May Faraj

Differential epigenomic and transcriptomic responses in subcutaneous adipose tissue between low and high responders to caloric restriction.

BACKGROUND Caloric restriction is recommended for the treatment of obesity, but it is generally characterized by large interindividual variability in responses. The factors affecting the magnitude of weight loss remain poorly understood. Epigenetic factors (ie, heritable but reversible changes to genomic function that regulate gene expression independently of DNA sequence) may explain some of the interindividual variability seen in weight-loss responses. OBJECTIVE The objective was to determine whether epigenetics and gene expression changes may play a role in weight-loss responsiveness. DESIGN Overweight/obese postmenopausal women were recruited for a standard 6-mo caloric restriction intervention. Abdominal subcutaneous adipose tissue biopsy samples were collected before (n = 14) and after (n = 14) intervention, and the epigenomic and transcriptomic profiles of the high and low responders to dieting, on the basis of changes in percentage body fat, were compared by using microarray analysis. RESULTS Significant DNA methylation differences at 35 loci were found between the high and low responders before dieting, with 3 regions showing differential methylation after intervention. Some of these regions contained genes known to be involved in weight control and insulin secretion, whereas others were localized in known imprinted genomic regions. Differences in gene expression profiles were observed only after dieting, with 644 genes being differentially expressed between the 2 groups. These included genes likely to be involved in metabolic pathways related to angiogenesis and cerebellar long-term depression. CONCLUSIONS These data show that both DNA methylation and gene expression are responsive to caloric restriction and provide new insights about the molecular pathways involved in body weight loss as well as methylation regulation during adulthood.

Apolipoprotein B, apolipoprotein A-I, insulin resistance and the metabolic syndrome

Purpose of review The goal of identifying subjects with metabolic syndrome is to detect those at higher risk of developing cardiovascular disease. Evidence continues to accumulate as to the superiority of apolipoprotein B and apolipoprotein A-I over the conventional lipoprotein lipids as markers of vascular risk. It would seem reasonable, therefore, to redefine the dyslipidemia of the metabolic syndrome incorporating apolipoproteins. Therefore, our objective is to elucidate how apolipoprotein B and apolipoprotein A-I amplify evidence of the interactions amongst metabolic syndrome, insulin resistance, abdominal obesity, and vascular risk. Recent findings In several large epidemiological studies, including the NHANES III database, apolipoprotein B/apolipoprotein A-I ratio was tightly linked to the metabolic syndrome and each of its components, the descending order being: low HDL cholesterol, high triglyceride, high waist circumference, high glucose, and high blood pressure. Moreover, apolipoprotein B associates more closely with inflammatory markers and insulin resistance than triglyceride and all cholesterol markers. Yet despite close association of the apolipoprotein B/apolipoprotein A-I ratio to metabolic syndrome, both are independent predictors of future myocardial infarction. Summary We believe that the dyslipidemia of the metabolic syndrome should be redefined to include apolipoprotein B and apolipoprotein A-I.

Acute Hyperglycemia Induces a Global Downregulation of Gene Expression in Adipose Tissue and Skeletal Muscle of Healthy Subjects

To define the effects of acute hyperglycemia per se (i.e., without the confounding effect of hyperinsulinemia) in human tissues in vivo, we performed global gene expression analysis using microarrays in vastus lateralis muscle and subcutaneous abdominal adipose tissue of seven healthy men during a hyperglycemic-euinsulinemic clamp with infusion of somatostatin to inhibit endogenous insulin release. We found that doubling fasting blood glucose values while maintaining plasma insulin in the fasting range modifies the expression of 316 genes in skeletal muscle and 336 genes in adipose tissue. More than 80% of them were downregulated during the clamp, indicating a drastic effect of acute high glucose, in the absence of insulin, on mRNA levels in human fat and muscle tissues. Almost all the biological pathways were affected, suggesting a generalized effect of hyperglycemia. The induction of genes from the metallothionein family, related to detoxification and free radical scavenging, indicated that hyperglycemia-induced oxidative stress could be involved in the observed modifications. Because the duration and the concentration of the experimental hyperglycemia were close to what is observed during a postprandial glucose excursion in diabetic patients, these data suggest that modifications of gene expression could be an additional effect of glucose toxicity in vivo.

Apolipoprotein B: a predictor of inflammatory status in postmenopausal overweight and obese women

Aims/hypothesisInflammation is implicated in the development of type 2 diabetes and CHD, but the trigger of inflammation is unclear. Although in vitro and animal studies support a role of elevated levels of atherosclerotic lipoproteins in the activation of inflammation, plasma cholesterol cannot predict inflammatory markers in humans. Moreover, the association between inflammatory markers and other traditional risk factors of diabetes and CHD is unclear. To increase our knowledge of in vivo regulation of inflammation, we examined the association between several traditional risk factors and inflammatory markers. We hypothesised that because apolipoprotein B (ApoB) reflects atherogenic particle number, it is the primary predictor of inflammatory status.Subjects, materials and methodsWe examined the association between several traditional risk factors and plasma high-sensitivity (hs) C-reactive protein (CRP), hsTNF-α, soluble TNF receptor 1, IL-6, orosomucoid, haptoglobin and α1-antitrypsin in 77 non-diabetic overweight and obese postmenopausal women.ResultsThe inflammatory markers correlated positively with total and abdominal adiposity, blood pressure, 2-h OGTT glucose, insulin resistance, triglyceride, total/HDL cholesterol, ApoB, ApoB:apolipoprotein A1 (ApoA1) ratio and Framingham CHD risk points. They correlated negatively with ApoA1, and total, LDL and HDL cholesterol. ApoB was an independent predictor of the interindividual variation in IL-6, hsCRP, orosomucoid, haptoglobin and α1-antitrypsin (R2 range 8–40%); other risk factors were less predictive. Compared with BMI-matched control subjects, women with hyperapobetalipoproteinaemia (hyperapoB) had higher hsTNF-α, IL-6, hsCRP and orosomucoid (increase 17–104%).Conclusions/interpretationApoB is the primary predictor of inflammatory markers in postmenopausal overweight and obese women. Given elevated levels of inflammatory markers in hyperapoB women, we hypothesise that hyperapoB women may have an increased risk of developing both CHD and diabetes.

Association between physical activity energy expenditure and inflammatory markers in sedentary overweight and obese women

Objective:Chronic subclinical inflammation and regular physical activity have opposing relationships to obesity-related metabolic diseases. Yet, the association between chronic inflammation and physical activity has rarely been examined in obese subjects. We examined the association between physical activity energy expenditure (PAEE), total (TEE) and resting energy expenditure (REE) and cardiorespiratory fitness (VO2peak) with inflammatory markers in overweight/obese women.Design:Cross-sectional study.Methods:The study included 152 overweight/obese postmenopausal women who were sedentary and free of chronic/inflammatory diseases (mean age: 57.5 (95% confidence interval (CI) 56.7–58.3) years, body mass index (BMI): 32.5 (95% CI 31.8–33.2) kg m−2). The following parameters were measured: TEE (doubly labeled water), REE (indirect calorimetry), PAEE (as (TEE × 0.90)−REE), VO2peak (ergocycle) and serum high-sensitive C-reactive protein (hsCRP), haptoglobin, soluble tumor necrosis factor-α receptor 1 (sTNFR1), interleukin-6, orosomucoid and white blood cells.Results:Sedentary women with the highest tertile of PAEE (1276 (1233–1319) kcal day−1) had lower concentrations of hsCRP and haptoglobin than those in the lowest tertile (587 (553–621) kcal day−1) after adjustment for fat mass (P<0.05). Soluble TNFR1 was positively correlated with VO2peak, TEE and REE (P<0.05), and hsCRP and orosomucoid were positively associated with REE (P<0.01), whereas haptoglobin was negatively associated with PAEE (P<0.05). In stepwise regression analyses that examined the concomitant associations of components of energy expenditure with inflammatory markers, PAEE remained the only predictor of hsCRP and haptoglobin (P<0.05), explaining 14 and 5%, respectively, of their variation,whereas REE was the only predictor of orosomucoid (r 2=0.05, P=0.02) after adjustment for fat mass. Adding leptin to the regression models results in similar relationships between inflammatory markers and components of energy expenditure.Conclusion:PAEE is an independent predictor of hsCRP and haptoglobin in sedentary overweight/obese postmenopausal women free of chronic disease. Our data support the role of physical activity in reducing subclinical inflammation and risk of metabolic and cardiovascular diseases.

Lifestyle behaviours and components of energy balance as independent predictors of ghrelin and adiponectin in young non-obese women

AIM Dysregulation of the normal levels of ghrelin, leptin and adiponectin in young non-obese subjects could promote food intake, diabetes and cardiovascular disease in later stages of life. Little information is available on how plasmatic concentrations of these hormones may be influenced by eating habits and/or components of energy balance in a young population, which if known, could facilitate their voluntary regulation. METHODS In this cross-sectional study we examined the predictors of fasting plasma ghrelin, adiponectin and leptin in a population of well-characterized young non-obese women (N = 63). Energy intake was assessed by 24-hour dietary recall, resting metabolic rate (RMR) by indirect calorimetry, physical activity energy expenditure (PAEE) by tri-axial accelerometer, physical fitness by VO(2 peak), and eating behaviors by self administrated questionnaire. RESULTS Lower RMR and higher HDL-cholesterol were independent predictors of higher plasma ghrelin explaining 17.6% of its variation even after correcting for BMI. Higher total or central fat mass was the only predictor of higher plasma leptin, and no other variable added any power to the prediction equation. Finally, higher energy intake and waist circumference and lower PAEE predicted lower plasma adiponectin in young non-obese women, explaining 43% of the variation in its concentrations even after correcting for total or central fat mass. CONCLUSION Components of the energy balance (ie: energy intake and/or expenditure) influence adiponectin and ghrelin circulating levels. That is, higher energy intake and lower physical activity independently predict lower adiponectin concentrations, whereas lower resting metabolic rate independently predicts higher ghrelin levels in young non-obese women. Prospective studies are needed to examine whether circulating concentrations of ghrelin and adiponectin can be voluntarily regulated by lifestyle interventions.

Caspases and inflammasomes in metabolic inflammation

Inflammation is an important contributor to the development of metabolic disease. Recent work has strongly implicated the inflammasome and caspase‐1 as having a pivotal role in the regulation of metabolism, obesity, insulin resistance and cardiovascular disease. Through multiple murine and human studies we now know that the inflammasome can be activated by metabolic triggers in vivo. Clinical studies also reveal the inflammasome to be a potential candidate for therapeutic intervention and provide a clear incentive for future work on this inflammatory pathway.

Circulating endocannabinoids in insulin sensitive vs. Insulin resistant obese postmenopausal women. A MONET group study

To measure the circulating levels of endocannabinoids and related molecules at fasting, after acute hyperinsulinemia and after weight loss in insulin sensitive vs. insulin resistant obese postmenopausal women.

Evaluation of insulin sensitivity with a new lipid-based index in non-diabetic postmenopausal overweight and obese women before and after a weight loss intervention

OBJECTIVE To evaluate the validity of a new lipid-based index (Disse index) in assessing insulin sensitivity (IS) compared with the hyperinsulinemic-euglycemic (HIEG) clamp in overweight and obese, non-diabetic, postmenopausal women, before and after a weight loss intervention. RESEARCH DESIGN AND METHODS Association between Disse index and the HIEG clamp was evaluated in 86 non-diabetic postmenopausal overweight and obese women before and after weight loss. Percentage changes (%Delta) were calculated for several fasting indices and compared with %Delta of HIEG clamp. RESULTS We observed a strong correlation between Disse index and HIEG clamp (r=0.69, P<0.001). This association was higher than those of homeostasis model assessment (HOMA), quantitative insulin sensitivity check index (QUICKI), and McAuley indices while no significant difference was observed with Revised-QUICKI. Percent change of Disse index (pre- versus post-weight loss program) was significantly correlated with %Delta of HIEG clamp (r=0.34, P<0.01). This correlation was similar to those observed for the other indices tested. CONCLUSIONS We validated the reliability of Disse index in assessing IS in non-diabetic post-menopausal overweight and obese women, before and after weight loss intervention. Disse index may be useful not only for insulin resistant diagnostics in this type of population, but also for the IS follow-up after a weight-loss program and weight stabilization. The presence of lipid elements in this fasting index improves the estimation of IS in overweight and obese non-diabetic post-menopausal women and could add more information about peripheral IS.

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.