundances of individual taxa were altered in a diet-specific manner: overfeeding saturated fat increased Proteobacteria, while unsaturated fat increased butyrate producers. Sugar overfeeding increased Lactococcus and Escherichia coli. Imputed functions of the gut microbiota were not affected by overfeeding. Several taxa affected by overfeeding significantly correlated with the changes in host metabolic markers. The baseline levels of proteobacterial family Desulfovibrionaceae, and especially genus Bilophila, were significantly associated to overfeeding-induced liver fat increase independently of the diet arm. In general, limited overlap was observed between the overfeeding-induced microbiota changes and the liver fat-associated microbiota features at baseline. CONCLUSIONS: Our work indicates that the human gut microbiota is resilient to short-term overfeeding on community level, but specific taxa are altered on diet composition-dependent manner. Generalizable microbiota signatures directly associated with liver steatosis could not be identified. Instead, the carriage of Bilophila was identified as a potential novel risk factor for diet-induced liver steatosis in humans. Clinical trial registry number: NCT02133144 listed on NIH website: ClinicalTrials.gov.

Magnitude of rise in proneurotensin is related to amount of triglyceride appearance in blood after standardized oral intake of both saturated and unsaturated fat.

BACKGROUND: In rodents, neurotensin contributes to high fat diet induced obesity by facilitation of intestinal fat absorption. The effect of oral lipid load on plasma proneurotensin and relationship with plasma triglycerides in humans is unknown. AIM: To investigate the acute effects of an oral lipid load on proneurotensin and plasma triglycerides and their interrelationships in healthy individuals. SETTING/ METHODS: Twenty-two healthy subjects were given 150 mL of full milk cream (54 g fat) and 59 mL of pure olive oil (54 g fat) in the fasted state at two different occasions separated by at least 1 week in random order. Venous blood was drawn at fasted before 0 h (h) and at 1 h, 2 h and 4 h after ingestion. Post-ingested values of proneurotensin and plasma triglycerides were compared with fasting levels and post ingestion Area Under the Curve (AUC) of proneurotensin was correlated with that of plasma triglycerides. RESULTS: An immediate rise of plasma proneurotensin and plasma triglycerides were observed after ingestion of cream with maximum increase at 2 h for proneurotensin [mean (95% confidence interval)] of 22 (12-31) pmol/L (P < 0.001) and at 3 h for triglycerides of 0.60 (0.43-0.78) mmol/L (P < 0.001). Similarly, plasma proneurotensin and plasma triglycerides increased after ingestion of olive oil with maximum increase of proneurotensin at 3 h of 62 (46-78) pmol/L (P < 0.001) and plasma triglycerides at 3 h of 0.32 (0.18-0.45) mmol/L (P < 0.001). The post lipid load AUC for proneurotensin correlated significantly with the AUC for plasma triglycerides both after cream (r = 0.49, P = 0.021) and olive oil (r = 0.55, P = 0.008), respectively. CONCLUSION: Proneurotensin increases after an oral lipid load of both cream and olive oil and the rise of post-ingestion plasma triglycerides is significantly related to the rise of post-ingestion proneurotensin.

Gender differences on oxidative stress markers and complement component C3 plasma values after an oral unsaturated fat load test / Diferencias de género en los marcadores de estrés oxidativo y los valores plasmáticos del componente c3 del complemento tras una sobrecarga oral con grasa insaturada

OBJECTIVE: Post-prandial lipaemia (PL), oxidative stress (OS), and complement component C3 (C3) values are related to the atherosclerosis process. The post-prandial response of C3 after an oral fat load test (OFLT) using unsaturated fat is poorly addressed. The aim of this study was to analyze and compare the post-prandial response of OS markers and C3 values in men and women after an OFLT using unsaturated fat. METHODS: The study included a total of 22 healthy subjects with normal lipids and normal blood glucose (11 men and 11 pre-menopausal women). An oral unsaturated fat load test (OFLT: 50g fat per m2 body surface) was performed using a commercial liquid preparation of long chain triglycerides (Supracal®). OS markers and C3 were measured using standardized methods at fasting state and every 2h up to 8h after the OFLT. RESULTS: Men showed statistically significant higher C3, oxidized glutathione (GSSG), and oxidized-reduced glutathione (GSSG/GSH) ratio values at fasting state compared to that obtained in women. In addition, post-prandial C3 values and GSSG/GSH ratios were significantly higher in men compared to women. The GSSG value and GSSG/GSH ratio significantly decreased in men after the OFLT compared to fasting values. In contrast, the post-prandial OS markers decrease observed in women was not statistically significant. CONCLUSIONS: In fasting state, men showed higher statistically significant C3 values and OS markers than women. The post-prandial OS markers (GSSG and GSSG/GSH ratio) significantly decrease after the OFLT with unsaturated fat in men compared to women

OBJETIVO: Los valores de lipemia postprandial (PL), estrés oxidativo (OS) y componente C3 del complemento (C3) están relacionados con el proceso de aterosclerosis. La respuesta postprandial de C3 tras una sobrecarga oral de grasa (OFLT) utilizando grasa insaturada no es completamente conocida. Nuestro objetivo fue analizar y comparar la respuesta postprandial de los marcadores de OS y los valores de C3 en hombres y mujeres después de una OFLT utilizando grasa insaturada. MÉTODOS: Estudiamos 22 sujetos normolipidémicos y normoglicémicos (11 hombres y 11 mujeres premenopáusicas). Se realizó una sobrecarga oral con grasa insaturada (OFLT: 50g de grasa por m2 de superficie corporal) utilizando una preparación líquida comercial de triglicéridos de cadena larga (Supracal®). Los marcadores OS y C3 se midieron utilizando métodos estandarizados en estado de ayuno y cada 2 horas hasta 8 horas después de OFLT. RESULTADOS: Los hombres mostraron valores significativamente mayores de C3, glutatión oxidado (GSSG) y glutatión reducido (GSSG/GSH) en estado de ayuno en comparación con los obtenidos en mujeres. Además, los valores de C3 postprandiales y la relación GSSG/GSH fueron significativamente más altos en los hombres que en las mujeres. El valor GSSG y la relación GSSG/GSH disminuyeron significativamente en los hombres después de OFLT en comparación con los valores de ayuno. En contraste, la disminución de marcadores postprandiales de OS observada en mujeres no fue estadísticamente significativa. CONCLUSIONES: En ayunas, los hombres muestran valores estadísticamente mayores de C3 y marcadores OS que las mujeres. Los marcadores OS postprandial (GSSG y GSSG/GSH ratio) disminuyen significativamente tras OFLT con grasa insaturada en los hombres en comparación con las mujeres

Gender differences on oxidative stress markers and complement component C3 plasma values after an oral unsaturated fat load test.

OBJECTIVE: Post-prandial lipaemia (PL), oxidative stress (OS), and complement component C3 (C3) values are related to the atherosclerosis process. The post-prandial response of C3 after an oral fat load test (OFLT) using unsaturated fat is poorly addressed. The aim of this study was to analyze and compare the post-prandial response of OS markers and C3 values in men and women after an OFLT using unsaturated fat. METHODS: The study included a total of 22 healthy subjects with normal lipids and normal blood glucose (11 men and 11 pre-menopausal women). An oral unsaturated fat load test (OFLT: 50g fat per m2 body surface) was performed using a commercial liquid preparation of long chain triglycerides (Supracal®). OS markers and C3 were measured using standardized methods at fasting state and every 2h up to 8h after the OFLT. RESULTS: Men showed statistically significant higher C3, oxidized glutathione (GSSG), and oxidized-reduced glutathione (GSSG/GSH) ratio values at fasting state compared to that obtained in women. In addition, post-prandial C3 values and GSSG/GSH ratios were significantly higher in men compared to women. The GSSG value and GSSG/GSH ratio significantly decreased in men after the OFLT compared to fasting values. In contrast, the post-prandial OS markers decrease observed in women was not statistically significant. CONCLUSIONS: In fasting state, men showed higher statistically significant C3 values and OS markers than women. The post-prandial OS markers (GSSG and GSSG/GSH ratio) significantly decrease after the OFLT with unsaturated fat in men compared to women.

Replacing Saturated Fats with Unsaturated Fats from Walnuts or Vegetable Oils Lowers Atherogenic Lipoprotein Classes Without Increasing Lipoprotein(a).

BACKGROUND: Walnuts have established lipid-/lipoprotein-lowering properties; however, their effect on lipoprotein subclasses has not been investigated. Furthermore, the mechanisms by which walnuts improve lipid/lipoprotein concentrations are incompletely understood. OBJECTIVES: We aimed to examine, as exploratory outcomes of this trial, the effect of replacing SFAs with unsaturated fats from walnuts or vegetable oils on lipoprotein subclasses, cholesterol efflux, and proprotein convertase subtilisin/kexin type 9 (PCSK9). METHODS: A randomized, crossover, controlled-feeding study was conducted in individuals at risk of cardiovascular disease (CVD) (n = 34; 62% men; mean ± SD age 44 ± 10 y; BMI: 30.1 ± 4.9 kg/m2). After a 2-wk run-in diet (12% SFAs, 7% PUFAs, 12% MUFAs), subjects consumed the following diets, in randomized order, for 6 wk: 1) walnut diet (WD) [57-99 g/d walnuts, 7% SFAs, 16% PUFAs [2.7% α-linolenic acid (ALA)], 9% MUFAs]; 2) walnut fatty acid-matched diet [7% SFAs, 16% PUFAs (2.6% ALA), 9% MUFAs]; and 3) oleic acid replaces ALA diet (ORAD) [7% SFAs, 14% PUFAs (0.4% ALA); 12% MUFAs] (all percentages listed are of total kilocalories ). Serum collected after the run-in (baseline) and each diet period was analyzed for lipoprotein classes and subclasses (vertical auto profile), cholesterol efflux, and PCSK9. Linear mixed models were used for data analysis. RESULTS: Compared with the ORAD, total cholesterol (mean ± SEM -8.9± 2.3 mg/dL; -5.1%; P < 0.001), non-HDL cholesterol (-7.4 ± 2.0 mg/dL; -5.4%; P = 0.001), and LDL cholesterol (-6.9 ± 1.9 mg/dL; -6.5%; P = 0.001) were lower after the WD; no other pairwise differences existed. There were no between-diet differences for HDL-cholesterol or LDL-cholesterol subclasses. Lipoprotein(a) [Lp(a)], cholesterol efflux, and PCSK9 were unchanged after the diets. CONCLUSIONS: In individuals at risk of CVD, replacement of SFAs with unsaturated fats from walnuts or vegetable oils improved lipid/lipoprotein classes, including LDL-cholesterol, non-HDL cholesterol, and total cholesterol, without an increase in Lp(a). These improvements were not explained by changes in cholesterol efflux capacity or PCSK9. This trial was registered at clinicaltrials.gov as NCT01235832.

Gene expression profile following an oral unsaturated fat load in abdominal obese subjects.

PURPOSE: Our aim was to evaluate the postprandial effect of an oral fat load test (OFLT) rich in unsaturated fatty acids on gene expression profile in peripheral blood mononuclear cells (PBMC) from subjects with abdominal obesity as an insulin resistance model and controls. METHODS: A total of 20 controls and 20 abdominal obese patients were studied. Metabolic parameters and oxidative stress markers were measured with standardized protocols. The whole gene expression at fasting state and after the OFLT (0, 4 and 8 h) was analysed using human HT-12-v4 expression beadchips, from Illumina. RESULTS: We found a significant decrease in plasma glucose, insulin and oxidative stress markers in abdominal obese patients and controls. We found beneficial metabolic postprandial gene expression in three genes: FKBP5, DDIT4 and DHRS9. Following an OFLT, the postprandial mRNA expression of FKBP5, and DDIT4 was downregulated while that of DHRS9 was overexpressed, both in nondiabetic normolipidemic subjects and in insulin-resistant subjects with abdominal obesity. CONCLUSIONS: Our results suggest that an OFLT rich in unsaturated fatty acids downregulates the expression of FKBP5, coding for the glucocorticoid receptor pathway, and that of DDIT4, involved in the oxidative stress response. These changes could favourably influence the insulin resistance and oxidative stress status in the postprandial state.

Appetite responses to high-fat diets rich in mono-unsaturated versus poly-unsaturated fats.

BACKGROUND: Modifying the type of dietary fat consumed may impact appetite, therefore having implications in weight management. OBJECTIVE: To test the effects of a 5-day, high-fat diet rich in poly-unsaturated fatty acids (PUFAs) and a diet rich in mono-unsaturated fatty acids (MUFAs) on markers of appetite. METHODS: Fifteen normal weight men participated in a randomized cross-over design with two controlled feeding trials (3d lead-in diet, pre-diet visit, 5d PUFA- or MUFA-rich diet, post-diet visit). The 5d diets (50% fat) were rich in either PUFA (25% of energy) or MUFA (25% of energy). At pre- and post-diet visits, subjects consumed breakfast and lunch test meals, rich in the FA corresponding to the 5-day diet. Fasting and postprandial subjective ratings of appetite were determined and blood draws were performed for 4h after each meal to determine changes in appetite hormones. An ad libitum buffet meal was given at the end of pre- and post-diet visits. RESULTS: Acutely, at the pre-diet visit, the PUFA-rich meal resulted in lower ghrelin (hunger hormone) (iAUC: -350.85 ±â€¯60.70 vs. -233.16 ±â€¯61.42 pg/ml/8h, for PUFA vs. MUFA, respectively; p < 0.05) and higher CCK (satiation hormone) (iAUC: 238.09 ±â€¯46.07 vs. 196.84 ±â€¯33.92 pM/8h, for PUFA vs. MUFA, respectively; p < 0.05). No other acute meal challenge differences were found. The 5d high PUFA diet resulted in lower hunger ratings (iAUC: -172.06 ±â€¯40.59 vs. -274.46 ±â€¯41.47 mm/8h, for pre-to post-diet, respectively; p < 0.05). However, energy intake, ratings of fullness, or PYY did not change from pre-to post-diet for either MUFA or PUFA, and no other changes were observed with the MUFA diet. CONCLUSIONS: Acutely, a PUFA-rich meal results in ghrelin suppression and higher CCK. After a 5-day high-fat diet, PUFAs suppressed postprandial hunger while MUFAs did not change any measures of appetite.

Effects of an energy-restricted low-carbohydrate, high unsaturated fat/low saturated fat diet versus a high-carbohydrate, low-fat diet in type 2 diabetes: A 2-year randomized clinical trial.

AIM: To examine whether a low-carbohydrate, high-unsaturated/low-saturated fat diet (LC) improves glycaemic control and cardiovascular disease (CVD) risk factors in overweight and obese patients with type 2 diabetes (T2D). METHODS: A total of 115 adults with T2D (mean [SD]; BMI, 34.6 [4.3] kg/m2 ; age, 58 [7] years; HbA1c, 7.3 [1.1]%) were randomized to 1 of 2 planned energy-matched, hypocaloric diets combined with aerobic/resistance exercise (1 hour, 3 days/week) for 2 years: LC: 14% energy as carbohydrate, 28% as protein, 58% as fat (<10% saturated fat); or low-fat, high-carbohydrate, low-glycaemic index diet (HC): 53% as CHO, 17% as protein, 30% as fat (<10% saturated fat). HbA1c, glycaemic variability (GV), anti-glycaemic medication effect score (MES, calculated based on the potency and dosage of diabetes medication), weight, body composition, CVD and renal risk markers were assessed before and after intervention. RESULTS: A total of 61 (LC = 33, HC = 28) participants completed the study (trial registration: http://www.anzctr.org.au/, ANZCTR No. ACTRN12612000369820). Reductions in weight (estimated marginal mean [95% CI]; LC, -6.8 [-8.8,-4.7], HC, -6.6 [-8.8, -4.5] kg), body fat (LC, -4.3 [-6.2, -2.4], HC, -4.6 [-6.6, -2.7] kg), blood pressure (LC, -2.0 [-5.9, 1.8]/ -1.2 [-3.6, 1.2], HC, -3.2 [-7.3, 0.9]/ -2.0 [-4.5, 0.5] mmHg), HbA1c (LC, -0.6 [-0.9, -0.3], HC, -0.9 [-1.2, -0.5] %) and fasting glucose (LC, 0.3 [-0.4, 1.0], HC, -0.4 [-1.1, 0.4] mmol/L) were similar between groups (P ≥ 0.09). Compared to HC, the LC achieved greater reductions in diabetes medication use (MES; LC, -0.5 [-0.6, -0.3], HC, -0.2 [-0.4, -0.02] units; P = 0.03), GV (Continuous Overall Net Glycemic Action calculated every 1 hour (LC, -0.4 [-0.6, -0.3], HC, -0.1 [-0.1, 0.2] mmol/L; P = 0.001), and 4 hours (LC, -0.9 [-1.3, -0.6], HC, -0.2 [-0.6, 0.1] mmol/L; P = 0.02)); triglycerides (LC, -0.1 [-0.3, 0.2], HC, 0.1 [-0.2, 0.3] mmol/L; P = 0.001), and maintained HDL-C levels (LC, 0.02 [-0.05, 0.1], HC, -0.1 [-0.1, 0.01] mmol/L; P = 0.004), but had similar changes in LDL-C (LC, 0.2 [-0.1, 0.5], HC, 0.1 [-0.2, 0.4] mmol/L; P = 0.85), brachial artery flow mediated dilatation (LC, -0.5 [-1.5, 0.5], HC, -0.4 [-1.4, 0.7] %; P = 0.73), eGFR and albuminuria. CONCLUSIONS: Both diets achieved comparable weight loss and HbA1c reductions. The LC sustained greater reductions in diabetes medication requirements, and in improvements in diurnal blood glucose stability and blood lipid profile, with no adverse renal effects, suggesting greater optimization of T2D management.

Problems with the 2015 Dietary Guidelines for Americans. An Alternative.

The updated 2015 Dietary Guidelines for Americans, published in January 2016, have stirred much controversy since the advisory report first appeared. Several important changes have been made, with some recommendations having greater scientific evidence for their support than others. The focus of this review is to discuss specific recommendations from the 2015 Dietary Guidelines for Americans that lack sound scientific evidence; these include: 1) Allowing approximately half of all grains to be refined; 2) The continued recommendations for fat-free or low-fat dairy and limitation of saturated fat intake to <10% of calories; 3) Sodium intake < 2,300 mg/day; and 4) Consumption of up to 27 g/day of "oils" (high in polyunsaturated fat or monounsaturated fat). Based on our review, the aforementioned recommendations found in the updated 2015 Dietary Guidelines for Americans may increase the incidence of cardiometabolic disease, diabetes, obesity, dyslipidemia, cardiovascular disease and possibly cancer.

[Effect of fats on cardiovascular disease prevention in Denmark].

In Denmark death from cardiovascular disease (CVD) has decreased, mainly due to a 72% reduction since 1990 in death from ischaemic heart disease from reduced smoking, elimination of industrial trans fatty acids in the diet, and more effective medical treatment. Replacement of saturated fat by carbohydrate and/or n-6 polyunsaturated fat may increase CVD, but it is reduced by substitution with n-3 fats, monounsaturated fat, or low glycaemic index carbohydrates. Despite a high saturated fat content dark chocolate and cheese may reduce CVD and diabetes risk and eggs may be neutral, and less restrictive dietary recommendations are indicated.

Dietary lipid unsaturation influences survival and oxidative modifications of an amyotrophic lateral sclerosis model in a gender-specific manner.

The implication of lipid peroxidation in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) derive from high abundance of peroxidation-prone polyunsaturated fatty acids in central nervous system and its relatively low antioxidant content. In the present work, we evaluated the effect of dietary changes aimed to modify fatty acid tissular composition in survival, disease onset, protein, and DNA oxidative modifications in the hSODG93A transgenic mice, a model of this motor neuron disease. Both survival and clinical evolution is dependent on dietary fatty acid unsaturation and gender, with high unsaturated diet, leading to loss of the disease-sparing effect of feminine gender. This was associated with significant increases in protein carbonyl and glycoxidative modifications as well as non-nuclear 8-oxo-dG, a marker of mitochondrial DNA oxidation. Comparison of these data with γH2AX immunostaining, a marker of DNA damage response, suggests that the highly unsaturated diet-blunted mitochondrial-nuclear free radical dependent crosstalk, since increased 8-oxo-dG was not correlated with increased DNA damage response. Paradoxically, the highly unsaturated diet led to lower peroxidizability but higher anti-inflammatory indexes. To sum up, our results demonstrate that high polyunsaturated fatty acid content in diets may accelerate the disease in this model. Further, these results reinforce the need for adequately defining gender as a relevant factor in ALS models, as well as to use structurally characterized markers for oxidative damage assessment in neurodegeneration.

The effects of carbohydrate, unsaturated fat, and protein intake on measures of insulin sensitivity: results from the OmniHeart trial.

OBJECTIVE: Impaired insulin sensitivity increases the risk of cardiovascular disease. Although calorie restriction and weight loss increase insulin sensitivity, the effects of modifying macronutrient composition on insulin sensitivity are uncertain. The purpose of this study is to determine the effects on insulin sensitivity of a carbohydrate-rich diet (CARB; similar to the Dietary Approaches to Stop Hypertension [DASH] diet), a protein-rich diet (PROT; protein predominantly from plant sources), and an unsaturated fat-rich diet (UNSAT; predominantly monounsaturated). RESEARCH DESIGN AND METHODS: This study was a randomized, controlled, three-period, crossover feeding study. The study participants were 164 individuals with prehypertension or stage 1 hypertension without diabetes. Diets were administered for 6 weeks each, with a washout period between diets of 2-4 weeks. Weight was held constant throughout the study. For our primary outcome, we calculated the quantitative insulin sensitivity check index (QUICKI) using the end-of-period fasting serum glucose and insulin. QUICKI is a validated measure of insulin sensitivity. The primary analyses used generalized estimating equations. RESULTS: At baseline, mean (SD) BMI was 30.2 (6.1) kg/m(2), and mean (SD) QUICKI was 0.35 (0.04). The UNSAT diet increased QUICKI by 0.005, more than the CARB diet (P = 0.04). PROT had no significant effect compared with CARB. CONCLUSIONS: A diet that partially replaces carbohydrate with unsaturated fat may improve insulin sensitivity in a population at risk for cardiovascular disease. Given the well-recognized challenges of sustaining weight loss, our results suggest an alternative approach for improving insulin sensitivity.

Reduced or modified dietary fat for preventing cardiovascular disease.

BACKGROUND: Reduction and modification of dietary fats have differing effects on cardiovascular risk factors (such as serum cholesterol), but their effects on important health outcomes are less clear. OBJECTIVES: To assess the effect of reduction and/or modification of dietary fats on mortality, cardiovascular mortality, cardiovascular morbidity and individual outcomes including myocardial infarction, stroke and cancer diagnoses in randomised clinical trials of at least 6 months duration. SEARCH METHODS: For this review update, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE, were searched through to June 2010. References of Included studies and reviews were also checked. SELECTION CRITERIA: Trials fulfilled the following criteria: 1) randomised with appropriate control group, 2) intention to reduce or modify fat or cholesterol intake (excluding exclusively omega-3 fat interventions), 3) not multi factorial, 4) adult humans with or without cardiovascular disease, 5) intervention at least six months, 6) mortality or cardiovascular morbidity data available. DATA COLLECTION AND ANALYSIS: Participant numbers experiencing health outcomes in each arm were extracted independently in duplicate and random effects meta-analyses, meta-regression, sub-grouping, sensitivity analyses and funnel plots were performed. MAIN RESULTS: This updated review suggested that reducing saturated fat by reducing and/or modifying dietary fat reduced the risk of cardiovascular events by 14% (RR 0.86, 95% CI 0.77 to 0.96, 24 comparisons, 65,508 participants of whom 7% had a cardiovascular event, I(2) 50%). Subgrouping suggested that this reduction in cardiovascular events was seen in studies of fat modification (not reduction - which related directly to the degree of effect on serum total and LDL cholesterol and triglycerides), of at least two years duration and in studies of men (not of women). There were no clear effects of dietary fat changes on total mortality (RR 0.98, 95% CI 0.93 to 1.04, 71,790 participants) or cardiovascular mortality (RR 0.94, 95% CI 0.85 to 1.04, 65,978 participants). This did not alter with sub-grouping or sensitivity analysis.Few studies compared reduced with modified fat diets, so direct comparison was not possible. AUTHORS' CONCLUSIONS: The findings are suggestive of a small but potentially important reduction in cardiovascular risk on modification of dietary fat, but not reduction of total fat, in longer trials. Lifestyle advice to all those at risk of cardiovascular disease and to lower risk population groups, should continue to include permanent reduction of dietary saturated fat and partial replacement by unsaturates. The ideal type of unsaturated fat is unclear.

Saturated fat, carbohydrates and cardiovascular disease.

The dietary intake of saturated fatty acids (SAFA) is associated with a modest increase in serum total cholesterol, but not with cardiovascular disease (CVD). Replacing dietary SAFA with carbohydrates (CHO), notably those with a high glycaemic index, is associated with an increase in CVD risk in observational cohorts, while replacing SAFA with polyunsaturated fatty acids (PUFA) is associated with reduced CVD risk. However, replacing a combination of SAFA and trans-fatty acids with n-6 PUFA (notably linoleic acid) in controlled trials showed no indication of benefit and a signal toward increased coronary heart disease risk, suggesting that n-3 PUFA may be responsible for the protective association between total PUFA and CVD. High CHO intakes stimulate hepatic SAFA synthesis and conservation of dietary SAFA . Hepatic de novo lipogenesis from CHO is also stimulated during eucaloric dietary substitution of SAFA by CHO with high glycaemic index in normo-insulinaemic subjects and during hypocaloric high-CHO/low-fat diets in subjects with the metabolic syndrome. The accumulation of SAFA stimulates chronic systemic low-grade inflammation through its mimicking of bacterial lipopolysaccharides and÷or the induction of other pro-inflammatory stimuli. The resulting systemic low-grade inflammation promotes insulin resistance, reallocation of energy-rich substrates and atherogenic dyslipidaemia that concertedly give rise to increased CVD risk. We conclude that avoidance of SAFA accumulation by reducing the intake of CHO with high glycaemic index is more effective in the prevention of CVD than reducing SAFA intake per se.

Dietary fat and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Epidemiologic studies have produced conflicting results with respect to an association of dietary fat with breast cancer. OBJECTIVE: We aimed to investigate the association between fat consumption and breast cancer. DESIGN: We prospectively investigated fat consumption in a large (n = 319,826), geographically and culturally heterogeneous cohort of European women enrolled in the European Prospective Investigation into Cancer and Nutrition who completed a dietary questionnaire. After a mean of 8.8 y of follow-up, 7119 women developed breast cancer. Cox proportional hazard models, stratified by age and center and adjusted for energy intake and confounders, were used to estimate hazard ratios (HRs) for breast cancer. RESULTS: An association between high saturated fat intake and greater breast cancer risk was found [HR = 1.13 (95% CI: 1.00, 1.27; P for trend = 0.038) for the highest quintile of saturated fat intake compared with the lowest quintile: 1.02 (1.00, 1.04) for a 20% increase in saturated fat consumption (continuous variable)]. No significant association of breast cancer with total, monounsaturated, or polyunsaturated fat was found, although trends were for a direct association of risk with monounsaturated fat and an inverse association with polyunsaturated fat. In menopausal women, the positive association with saturated fat was confined to nonusers of hormone therapy at baseline [1.21 (0.99, 1.48) for the highest quintile compared with the lowest quintile; P for trend = 0.044; and 1.03 (1.00, 1.07) for a 20% increase in saturated fat as a continuous variable]. CONCLUSIONS: Evidence indicates a weak positive association between saturated fat intake and breast cancer risk. This association was more pronounced for postmenopausal women who never used hormone therapy.

Dietary fat in infancy should be more focused on quality than on quantity.

OBJECTIVE: The primary aim was to assess, the association of the quantity and quality of dietary fat intake from 6 to 12 months of age and serum lipids at 12 months. SUBJECTS/METHODS: Three hundred healthy term Swedish infants were recruited in a longitudinal prospective study at the age of 6 months; 276 remained in the study at 12 months. Food records and anthropometric data were collected monthly from 6 to 12 months; serum lipids were analysed at 6 and 12 months. RESULTS: Swedish infants had a total fat intake within the Nordic recommendations, but intake of polyunsaturated fatty acids (PUFA) was low (5.6 percent of total energy (E%)) and intake of saturated fatty acids (SAFA) was high (15.1 E%). Higher PUFA intake was associated with lower total serum cholesterol (TC, B=-0.13, P=0.003), lower low-density-lipoprotein cholesterol (LDL-C, B=-0.12, P=0.004) and apolipoprotein B (B=-0.03) (P=0.034) in girls but not in boys. When data from the present study were compared to data from similar studies in Finland and Iceland, it appears that the quality of the dietary fat has greater impact on serum lipid levels than the quantity of fat in the diet. CONCLUSIONS: Higher PUFA and lower SAFA intakes may reduce TC and LDL-C early in life, particularly in girls. Further, with respect to lowering serum lipid concentrations in early childhood it seems appropriate to set focus on fat quality rather than the quantity. SPONSORSHIPS: Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (Formas), Swedish Research Council, Medicine, Stiftelsen Oskar Foundation, Sven Jerring Foundation, Samariten Foundation, Stiftelsen Goljes minne and Semper AB.