Metabolic Fitness in Active Reduced-Obese Individuals

TREMBLAY, ANGELO, ERIC DOUCET, PASCAL IMBEAULT, PASCALE MAURIÈGE, JEAN-PIERRE DESPRÉS, AND DENIS RICHARD. Metabolic fitness in active reduced-obese individuals. Obes Res. Objective: To verify whether a physical activity-low-fat diet follow-up could normalize the metabolic risk profile of reduced-obese men and women having undergone considerable weight loss through energy restriction and drug therapy. Research Methods and Procedures: Twenty obese individuals (12 men, 8 women) participated in a weight-reducing program that included two phases. In the first phase, a non-macronutrient-specific dietary restriction of about 700 kcal/day was prescribed to induce weight loss over 15 weeks, with either fenfluramine or placebo. The second phase consisted of a physical activity-low-fat diet follow-up that was maintained as long as subjects did not experience resistance to further body weight and fat loss. Resistance to lose fat occurred after a mean cumulative fat loss of 14 and 8 kg in men and women, respectively. Results: Despite this substantial decrease in body fat, subjects' adiposity remained much higher at the end of this protocol than values observed in lean control subjects. However, fasting plasma levels of insulin, cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, and triglyceride as well as the response of insulin and glucose to oral glucose were normalized at the end of the physical activity-low-fat diet follow-up. Discussion: These results indicate that further weight and fat losses may not be justified when a moderate body weight loss resulting in a highly favorable improvement of metabolic risk profile is achieved in patients who would have still been diagnosed as overweight or obese on the basis of criteria currently promoted by public health agencies.     

Fucoxanthin-rich seaweed extract suppresses body weight gain and improves lipid metabolism in high-fat-fed C57BL/6J mice

An ethanol extract of fucoxanthin-rich seaweed was examined for its effectiveness as a nutraceutical for body fat-lowering agent and for an antiobese effect based on mode of actions in C57BL/6J mice. Animals were randomized to receive a semi-purified high-fat diet (20% dietary fat, 10% corn oil and 10% lard) supplemented with 0.2% conjugated linoleic acid (CLA) as the positive control, 1.43% or 5.72% fucoxanthin-rich seaweed ethanol extract (Fx-SEE), equivalent to 0.05% or 0.2% dietary fucoxanthin for six weeks. Results showed that supplementation with both doses of Fx-SEE significantly reduced body and abdominal white adipose tissue (WAT) weights, plasma and hepatic triglyceride (TG), and/or cholesterol concentrations compared to the high-fat control group. Activities of adipocytic fatty acid (FA) synthesis, hepatic FA and TG synthesis, and cholesterol–regulating enzyme were also lowered by Fx-SEE supplement. Concentrations of plasma high-density lipoprotein-cholesterol, fecal TG and cholesterol, as well as FA oxidation enzyme activity and UCP1 mRNA expression in epididymal WAT were significantly higher in the Fx-SEE groups than in the high-fat control group. CLA treatment reduced the body weight gain and plasma TG concentration. Overall, these results indicate that Fx-SEE affects the plasma and hepatic lipid profile, fecal lipids and body fat mass, and alters hepatic cholesterol metabolism, FA synthesis and lipid absorption.     

Leptin promotes biliary cholesterol elimination during weight loss in ob/ob mice by regulating the enterohepatic circulation of bile salts

Leptin administration to obese C57BL/6J (ob/ob) mice results in weight loss by reducing body fat. Because adipose tissue is an important storage depot for cholesterol, we explored evidence that leptin-induced weight loss in ob/ob mice was accompanied by transport of cholesterol to the liver and its elimination via bile. Consistent with mobilization of stored cholesterol, cholesterol concentrations in adipose tissue remained unchanged during weight loss. Plasma cholesterol levels fell sharply, and microscopic analyses of gallbladder bile revealed cholesterol crystals as well as cholesterol gallstones. Surprisingly, leptin reduced biliary cholesterol secretion rates without affecting secretion rates of bile salts or phospholipids. Instead, cholesterol supersaturation of gallbladder bile was due to marked decreases in bile salt hydrophobicity and not to hypersecretion of biliary cholesterol per se, such as occurs in humans during weight loss. In addition to regulating bile salt composition, leptin treatment decreased bile salt pool size. The smaller, more hydrophilic bile salt pool was associated with substantial decreases in intestinal cholesterol absorption. Within the liver, leptin treatment reduced the activity of 3-hydroxy-3-methylglutaryl-CoA reductase, but it did not change activities of cholesterol 7alpha-hydroxylase or acyl-CoA:cholesterol acyltransferase. These data suggest that leptin regulates biliary lipid metabolism to promote efficient elimination of excess cholesterol stored in adipose tissue. Cholesterol gallstone formation during weight loss in ob/ob mice appears to represent a pathologic consequence of an adaptive response that prevents absorption of biliary and dietary cholesterol.     

Scallop protein with endogenous high taurine and glycine content prevents high-fat,high-sucrose-induced obesity and improves plasma lipid profile in male C57BL/6J mice

High-protein diets induce alterations in metabolism that may prevent diet-induced obesity. However, little is known as to whether different protein sources consumed at normal levels may affect diet-induced obesity and associated co-morbidities. We fed obesity-prone male C57BL/6J mice high-fat, high-sucrose diets with protein sources of increasing endogenous taurine content, i.e., chicken, cod, crab and scallop, for 6 weeks. The energy intake was lower in crab and scallop-fed mice than in chicken and cod-fed mice, but only scallop-fed mice gained less body and fat mass. Liver mass was reduced in scallop-fed mice, but otherwise no changes in lean body mass were observed between the groups. Feed efficiency and apparent nitrogen digestibility were reduced in scallop-fed mice suggesting alterations in energy utilization and metabolism. Overnight fasted plasma triacylglyceride, non-esterified fatty acids, glycerol and hydroxy-butyrate levels were significantly reduced, indicating reduced lipid mobilization in scallop-fed mice. The plasma HDL-to-total-cholesterol ratio was higher, suggesting increased reverse cholesterol transport or cholesterol clearance in scallop-fed mice in both fasted and non-fasted states. Dietary intake of taurine and glycine correlated negatively with body mass gain and total fat mass, while intake of all other amino acids correlated positively. Furthermore taurine and glycine intake correlated positively with improved plasma lipid profile, i.e., lower levels of plasma lipids and higher HDL-to-total-cholesterol ratio. In conclusion, dietary scallop protein completely prevents high-fat, high-sucrose-induced obesity whilst maintaining lean body mass and improving the plasma lipid profile in male C57BL/6J mice.     

Polymorphisms in ABCG5 and ABCG8 transporters and plasma cholesterol levels

ABCG5 and ABCG8 transporters play an important role in the absorption and excretion of sterols. Missence polymorphisms (Gln604Glu in the ABCG5 and Asp19His, Tyr54Cys, Thr400Lys, and Ala632Val in the ABCG8) in these genes have been described. In 131 males and 154 females whose dietary composition markedly changed and lipid parameters decreased over an 8-year follow-up study (total cholesterol decreased from 6.21+/-1.31 mmol/l in 1988 to 5.43+/-1.06 mmol/l in 1996), these polymorphisms were investigated using PCR. Plasma lipid levels and changes in plasma lipid levels were independent of the Gln604Glu polymorphism in ABCG5 and Asp19His and the Ala632Val polymorphisms in ABCG8. The Tyr54Cys polymorphism influenced the degree of reduction in total plasma cholesterol (delta -0.49 mmol/l in Tyr54 homozygotes vs. delta +0.12 mmol/l in Cys54 homozygotes, p<0.04) and LDL-cholesterol (delta -0.57 mmol/l in Tyr54 homozygotes vs. delta +0.04 mmol/l in Cys54 homozygotes, p<0.03) levels between 1988 and 1996 in females, but not in males. Male Thr400 homozygotes exhibited a greater decrease in total cholesterol (delta -0.90 mmol/l vs. delta -0.30 mmol/l, p<0.02) and LDL-cholesterol (delta -0.62 mmol/l vs. delta -0.19 mmol/l, p<0.04) than Lys400 carriers. No such association was observed in females. We conclude that Tyr54Cys and Thr400Lys variations in the ABCG8 gene may play a role in the genetic determination of plasma cholesterol levels and could possibly influence the gender-specific response of plasma cholesterol levels after dietary changes. These polymorphisms are of potential interest as genetic variants that may influence the lipid profile.     

Coconut oil induces short-term changes in lipid composition and enzyme activity of chick hepatic mitochondria

We studied the short-term effects of a 20% coconut oil supplementation to the chick diet on lipid composition of liver and hepatic mitochondria, and changes that occurred in mitochondrial-associated enzymes as a result of this diet. No significant differences were observed in the lipid contents of liver when young chicks were fed the experimental diet, whereas hepatic mitochondria rapidly changed in response to this diet. Total cholesterol significantly increased in mitochondria at 24 hours of coconut oil diet feeding and decreased when dietary treatment was prolonged for 5 to 14 days. Changes in total mitochondrial phospholipids showed an inverse profile. A significant decrease in phosphatidylethanolamine and an increase in sphingomyelin were found at 24 hours. The cholesterol/phospholipid molar ratio significantly and rapidly (24 hours) increased in mitochondria from treated animals. Cytochrome oxidase activity drastically increased after 24 hours of experimental diet feeding and lowered to the control values when dietary manipulation was prolonged for 5 to 14 days. ATPase activity showed an inverse profile. Changes in cytochrome oxidase activity were parallel to changes in the cholesterol/phospholipid molar ratio, whereas changes in ATPase activity showed an inverse correlation with changes in this molar ratio. To our knowledge, this is one of the first reports on the very rapid response (24 hours) of mitochondrial lipid composition and function to saturated fat feeding.     

Core modification of human low-density lipoprotein by artificial triacylglycerol emulsion

To determine whether an apolipoprotein-free artificial triacylglycerol emulsion can substitute for VLDL in studying cholesterol ester-triacylglycerol exchange processes between triacylglycerol-rich lipoproteins and cholesterol ester-rich lipoproteins, we used Intralipid to modify human plasma LDL. Intralipid was incubated with LDL in the presence of lipoprotein-poor plasma (d greater than 1.21 g/ml) at 37 degrees C. Intralipid served as an acceptor for cholesterol ester and as a donor of triacylglycerol, modifying the low-density lipoproteins so that triacylglycerol became the major core lipid in the particle - the contribution of cholesterol ester to LDL mass decreased from 38% to 18%, while that of triacylglycerol increased from 4.9% to 26%. On lipolysis most added LDL triacylglycerol (59-72%) was hydrolyzed, resulting in a smaller particle than the "native' LDL particle with net loss of cholesterol ester. Incubation of LDL with the original Intralipid emulsion resulted in modified LDL with a high relative weight of phospholipid (27.7%). On removal of excess phospholipid from Intralipid and incubation of the resultant "washed' Intralipid with LDL, the relative weight of phospholipid in modified LDL decreased to 20%, which was similar to that observed after incubation of LDL with VLDL. We demonstrate that artificial triacylglycerol emulsion can indeed substitute for VLDL in neutral lipid exchange processes, and further confirm that transfer of core cholesterol ester and triacylglycerol occurs independently of the apolipoproteins present in triacylglycerol-rich lipoproteins and LDL.     

Thematic review series: patient-oriented research. Dietary fat, carbohydrate, and protein: effects on plasma lipoprotein patterns

In general, under isoweight conditions, different types of dietary protein or individual amino acids have little effect on lipoprotein patterns. Dietary carbohydrate tends to increase plasma triglyceride when it displaces fat, accompanied by a decrease in HDL cholesterol concentrations. Potential differential effects of types of carbohydrate are difficult to assess because of differences in rates of absorption and confounding of dietary fiber. Saturated fatty acids increase LDL and HDL cholesterol, whereas trans fatty acids increase LDL but not HDL cholesterol. Unsaturated fatty acids decrease LDL and HDL cholesterol, polyunsaturated more so than monounsaturated. There has been considerable interest in the potential benefit of major shifts in dietary macronutrients on weight loss and lipoprotein patterns. Short-term data favor substituting protein and fat for carbohydrate, whereas long-term data have failed to show a benefit for weight loss. During an active weight loss period low-carbohydrate diets more favorably affect triglyceride and HDL and less favorably affect LDL cholesterol concentrations. Additional efforts need to be focused on gaining a better understanding of the effect of dietary macronutrient profiles on established and emerging cardiovascular disease risk factors, mechanisms for changes observed and contributors to individual variability. Such data are needed to allow reassessment and, if necessary, modification of current recommendations.     

Influence of low cholesterol eggs enriched with vitamin-E and omega-3 fatty acid on blood lipid profile of Wistar rats

In the recent past, low cholesterol eggs enriched with vitamin-E and omega-3 fatty acid have been developed and are marketed under different brands claiming them as heart friendly. The influence of these eggs (smart eggs) on lipid profile of rats was evaluated in comparison to that of the standard eggs. Data of 4 week dietary treatment revealed that total plasma cholesterol, low density lipoprotein (LDL) and very low density lipoprotein (VLDL) cholesterol increased only 22% in rats fed on diet containing 4 smart eggs per kg of semi-synthetic diet in contrast to the increase of more than 100 % when fed on diet containing standard eggs. The results suggest that it is not the low cholesterol content alone but also vitamin E and omega-3 fatty acids present in smart eggs that act synergically to prevent a substantial change in blood lipid profile and impose no serious risk to the health of the consumers.     

Variations in Body Composition and Plasma Lipids in Response to a High‐Carbohydrate Diet

Objective: To examine the extent to which variations in body composition modulate changes in the lipid profile in response to the ad libitum consumption of a diet rich in carbohydrates (CHOs) (high‐CHO diet: 58% of energy as CHOs) or high in fat and in monounsaturated fatty acids (MUFAs) (high‐MUFA diet: 40% of energy as fat, 23% as MUFAs). Research Methods and Procedures: Sixty‐three men were randomly assigned to one of the two diets that they consumed for 6 to 7 weeks. Body composition and fasting plasma lipid levels were measured at the beginning and the end of the dietary intervention. Results: The high‐CHO and high‐MUFA diets induced significant and comparable reductions in body weight and waist circumference. These changes were accompanied by significant and comparable (p < 0.01) reductions in total plasma cholesterol and low‐density lipoprotein cholesterol levels. However, the high‐MUFA diet had more beneficial effects on plasma triglyceride concentrations (p < 0.01) and on plasma high‐density lipoprotein cholesterol levels (p = 0.02) compared with the high‐CHO diet. Diet‐induced changes in waist circumference were significantly associated with changes in low‐density lipoprotein cholesterol levels in the high‐CHO group (r = 0.39, p = 0.03) but not in the high‐MUFA group (r = 0.16, p = 0.38). Discussion: Improvements in plasma lipids induced by the ad libitum consumption of a high‐CHO diet seem to be partly mediated by changes in body weight, whereas lipid changes induced by the high‐MUFA diet seem to be independent of changes in body weight.     

Effect of exercise intensity and training on antioxidants and cholesterol profile in cyclists

The aim of this work was to evaluate the effect of different intensity of exercise and different training status on antioxidants and cholesterol profile in cyclists. 33 male cyclists (17 amateur and 16 professional cyclists) participated in this study. The amateurs all trained 14 +/- 1 h each week, and their VO(2) max was 62.5 +/- 1.8 ml/Kg x min; the professionals all trained 24 +/- 1 h each week, and their VO(2) max was 80.2 +/- 1.6 ml/Kg x min. Amateurs were submitted to the maximal and submaximal prolonged exercise tests. Professionals were submitted to a mountain stage (170 km) of cycling competition. Serum lipid and cholesterol profile (triglycerides, total cholesterol, HDL-cholesterol, LDL-cholesterol and VLDL-cholesterol) and plasma antioxidant capacity (ascorbic acid, alpha-tocopherol, retinol, beta-carotene and others) were measured before and after exercise tests. Hematological determinations (number of erythrocytes, hematocrit and hemoglobin concentration) and dietary intake were also measured. No significant differences were observed in basal values (before exercise tests) of amateur and professional cyclists. Negligible differences were found between dietary intake of amateur and professional cyclists, and also the results of hematological values showed there was no effect of degree of hydration or dietary intake on blood levels of studied antioxidant and lipid parameters. An increase in plasma levels of vitamin C, vitamin E, triglycerides and VLDL-cholesterol levels, and also a decrease of beta-carotene and LDL-cholesterol. were observed in well-trained professional cyclists after the cycling stage - an endurance exercise--but not in amateur cyclists. Amateur cyclists showed only mild increases in total cholesterol after maximal and submaximal exercise, while a rise in HDL-cholesterol was only observed after maximal exercise; none of these changes were observed in professional cyclists. Plasma levels of antioxidant vitamins and carotenes, and also serum lipids, total cholesterol and lipoprotein-cholesterol showed an overall response to exercise, and their increase and/or decrease must be explained as a consequence of the different training status of sportsmen and intensity and duration of exercise tests.     

Effect of dietary chitosans with different viscosity on plasma lipids and lipid peroxidation in rats fed on a diet enriched with cholesterol

To investigate the effect of dietary chitosan on lipid metabolism, male SD (Sprague-Dawley) rats were fed a cholesterol-enriched diet containing 5% cellulose (CE), 5% chitosan (CCS; high viscosity), or 5% chitosan (FCS; low viscosity) for 4 weeks. The two types of chitosan with a comparable degree of deacetylation had a different molecular weight and intrinsic viscosity. Significantly (p < 0.05) lower plasma total cholesterol, LDL-cholesterol and VLDL-cholesterol concentrations were observed in the rats fed on the chitosan diets. In addition, chitosan significantly increased the fecal cholesterol and triglyceride contents. Although no significant difference in body weight was found among the dietary groups, the rats fed on the chitosan diets had lower relative liver weight when compared with those fed on the cellulose diet. Both of the chitosan groups had significantly lower liver total lipid and total cholesterol contents compared to the cellulose group, although the FCS group was less effective. The plasma and liver thiobarbituric acid reactive substances (TBAR) values were similar in the CE and FCS groups, while the CCS group had increased liver TBAR values. Although a significant increase in liver glucose-6-phosphate dehydrogenase activity was observed in the CCS group, no significant change was found in the FCS group. The observed influence of chitosans with different viscosity on the plasma lipid level, liver lipids and lipid peroxidation suggests that, while the hypocholesterolemic action of chitosans with different viscosity was similar, changes in the liver lipids and liver peroxidation status depended on their molecular weight when the deacetylation degree was comparable.     

Protein-protein interaction heterogeneity of plasma apolipoprotein A1 in nephrotic syndrome

Apolipoprotein A1 (apoA1) is a component of the high density lipoproteins (HDL) that regulates the transport of cholesterol between the liver and peripheral cells and modulates the removal of any excess of cholesterol from membranes. Any variation in apoA1 composition may modify the plasma lipid profile and be involved in atherogenesis. We investigated apoA1 composition in plasma of 6 children with nephrotic syndrome, a condition characterized by high levels of cholesterol in plasma and by a high risk to develop atherosclerosis. Non-denaturing two-dimensional electrophoresis (Nat/SDS-PAGE), mass spectrometry, western blot and pull down experiments were done to characterize proteins and define putative interactions. ApoA1 was resolved in 12 variants, 6 of which had a slightly lower molecular weight (18-19 KDa) and migrated on the same axes of the β chain of haptoglobin (Hp). Low molecular weight apoA1 were observed in carriers of different Hp haplotypes (including one homozygous for the rare ββα1α1) ruling out any contaminant effect of co-migration of apoA1 with Hp α2 chain. Overall, apoA1 isoforms were much more present in plasma of nephrotic patients compared to a normal profile. These findings show that apoA1 plasma in nephrotic syndrome is heterogeneous in terms of molecular weight. Low molecular weight fragments lack internal structural domains and likely form macro-aggregates with Hp. Fragmentation and transport of apoA1 may be involved in the general disorder of lipid metabolism that characterizes nephrotic syndrome.     

饲料糖和脂水平对团头鲂生长性能及血浆代谢物的影响

实验以初重(6.20±0.01) g的团头鲂(Megalobrama amblycephala)幼鱼为研究对象,分别投喂高糖低脂(HCLL, 45%糖和2%脂)、中糖中脂(MCML, 30%糖和8%脂)和低糖高脂(LCHL, 15%糖和14%脂)的3种等氮饲料56d,以探究饲料不同糖和脂水平对团头鲂生长性能、鱼体生化组成、营养沉积及血浆代谢物的影响。实验结果显示,饲料糖和脂水平对团头鲂摄食率无显著性影响。随饲料糖水平降低和脂水平升高,团头鲂幼鱼特定生长率和饲料效率提高。高糖低脂饲料未造成肝脏糖原或甘油三酯含量的显著沉积,且各饲料组间肝体比、脏体比及肥满度均无显著性差异。饲料糖和脂水平对团头鲂鱼体生化组成无显著性影响,但随饲料糖水平降低和脂水平增加,团头鲂蛋白沉积率升高,脂肪沉积率降低。另外,血浆葡萄糖、甘油三酯、游离脂肪酸和胆固醇含量各组间均无显著性差异。低糖高脂组血浆低密度脂蛋白胆固醇显著升高,表明肝脏将脂质转运至外周组织以维持肝脏脂稳态。研究结果表明,团头鲂对饲料脂利用优于糖类,且具有较好地应答饲料糖和脂水平的代谢机制,研究结果可为团头鲂的饲料配方设计提供支撑。     

Liver fatty acid binding protein gene ablation potentiates hepatic cholesterol accumulation in cholesterol-fed female mice

Although liver fatty acid binding protein (L-FABP) is postulated to influence cholesterol homeostasis, the physiological significance of this hypothesis remains to be resolved. This issue was addressed by examining the response of young (7 wk) female mice to L-FABP gene ablation and a cholesterol-rich diet. In control-fed mice, L-FABP gene ablation alone induced hepatic cholesterol accumulation (2.6-fold), increased bile acid levels, and increased body weight gain (primarily as fat tissue mass). In cholesterol-fed mice, L-FABP gene ablation further enhanced the hepatic accumulation of cholesterol (especially cholesterol ester, 12-fold) and potentiated the effects of dietary cholesterol on increased body weight gain, again mainly as fat tissue mass. However, in contrast to the effects of L-FABP gene ablation in control-fed mice, biliary levels of bile acids (as well as cholesterol and phospholipids) were reduced. These phenotypic alterations were not associated with differences in food intake. In conclusion, it was shown for the first time that L-FABP altered cholesterol metabolism and the response of female mice to dietary cholesterol. While the biliary and lipid phenotype of female wild-type L-FABP+/+ mice was sensitive to dietary cholesterol, L-FABP gene ablation dramatically enhanced many of the effects of dietary cholesterol to greatly induce hepatic cholesterol (primarily cholesterol ester) and triacylglycerol accumulation as well as to potentiate body weight gain (primarily as fat tissue mass). Taken together, these data support the hypothesis that L-FABP is involved in the physiological regulation of cholesterol metabolism, body weight gain, and obesity.     

Increased calcium intake reduces plasma cholesterol and improves vasorelaxation in experimental renal failure

Chronic renal failure (CRF) is associated with abnormal lipid metabolism and high prevalence of vascular complications. Calcium salts are commonly used in CRF as phosphate binders. Increased calcium intake may also lower plasma cholesterol and beneficially influence vascular tone. Therefore, we investigated the influence of increasing dietary calcium from 0.3% to 3.0% for 8 wk after 5/6 nephrectomy (NTX) on plasma cholesterol and mesenteric resistance vessel tone in male Sprague-Dawley rats. The groups were Sham, Sham-Calcium, NTX, and NTX-Calcium (n = 10-11). Blood pressure was modestly elevated after NTX, whereas the plasma creatinine, urea nitrogen, phosphate, and parathyroid hormone levels were clearly increased. The high-calcium diet suppressed plasma phosphate and parathyroid hormone but was without effect on blood pressure. The NTX resulted in 1.6-fold elevation in plasma total cholesterol and 40% reduction in high density-to-low density lipoprotein ratio (HDL/LDL). However, the lipid profile in NTX rats on the high-calcium diet did not differ from sham-operated controls. The endothelium-mediated relaxations induced by acetylcholine were impaired in NTX rats, whereas the response was normalized by a high-calcium diet. No differences in vasorelaxations by the endothelium-independent vasodilator nitroprusside were detected. In conclusion, improved vasorelaxation after a high-calcium diet could be due to reduced plasma total cholesterol and ameliorated HDL/LDL ratio, although decreased plasma phosphate and parathyroid hormone may also play a significant role in the vascular effects of increased calcium intake.     

Enriched Environment-induced Maternal Weight Loss Reprograms Metabolic Gene Expression in Mouse Offspring

The global prevalence of weight loss is increasing, especially in young women. However, the extent and mechanisms by which maternal weight loss affects the offspring is still poorly understood. Here, using an enriched environment (EE)-induced weight loss model, we show that maternal weight loss improves general health and reprograms metabolic gene expression in mouse offspring, and the epigenetic alterations can be inherited for at least two generations. EE in mothers induced weight loss and its associated physiological and metabolic changes such as decreased adiposity and improved glucose tolerance and insulin sensitivity. Relative to controls, their offspring exhibited improved general health such as reduced fat accumulation, decreased plasma and hepatic lipid levels, and improved glucose tolerance and insulin sensitivity. Maternal weight loss altered gene expression patterns in the liver of offspring with coherent down-regulation of genes involved in lipid and cholesterol biosynthesis. Epigenomic profiling of offspring livers revealed numerous changes in cytosine methylation depending on maternal weight loss, including reproducible changes in promoter methylation over several key lipid biosynthesis genes, correlated with their expression patterns. Embryo transfer studies indicated that oocyte alteration in response to maternal metabolic conditions is a strong factor in determining metabolic and epigenetic changes in offspring. Several important lipid metabolism-related genes have been identified to partially inherit methylated alleles from oocytes. Our study reveals a molecular and mechanistic basis of how maternal lifestyle modification affects metabolic changes in the offspring.     

Tendon xanthomas in familial hypercholesterolemia are associated with a differential inflammatory response of macrophages to oxidized LDL

Tendon xanthomas (TX) are pathognomonic lipid deposits commonly found in familial hypercholesterolemia (FH) patients. The aim of this study was to determine whether macrophages from FH patients with TX (TX+) have higher predisposition to foam cells formation after oxidized LDL (oxLDL) overload than those from FH patients without TX (TX-), and if their differential gene expression profile could explain these different phenotypes. Total RNA pools from macrophages from FH patients TX+ and TX- were analyzed using Affymetrix oligonucleotide arrays to evaluate the gene expression profile in presence and absence of oxLDL. Also, the intracellular lipid content was measured by fluorescence flow cytometry. Results of these studies suggest that macrophages from FH subjects TX+ compared to those TX- have a differential response to oxLDL, since they show higher intracellular cholesterol ester accumulation and a differential gene expression profile. The gene array data were validated by relative quantitative real-time RT-PCR and quantitative ELISA in culture media and plasma samples. FH subjects TX+ showed increased plasma tryptase, TNF-alpha, IL-8 and IL-6 concentrations. We propose that TX formation are associated with higher intracellular lipid content, and higher inflammatory response of macrophages in response to oxLDL.     

Effects of blocking plasma lipid transfer protein activity in the rabbit

Plasma lipid transfer protein activity was completely blocked in rabbits for up to 48 h by infusion with goat antibody to rabbit lipid transfer protein. Lipid transfer protein activity in plasma of control animals, infused with antibody from a non-immune goat, decreased during the experiment but was never less than 50% of pre-infusion levels. During the period that lipid transfer protein activity was completely blocked, there were changes in high-density lipoprotein composition (expressed as % by weight) with a reduction in triacylglycerol from 8.4 +/- 2.4% to 1.0 +/- 0.2% (P less than 0.05) and an increase in esterified cholesterol from 10.7 +/- 1.7% to 14.5 +/- 0.3% (P less than 0.1). In conjunction with the observed changes in high-density lipoprotein composition, there was an increase in high-density lipoprotein particle size from a mean radius of 4.7 to 5.4 nm. The change in composition and particle size was not observed in high-density lipoproteins from control animals. There was a change in the distribution of plasma cholesterol in control animals, with a fall in the proportion of cholesterol in high-density lipoproteins (P less than 0.02) and consequently an increase in the proportion of cholesterol in low-density lipoproteins (P less than 0.02). However, the distribution of plasma cholesterol in animals in which lipid transfer protein activity was inhibited was maintained at original levels during the period of inhibition. Consequently, in these animals, there was a less atherogenic distribution of cholesterol during the period of lipid transfer protein inhibition when compared with control animals. The changes observed in lipoproteins, in the absence of lipid transfer protein activity, demonstrate that lipid transfer protein modifies lipoproteins in vivo and appears to contribute to a more atherogenic lipid profile.