Two weeks of western diet disrupts liver molecular markers of cholesterol metabolism in rats.

BACKGROUND: The present study was designed to test the hypothesis that in the liver, excessive fat accumulation impairs cholesterol metabolism mainly by altering the low-density lipoprotein-receptor (LDL-R) pathway. METHOD: Young male Wistar rats were fed standard (SD), high fat (HFD; 60% kcal) or Western (WD; 40% fat + 35% sucrose (17.5% fructose)) diets for 2 or 6 weeks. RESULTS: Weight gain (~ 40 g) was observed only following 6 weeks of the obesogenic diets (P < 0.01). Compared to the 2-week treatment, obesogenic diets tripled fat pad weight (~ 20 vs 7 g) after 6 weeks. Hepatic triglyceride (TG) levels were greater in response to both the WD and HFD compared to the SD (P < 0.01) at 2 and 6 weeks and their concentrations were greater (P < 0.05) in WD than HFD at 2 weeks. Plasma total cholesterol levels were higher (P < 0.05) in animals submitted to WD. After 2 and 6 weeks, liver expression of LDL-R, proprotein convertase subtilisin/kexin 9 (PCSKk9) and sterol regulatory element binding protein 2 (SREBP2), involved in LDL-cholesterol uptake, was lower in animals submitted to WD than in others treated with HFD or SD (P < 0.01). Similarly, low-density lipoprotein-receptor-related protein 1 (LRP1) and acyl-CoA cholesterol acyltransferase-2 (ACAT-2) mRNA levels were lower (P < 0.01) among WD compared to SD-fed rats. Expression of the gene coding the main regulator of endogenous cholesterol synthesis, 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCoAR) was reduced in response to WD compared to SD and HFD at 2 (P < 0.001) and 6 (P < 0.05) weeks. Being enriched in fructose, the WD strongly promoted the expression of carbohydrate-response element binding protein (ChREBP) and acetyl-CoA carboxylase (ACC), two key regulators of de novo lipogenesis. CONCLUSION: These results show that the WD promptly increased TG levels in the liver by potentiating fat storage. This impaired the pathway of hepatic cholesterol uptake via the LDL-R axis, promoting a rapid increase in plasma total cholesterol levels. These results indicate that liver fat content is a factor involved in the regulation of plasma cholesterol.

Exercise training increased gene expression of LDL-R and PCSK9 in intestine: link to transintestinal cholesterol excretion.

Transintestinal cholesterol excretion (TICE) is known as an alternate non-biliary route of cholesterol excretion from the body. The aim of this study was to determine whether exercise training has effects on intestinal membrane receptors involved in TICE in intact and ovariectomized (Ovx) rats. Sprague-Dawley rats were first divided into 4 groups: Sham operated and Ovx rats fed a standard diet (Sham-SD; Ovx-SD), or a high cholesterol diet (Sham-Chol; Ovx-Chol). These 4 groups were subsequently subdivided into either sedentary or voluntary wheel running groups for 6 weeks. The cholesterol diet resulted in increased hepatic cholesterol accumulation (p< 0.001) in both Sham and Ovx rats. Exercise training increased (p < 0.01) transcripts of intestinal low density lipoprotein receptor (LDL-R) and proprotein convertase subtilisin/kexin type 9 (PCSK9), which are involved in trans-intestinal cholesterol uptake from circulation, in both Sham and Ovx rats compared to rats remaining sedentary in all diet conditions. The up-regulation of intestinal gene expression of LDL-R and PCSK9 following voluntary wheel running in intact and Ovx rats suggests that exercise training may contribute to elimination of cholesterol through the TICE pathway.

A one-year resistance training program following weight loss has no significant impact on body composition and energy expenditure in postmenopausal women living with overweight and obesity.

Resistance training (RT) has been shown to decrease fat mass (FM), and increase fat-free mass (FFM), which can be a useful for weight loss maintenance. OBJECTIVE: To examine the effects of a 1-year RT intervention on weight loss maintenance following a 6-month dietary weight loss intervention. DESIGN: Following a 6-month dietary weight loss intervention (-6% ±â€¯5.8; 5.05 kg ±â€¯4.45), 70 postmenopausal women living with overweight or obesity were randomized to a control group (n = 34) or a RT group (n = 36) (3×/week first 6 months, 2×/week last 6 months, 70-80% of 1-repetition maximum). Body composition (DXA), abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) (CT scan), resting energy expenditure (EE) (indirect calorimetry), physical activity EE and total daily EE were measured (doubly-labelled water). RESULTS: A total of 54 participants completed the study (control group n = 29; RT group n = 25) and compliance to the RT program was on average 64%. Significant regains were noted for body weight 0.98 (3.71) kg vs. 1.33 (3.94) kg and FM regain 1.32 (2.69) kg vs. 0.81 (3.26) kg in control and RT groups after the 1-year weight maintenance phase. No group differences were noted. Resting EE and total daily EE did not change after the weight maintenance phase, and no differences were observed between groups. Both groups had significantly greater than predicted decrease in resting EE after the 6-month dietary intervention and at the end of the 1-year weight-loss maintenance phase. CONCLUSIONS: Our results suggest that a 1-year RT intervention following a 6-month dietary weight loss intervention does not improve weight loss maintenance, body composition or EE in post-menopausal women living with overweight or obesity.

Body composition, cardiometabolic risk factors, physical activity, and inflammatory markers in premenopausal women after a 10-year follow-up: a MONET study.

OBJECTIVE: Menopausal transition and postmenopause are usually associated with changes in body composition and a decrease in physical activity energy expenditure (PAEE). This study investigated body composition, cardiometabolic risk factors, PAEE, and inflammatory markers in premenopausal women after a 10-year follow-up. METHODS: In all, 102 premenopausal women participated in the 5-year observational longitudinal Montreal Ottawa New Emerging Team (MONET) study. This present substudy included 48 participants (age: 60.0 ±â€Š1.7 years; body mass index: 23.2 ±â€Š2.2 kg/m) 6.0 ±â€Š0.3 years after completion of the initial MONET study. Measures included body composition, waist circumference (WC), fasting glucose and insulin levels, insulin sensitivity (QUICKI model), plasma lipid levels, PAEE, and inflammatory markers. RESULTS: Compared with baseline measures of the MONET study, analyses revealed no significant increase in body weight, although there were significant increases in WC, fat mass (FM), % FM, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol, haptoglobin, apolipoprotein B, ferritin, adiponectin, and soluble cluster of differentiation 14 (all P < 0.001) after the 10-year follow-up. However, significant decreases were observed for fat-free mass, PAEE, fasting glucose levels, interleukin-8 levels, and soluble tumor necrosis factor receptors 1 and 2 (sTNFR-1 and sTNFR-2) levels (all P < 0.05). To determine the effect of postmenopausal years, data were restructured based on final menstrual period (FMP), and one-way analyses of variance were performed.Waist circumference, % FM, total cholesterol, high-density lipoprotein cholesterol, apolipoprotein B, ferritin, adiponectin, and soluble cluster of differentiation 14 were higher in early and late postmenopausal periods in these women. sTNFR-1 and sTNFR-2 levels were higher at the FMP and early postmenopausal years as compared with the late postmenopausal periods. Finally, interleukin-8 levels were lower in years after FMP. CONCLUSION: The number of years elapsed since the FMP can affect body composition, cardiometabolic risk factors, and inflammatory markers in healthy premenopausal women going through menopausal transition and postmenopausal periods.

The effect of exercise training on upregulation of molecular markers of bile acid metabolism in the liver of ovariectomized rats fed a cholesterol-rich diet.

BACKGROUND: Small heterodimer partner (SHP) is an important transcriptional factor involved in the regulation of glucose, lipid, and bile acid metabolism in the liver. SHP has been reported to be down-regulated in ovariectomized (Ovx) mice and up-regulated by estrogens suggesting a link between estrogens and SHP. The aim of the present study was to determine the effects of exercise training on SHP and key molecular markers of cholesterol and bile acid homeostasis in Ovx rats under cholesterol feeding. METHODS: Our main experimental group was composed of Ovx rats fed a high-cholesterol diet (Ovx-Chol) that was compared to a group of Ovx rats fed a standard diet (Ovx-SD) and a group of sham operated rats fed the cholesterol diet (Sham-Chol). These three groups of Ovx and sham rats were subdivided into either voluntary wheel running (Tr) or sedentary (Sed) groups for 5 weeks. The mRNA expression of all genes was measured by quantitative real-time polymerase chain reaction. RESULTS: Liver total cholesterol levels were not affected by exercise training in any of the experimental conditions. Cholesterol feeding in both sham and Ovx rats resulted in significantly higher hepatic cholesterol accumulation than in Ovx-SD (P < 0.001). Hepatic low density lipoprotein receptor (LDL-R) involved in cholesterol uptake from circulation was not influenced by training. A main effect of training was, however, found for transcripts of SHP and cholesterol 7 alpha-hydroxylase (CYP7A1, P < 0.050). CYP7A1 is the main gene involved in bile acid biosynthesis from cholesterol. CONCLUSION: These results suggest that voluntary wheel running modulates cholesterol metabolism in Ovx animals through up-regulation of SHP and bile acid formation.

Energy Density is Not a Consistent Correlate of Adiposity in Women During the Menopausal Transition.

PURPOSE: The association between the energy density (ED) of foods and adiposity has been reported previously. However, whether the contribution of ED to adiposity remains significant when controlled for energy intake (EI) and physical activity energy expenditure (PAEE) remains to be clearly established. We aimed to investigate the independent contribution of ED to variations in body composition in women during the menopausal transition. METHODS: Sixty-seven women from the MONET cohort study were analyzed. Seven-day food records were used to assess EI and ED. Body composition (body fat mass (FM) and trunk-fat mass (TFM)) was measured with dual-energy X-ray absorptiometry; PAEE was assessed with accelerometers. This secondary analysis of data included measurements obtained at years 1 and 5 of the study. RESULTS: Mean ED was correlated with FM (r = 0.22; P = 0.04) and TFM (r = 0.22; P = 0.04) at year 1, but not at year 5. The multiple regression analysis showed that EI and ED contributed to 14% of the variance in FM and TFM at year 1. CONCLUSION: These results suggest that ED is a modest but inconsistent determinant of adiposity in healthy women at the time of the menopause transition.

Dynamics of hepatic and intestinal cholesterol and bile acid pathways: The impact of the animal model of estrogen deficiency and exercise training.

Plasma cholesterol level is determined by a complex dynamics that involves transport lipoproteins which levels are tightly dependent on how the liver and the intestine regulate cholesterol and biliary acid metabolism. Regulation of cholesterol and biliary acids by the liver and the intestine is in turn coupled to a large array of enzymes and transporters that largely influence the inflow and the outflow of cholesterol and biliary acids through these organs. The activity of the key regulators of cholesterol and biliary acids may be influenced by several external factors such as pharmacological drugs and the nutritional status. In recent years, more information has been gathered about the impact of estrogens on regulation of cholesterol in the body. Exposure to high levels of estrogens has been reported to promote cholesterol gallstone formation and women are twice as likely as men to develop cholesterol gallstones. The impact of estrogen withdrawal, such as experienced by menopausal women, is therefore of importance and more information on how the absence of estrogens influence cholesterol regulation is started to come out, especially through the use of animal models. An interesting alternative to metabolic deterioration due to estrogen deficiency is exercise training. The present review is intended to summarize the present information that links key regulators of cholesterol and biliary acid pathways in liver and intestine to the absence of estrogens in an animal model and to discuss the potential role of exercise training as an alternative.

GLUT2 proteins and PPARγ transcripts levels are increased in liver of ovariectomized rats: reversal effects of resistance training.

PURPOSE: This study investigated the effects of ovariectomy (Ovx) and 12 weeks of resistance training (RT) on gene expression of GLUT2, the main glucose transporter in the liver, and on PPARγ, a transcription factor known to target GLUT2 expression. METHODS: Forty Holtzman rats were divided into 5 groups: Sham-sedentary (Sed), Sham- RT, Ovx-Sed, Ovx-RT, and Ovx-Sed with hormone replacement (E2). The RT protocol consisted of sessions held every 72 h for 12 weeks, during which the animals performed 4 to 9 vertical climbs (1.1 m) at 2 min intervals with progressively heavier weights (30 g after the fourth climb) tied to the tail. The E2 silastic capsule was inserted into the rats' backs 48 hours before the first RT session. RESULTS: In addition to liver fat, GLUT2 protein levels and PPARγ transcripts were increased (P < 0.05) in Ovx compared to Sham-Sed animals, suggesting increased hepatic glucose uptake under estrogen deficient conditions. RT and E2 in Ovx rats decreased liver fat accumulation as well as GLUT2 and PPARγ gene expression to the level of Sham- Sed animals. CONCLUSION: The results of this study suggest that liver GLUT2 as well as PPARγ expression in Ovx rats are accompanied by increased fat accumulation and glucose uptake, thus providing a substrate for increased de novo lipogenesis. RT appears to be an appropriate exercise model to circumvent these effects.

Effect of the menopausal transition and physical activity energy expenditure on inflammatory markers: a MONET group study.

OBJECTIVE: Menopausal transition is usually associated with changes in body composition and a decrease in physical activity energy expenditure. Adipose tissue, especially visceral fat, is an important source of inflammatory markers, which contributes to the development of a proinflammatory state. Conversely, high levels of physical activity and exercise have an anti-inflammatory effect. This study aimed to investigate the impact of menopausal transition and physical activity on inflammatory makers. METHODS: One hundred two healthy premenopausal women participated in a 5-year longitudinal study. The present secondary analyses were performed on 58 participants with a full set of data (age: 49.6 ±â€Š1.7 y; body mass index: 23.3 ±â€Š2.4 kg/m). Measures included body composition, waist circumference, fasting glucose and insulin levels, insulin sensitivity, plasma lipid levels, cardiorespiratory fitness, physical activity energy expenditure, and inflammatory markers. RESULTS: Repeated measure analyses revealed, after the 5-year follow-up, significant increases in ferritin, interleukin-8 (IL-8), and soluble tumor necrosis factor-α receptor 1 and 2 (sTNFR1 and sTNFR2) (P < 0.001), and a significant decrease in serum high-sensitive C-reactive protein (P < 0.05). Positive correlations were observed between change (year 5 to baseline) in waist circumference and changes in high-sensitive C-reactive protein, orosomucoid (ORM), haptoglobin, and apolipoprotein B (ApoB) levels (0.26 ≤ r ≤ 0.34; P < 0.05), and between change in peripheral fat and changes in ORM, ApoB, sTNFR2 (0.28 ≤ r ≤ 0.39; P < 0.05). On the contrary, negative correlations were found between change in physical activity energy expenditure and changes in ORM as well as ApoB (r = -0.35 and r = -0.36, respectively; P < 0.05). No significant correlations were found between change in cardiorespiratory fitness, glucose, insulin, insulin sensitivity and changes in inflammatory markers. Multiple regression analyses showed that changes in physical activity energy expenditure and waist circumference together explained 23% of the individual variance of change in ORM (P < 0.05). Also, change in physical activity energy expenditure explained 15% (P < 0.05) of the variance of change in ApoB. Fat mass change explained 15% (P < 0.05) of the variance of change in IL-8, and finally change in peripheral fat explained 15% of variance of change in sTNFR2 (P < 0.05). CONCLUSIONS: The present study indicates that the menopausal transition is accompanied by an increase in inflammatory markers, namely ferritin, IL-8, sTNFR1, and sTNFR2. The increase in IL-8 and sTNFR2 with menopause could be explained, in part, by changes in fat mass and peripheral fat, respectively.

Influence of cardiorespiratory fitness and physical activity levels on cardiometabolic risk factors during menopause transition: A MONET study.

To determine the influence of cardiorespiratory fitness (hereafter "fitness") and physical activity levels on cardiometabolic risk factors in premenopausal women going through the menopause transition. An ancillary study including 66 premenopausal women who participated to a 5-year observational, longitudinal study (2004 to 2009 in Ottawa) on the effects of menopause transition on body composition and cardiometabolic risk factors. Women underwent a graded exercise test on treadmill to measure peak oxygen uptake (VO2 peak) at year 1 and 5 and physical activity levels were measured using accelerometers. Cardiometabolic risk factors included: waist circumference, fasting plasma lipids, glucose and insulin levels, HOMA-IR score, c-reactive protein, apolipoprotein B (apoB) and resting systolic and diastolic blood pressure. Change in fitness was not associated with changes in cardiometabolic risk factors. The changes in total physical activity levels on the other hand showed a significant negative association with apoB levels. Three-way linear mixed model repeated measures, showed lower values of waist circumference, fasting triglycerides, insulin levels, HOMA-IR score, apoB and diastolic blood pressure in women with a fitness ≥ 30.0 mlO2 kg(- 1) min(- 1) compared to women with a fitness < 30.0 mlO2 kg(- 1) min(- 1) (P < 0.05). However, only fasting triglycerides was lower in women with physical activity levels ≥ 770.0 Kcal/day (P < 0.05). Between fitness and physical activity levels, fitness was associated with more favorable values of cardiometabolic risk factors in women followed for 5 years during the menopause transition.

Combined Effects of Rosuvastatin and Exercise on Gene Expression of Key Molecules Involved in Cholesterol Metabolism in Ovariectomized Rats.

The purpose of this study was to investigate the effects of three weeks of rosuvastatin (Ros) treatment alone and in combination with voluntary training (Tr) on expression of genes involved in cholesterol metabolism (LDLR, PCSK9, LRP-1, SREBP-2, IDOL, ACAT-2 and HMGCR) in the liver of eight week-old ovariectomized (Ovx) rats. Sprague Dawley rats were Ovx or sham-operated (Sham) and kept sedentary for 8 weeks under a standard diet. Thereafter, rats were transferred for three weeks in running wheel cages for Tr or kept sedentary (Sed) with or without Ros treatment (5mg/kg/day). Six groups were formed: Sham-Sed treated with saline (Sal) or Ros (Sham-Sed-Sal; Sham-Sed-Ros), Ovx-Sed treated with Sal or Ros (Ovx-Sed-Sal; Ovx-Sed-Ros), Ovx trained treated with Sal or Ros (Ovx-Tr-Sal; Ovx-Tr-Ros). Ovx-Sed-Sal rats depicted higher (P < 0.05) body weight, plasma total cholesterol (TC) and LDL-C, and liver TC content compared to Sham-Sed-Sal rats. In contrast, mRNA levels of liver PCSK9, LDLR, LRP-1 as well as plasma PCSK9 concentrations and protein levels of LRP-1 were reduced (P < 0.01) in Ovx-Sed-Sal compared to Sham-Sed-Sal rats. However, protein levels of LDLR increased (P < 0.05) in Ovx-Sed-Sal compared to Sham-Sed-Sal rats. Treatment of Ovx rats with Ros increased (P < 0.05) mRNA and protein levels of LRP-1 and PCSK9 but not mRNA levels of LDLR, while its protein abundance was reduced at the level of Sham rats. As a result, plasma LDL-C was not reduced. Exercise alone did not affect the expression of any of these markers in Ovx rats. Overall, Ros treatment corrected Ovx-induced decrease in gene expression of markers of cholesterol metabolism in liver of Ovx rats, but without reducing plasma LDL-C concentrations. Increased plasma PCSK9 levels could be responsible for the reduction of liver LDLR protein abundance and the absence of reduction of plasma LDL-C after Ros treatment.

High dietary cholesterol and ovariectomy in rats repress gene expression of key markers of VLDL and bile acid metabolism in liver.

BACKGROUND: The purpose of the study was to evaluate the effects of high dietary cholesterol in ovariectomized (Ovx) rats on several key markers of hepatic cholesterol and bile acid metabolism. METHOD: Ovx and sham operated (Sham) rats were given either a standard diet (SD), a SD diet supplemented with 0.25% cholesterol (SD + Chol), or a high fat diet supplemented with 0.25% cholesterol (HF + Chol) for 5 weeks. RESULTS: Ovx was associated with higher (P < 0.05) liver total cholesterol (TC) under the SD and the SD + Chol diet, while liver triglyceride (TG) content was higher in Ovx than in Sham rats in all 3 diet conditions. Surprisingly, the SD + Chol diet was associated with lower (P < 0.001) plasma TC and TG levels in Ovx than in Sham rats, suggesting a decrease in VLDL secretion. Accordingly, several transcripts of key markers of VLDL synthesis including microsomal TG transfer protein (Mttp) and Apob-100 were decreased (P < 0.05) in Ovx compared to Sham rats under the three dietary conditions and even more so for Mttp and Apob-100 when rats were fed the SD + Chol diet. Transcripts of bile acid transporters including bile salt export pump (Bsep) and Na + -taurocholate cotransporting polypeptide (Ntcp) were decreased by the addition of cholesterol to the SD diet in both Ovx and Sham rats. CONCLUSION: These results indicate that a high cholesterol feeding and ovariectomy combine to reduce the gene expression of key markers of VLDL synthesis suggesting a reduction in excretion of cholesterol from the liver.

Effects of Acute Supramaximal Cycle Exercise on Plasma FFA Concentration in Obese Adolescent Boys.

AIMS: The aims of the present study are 1) to evaluate the free fatty acid (FFA) profile and 2) to determine the relative anaerobic and aerobic contributions to total energy consumption during repeated supramaximal cycling bouts (SCE) in adolescent boys with different body weight statuses. MATERIALS AND METHODS: Normal-weight (NW), overweight (OW), and obese (OB) adolescent boys (n =15 per group) completed a SCE sessions consisted of 6 x 6s maximal sprints with 2 min of passive rest between each repetition. Plasma FFA levels were determined at rest, immediately after a 10 min warm-up, and immediately at the end of SCE. The anaerobic and aerobic contributions (%) were measured via repeated SCE bouts. Insulin resistance was calculated using the homoeostatic model assessment (HOMA-IR) index. RESULTS: The FFA concentrations measured immediately after SCE were higher in the OB group than in the OW and NW (p<0.01 and p<0.01, respectively) groups. Moreover, the anaerobic contributions to SCE were significantly lower in obese adolescents (p<0.01) and decreased significantly during the 2nd, 3rd and 4th repetitions. The FFA levels were significantly associated with the HOMA-IR index and aerobic contribution among adolescent boys (r=0.83 and r=0.91, respectively, p<0.01). CONCLUSION: In contrast to the NW and OW groups, there is an increase in lipid mobilization and sift to aerobic energy metabolism during SCE in the OB group.

Effect of a high-fat diet on the hepatic expression of nuclear receptors and their target genes: relevance to drug disposition.

More than 1·4 billion individuals are overweight or obese worldwide. While complications often require therapeutic intervention, data regarding the impact of obesity on drug disposition are scarce. As the influence of diet-induced obesity on drug transport and metabolic pathways is currently unclear, the objective of the present study was to investigate the effect of high fat feeding for 13 weeks in female Sprague-Dawley rats on the hepatic expression of the nuclear receptors pregnane X receptor (PXR), constitutive androstane receptor (CAR), liver X receptor (LXR) and farnesoid X receptor (FXR) and several of their target genes. We hypothesised that high fat feeding would alter the gene expression of major hepatic transporters through a dysregulation of the expression of the nuclear receptors. The results demonstrated that, along with a significant increase in body fat and weight, a high-fat diet (HFD) induced a significant 2-fold increase in the expression of PXR as well as a 2-, 5- and 2·5-fold increase in the hepatic expression of the PXR target genes Abcc2, Abcb1a and Cyp3a2, respectively (P< 0·05). The expression levels of FXR were significantly increased in rats fed a HFD in addition to the increase in the expression levels of FXR target genes Abcb11 and Abcb4. The expression levels of both LXRα and LXRß were slightly but significantly increased in rats fed a HFD, and the expression levels of their target genes Abca1 and Abcg5, but not Abcg8, were significantly increased. The expression of the nuclear receptor CAR was not significantly altered between the groups. This suggests that a HFD may induce changes in the hepatobiliary transport and metabolism of endogenous and exogenous compounds.

Changes in glucose disposal after a caloric restriction-induced weight loss program in obese postmenopausal women: characteristics of positive and negative responders in a Montreal-Ottawa New Emerging Team study.

OBJECTIVE: This study aims to investigate individual characteristics that explain interindividual variations in glucose disposal in response to a 6-month weight loss program in obese postmenopausal women. METHODS: The cohort was divided into tertiles based on changes in glucose disposal after weight loss. Only women in the upper tertile (positive responders: Δ glucose disposal ≥ 0.92 mg/kg/min; n = 19) and lower tertile (negative responders: Δ glucose disposal ≤ -0.23 mg/kg/min; n = 19) were considered for analyses. Outcome measures included body weight, lean body mass (LBM), LBM index (= LBM / height [m]), fat mass (FM), FM index (= FM / height [m]), visceral fat, subcutaneous abdominal fat, high-sensitivity C-reactive protein (hsCRP) levels, interleukin-6, lipid profile, physical activity levels, fasting blood glucose and insulin levels, glucose disposal by hyperinsulinemic-euglycemic clamp technique, and resting blood pressure. RESULTS: At baseline, positive responders had higher triglycerides and hsCRP levels and lower glucose disposal (0.01 < P < 0.05) than negative responders. Except for visceral fat, the entire cohort showed significant decreases in all measures of body composition (P < 0.005) after weight loss, with greater decreases in body weight, body mass index, and FM index in positive responders (P < 0.005). Finally, data revealed that only positive responders showed decreases in LBM, LBM index, and hsCRP levels after weight loss (P between 0.01 and 0.001). CONCLUSIONS: An important interindividual variability in changes in glucose disposal after weight loss is observed. Interestingly, participants who display improvements in glucose disposal also show significant decreases in LBM, LBM index, and hsCRP after weight loss.

Changes in leptin and peptide YY do not explain the greater-than-predicted decreases in resting energy expenditure after weight loss.

CONTEXT: It is unknown whether leptin and peptide YY (PYY) influence changes in resting energy expenditure (REE), independently of fat mass (FM) and fat-free mass (FFM) in addition to changes in other energy expenditure (EE) components during weight loss. OBJECTIVE: The objective of the study was to examine the relationships between leptin, PYY, and body composition with different EE components before and after weight loss and whether changes in leptin and PYY were associated with differences in predicted vs measured REE after the intervention. DESIGN: This was a randomized controlled design. SETTING: The study was conducted in a laboratory. PARTICIPANTS: Participants were ninety-three overweight/obese postmenopausal women (aged 58.1 ± 4.8 y; body mass index 32.1 ± 4.3 kg/m(2)). INTERVENTION: Interventions included a 6-month caloric restriction diet alone or caloric restriction diet+resistance training. MAIN OUTCOME MEASURES: Body composition (dual energy x-ray absorptiometry), REE (indirect calorimetry), total EE (TEE; doubly labeled water), and fasting leptin and total PYY before and after weight loss were measured. RESULTS: Both interventions yielded significant decreases in weight, FFM, REE, and leptin, whereas a significant time × group interaction was noted for FM (greater decrease in FM in the diet+resistance training group) (P < .05 for all outcomes). No significant differences in TEE, physical activity EE, and PYY were noted between baseline and after the intervention. Age, FFM, leptin, and PYY were the best predictors of baseline REE (R(2) = 0.77; P = .0001), whereas age, FFM, and FM were associated with REE after the intervention (R(2) = 0.88; P = .0001). The same predictors, except for leptin, were significantly related to TEE at baseline (R(2) = 0.70; P = .0001) and after the intervention (R(2) = 0.29; P = .0001), whereas only PYY was a significant predictor of physical activity EE at baseline and after the intervention. Changes in FM and leptin accounted for 27% of the variance in ΔREE (P = .0001). Greater predicted vs measured REE was noted after the intervention (P = .02). However, Δ leptin and ΔPYY were not significant predictors of the differences between postintervention measurement and predicted REE. CONCLUSIONS: Δ Leptin and ΔFM were strong contributors to changes in REE. However, Δ leptin and ΔPYY were not significant predictors of the differences between predicted and measured REE after the intervention.

Impaired VLDL assembly: a novel mechanism contributing to hepatic lipid accumulation following ovariectomy and high-fat/high-cholesterol diets?

The aim of the present study was to identify molecular mechanisms involved in liver fat and cholesterol accumulation in ovariectomised (Ovx) rats fed with high-cholesterol diets. VLDL assembly and bile acid metabolism were specifically targeted. After being either Ovx or sham-operated, the rats were fed a standard diet or a high-fat diet containing 0, 0·25 or 0·5 % cholesterol for 6 weeks. Although Ovx rats exposed to dietary cholesterol intake accumulated the greatest amount of hepatic fat and cholesterol, plasma cholesterol levels were lower (P< 0·05) in these animals than in the corresponding control rats. Accompanying this observation, ovariectomy and dietary cholesterol intake resulted in a down-regulation (P< 0·05) of the expression of genes associated with VLDL assembly, including microsomal TAG transfer protein, diacylglycerol acyltransferase 2, acyl-CoA:cholesterol acyltransferase 2 and apoB-100 as well as genes associated with bile acid metabolism including farnesoid X receptor and bile salt export pump (P< 0·01). These results indicate that high-fat/high-cholesterol diets and ovariectomy concomitantly disrupt hepatic lipid output through defects in VLDL assembly and, most probably, secretion. The results also point to a defect in hepatic bile acid secretion. The present study offers novel insights into intrahepatic lipid metabolism, which may be relevant to metabolic complications found in postmenopausal women.

Exercise training decreases gene expression of endo- and xeno-sensors in rat small intestine.

The purpose of the study was to test the hypothesis that gene expression of members of the nuclear receptor (NR) superfamily known to act as endo- and xeno-sensors is reduced in the ileum of exercise-trained (Tr) rats. Healthy female rats were either treadmill-trained for 8 weeks, 5 times/week, or remained sedentary (Sed). Training resulted in a significant (p < 0.05) decrease in plasma free fatty acid (0.18 ± 0.01 to 0.15 ± 0.01 mmol/L) and glycerol (24.8 ± 0.8 to 18.7 ± 0.8 mg/L) concentrations. Gene expressions of NRs farnesoid X receptor (FXR; p < 0.05), liver X receptor (LXR; p < 0.05), pregnane X receptor (PXR; p < 0.01), and retinoid X receptor (RXR; p < 0.06) were reduced in the ileum of Tr compared with Sed animals. Tr was also associated with a reduction (p < 0.05) in gene expression of FXR downstream heterodimeric organite solute transporters α (OSTα) and ß (OSTß) involved in the transport of bile acids, LXR downstream genes heterodimeric ATP-binding cassette transporters (ABCG5/G8) involved in transport of absorbed cholesterol back to the lumen, and Niemann-Pick C1-like 1 (NPC1L1) involved in cholesterol absorption. These data indicate that exercise training lowers the expression of molecules involved in the defense system of the ileum against endobiotic and xenobiotic insults under normal conditions, thus, suggesting that regular exercise contributes to the intestinal maintenance of cholesterol and bile acid homeostasis.

Impact of energy restriction with or without resistance training on energy metabolism in overweight and obese postmenopausal women: a Montreal Ottawa New Emerging Team group study.

OBJECTIVE: The present study measured the impact of adding resistance training to an energy-restricted diet on the components of energy expenditure in overweight or obese postmenopausal women. METHODS: Participants (n = 137) were randomly divided into two groups: (1) a diet and resistance training (DRT) group and (2) a diet-only (DO) group. Women followed a 6-month energy-restricted diet consisting of 2,100 to 3,360 kJ less than daily needs. The DRT group also followed a resistance training program (three times a week). Resting energy expenditure (REE) was measured by indirect calorimetry. Total energy expenditure was measured with doubly labeled water. Body composition was measured by dual-energy x-ray absorptiometry. RESULTS: Eighty nine women were included in the analyses for this study (DRT, n = 21; DO, n = 68). REE in both groups was significantly lower after the intervention (mean difference ± SD: DO, -0.26 ± 0.4 MJ d; DRT, -0.33 ± 0.4 MJ d; P ≤ 0.05). Relative REE, expressed per kilogram of lean body mass corrected for fat mass change, remained stable in both groups. Physical activity energy expenditure remained stable in both groups (mean difference ± SD: DO, 0.02 ± 1 MJ d, P = 0.91; DRT, -0.14 ± 1 MJ d, P = 0.64). CONCLUSIONS: Adding resistance training to an energy-restricted diet does not significantly alter any compartment of energy expenditure. REE is lower owing to reduction in body composition compartments, but relative REE is not significantly altered.

Synergistic associations of physical activity and diet quality on cardiometabolic risk factors in overweight and obese postmenopausal women.

Healthy diet and physical activity are associated with a lower cardiometabolic risk (CMR). Little is known about whether they interact to improve CMR. The purpose of the present study was to determine the synergistic associations of diet quality and physical activity energy expenditure (PAEE) on CMR factors. The present study was an a posteriori analysis of two cross-sectional studies on 124 inactive non-diabetic postmenopausal women with a BMI ≥ 27 kg/m². The following factors were measured: diet quality (assessed by the Canadian Healthy Eating Index (C-HEI) from a 3 d food record); PAEE (doubly labelled water); body composition (dual-energy X-ray absorptiometry, computed tomography scan); lipoprotein profile (total, HDL- and LDL-cholesterol (HDL-C and LDL-C), non-HDL-C, total cholesterol:HDL-C, TAG, apoA1, apoB, apoA1:apoB and LDL-C:apoB); insulin sensitivity (homeostasis model assessment of insulin resistance and hyperinsulinaemic-euglycaemic clamp); inflammatory markers (high-sensitivity C-reactive protein (hs-CRP), haptoglobin, orosomucoid, IL-6 and leucocyte count). The association of the interaction PAEE × C-HEI and CMR factors was evaluated by hierarchical regressions. Fat mass-adjusted ANCOVA determined the interaction between PAEE and the C-HEI. In hierarchical regressions, the interaction PAEE × C-HEI was a correlate of more favourable values of HDL-C, apoB, apoA1:apoB and LDL-C:apoB ratios, and hs-CRP, while only PAEE was a negative correlate of haptoglobin. Compared with those in the low-PAEE/low-C-HEI group, women in the high-PAEE/high-C-HEI group had 10 % higher HDL-C, 13 % lower apoB, 11 % larger LDL particles and 28 % lower hs-CRP concentrations (P< 0·05). PAEE and the C-HEI have a synergistic association with the CMR profile. These results support the integration of both diet quality and physical activity in the management of CMR.