Body composition phenotypes in pathways to obesity and the metabolic syndrome.

Dynamic changes in body weight have long been recognized as important indicators of risk for debilitating diseases. While weight loss or impaired growth can lead to muscle wastage, as well as to susceptibility to infections and organ dysfunctions, the development of excess fat predisposes to type 2 diabetes and cardiovascular diseases, with insulin resistance as a central feature of the disease entities of the metabolic syndrome. Although widely used as the phenotypic expression of adiposity in population and gene-search studies, body mass index (BMI), that is, weight/height(2) (H(2)), which was developed as an operational definition for classifying both obesity and malnutrition, has considerable limitations in delineating fat mass (FM) from fat-free mass (FFM), in particular at the individual level. After an examination of these limitations within the constraints of the BMI-FM% relationship, this paper reviews recent advances in concepts about health risks related to body composition phenotypes, which center upon (i) the partitioning of BMI into an FM index (FM/H(2)) and an FFM index (FFM/H(2)), (ii) the partitioning of FFM into organ mass and skeletal muscle mass, (iii) the anatomical partitioning of FM into hazardous fat and protective fat and (iv) the interplay between adipose tissue expandability and ectopic fat deposition within or around organs/tissues that constitute the lean body mass. These concepts about body composition phenotypes and health risks are reviewed in the light of race/ethnic variability in metabolic susceptibility to obesity and the metabolic syndrome.

Large differences in the prevalence of normal weight obesity using various cut-offs for excess body fat

BACKGROUND AND AIMS: Normal weight obesity (NWO) has been defined as an excessive body fat (BF) associated with a normal body mass index (BMI). Still, little is known regarding the effect of differing cut-offs for %BF on the prevalence of NWO. We thus conducted a study to assess the effect of modifying the cut-offs for excessive %BF on the prevalence of NWO. METHODS: We examined a convenience sample of 1523 Portuguese adults. BF was measured by validated hand-held bioimpedance. NWO was defined as a BMI < 25 kg/m2 and a %BF >30% or according to sex- and age-specific %BF cut-offs. RESULTS: Prevalence of NWO was 10.1% in women and 3.2% in men. In women, prevalence of NWO increased considerably with age, and virtually all women aged over 55 with a BMI < 25 kg/m2 were actually considered as NWO. Using sex-specific cut-offs for BF (men: 29.1%; women: 37.2%) led to moderately lower prevalence of NWO in women. Using sex and age-specific cut-offs for %BF considerably decreased the prevalence of NWO in women, i.e. 0.5e2.5% (depending on the criterion) but not in men, i.e. 1.9e3.4%. CONCLUSIONS: In women, the prevalence of NWO varies considerably according to the cut-off used to define excess BF, whereas a much smaller variation is found in men. While further studies are needed to describe the risk associated with NWO using various %BF cut-offs, this study suggests that sex- and age-specific cut-offs may be preferred.

Loss of insulin synthesis and beta cell survival induced by oxidized LDL require activation of reticulum endoplasmic stress: a mechanism countered by HDL

Elevated circulating concentrations in modified LDL-cholesterol particles (e.g. oxidised LDL) and low levels in HDL increase not only the risk for diabetic patients to develop cardiovascular diseases but also may contribute to development and progression of diabetes by directly having adverse effects on β-cells. Chronic exposure of β-cells to 2 mM human oxidised LDL-cholesterol (oxLDL) increases the rate of apoptosis, reduce insulin biosynthesis and the secretory capacity of the cells in response to nutrients. In line with the protective role, HDL efficiently antagonised the harmful effects of ox- LDL, suggesting that low levels of HDL would be inefficient to protect β-cells against oxLDL attack in patients. Activation of endoplasmic reticulum (ER) stress is pointed out to contribute to β-cell dysfunction elicited by environmental stressors. In this study we investigated whether activation of ER stress is required for oxLDL to mediate detrimental effects on β-cells and we tested the potential antagonist properties of HDL: The mouse MIN6 insulin-secreting cells were cultured with 2 mM of LDL-cholesterol preparation (native or in vitro oxidized) in the presence or absence of 1 mM of HDL-cholesterol or the ER stress inhibitor 4-phenylbutyrate (4-PBA): Prolonged exposure of MIN6 cells to 2 mM oxLDL-cholesterol for 48 hours led to an increase in expression of ER stress markers such as ATF4, CHOP and p58 and stimulated the splicing of XBP-1 whereas, induction of these markers was not observable in the cells cultured with native LDL. Treatment of the cells with the 4-PBA chemical chaperone molecule efficiently blocked activation of the ER stress markers induced by oxLDL. The latter mediates β-cell dysfunction and apoptosis by diminishing the expression of islet brain 1 (IB1) and Bcl2. The levels of these two proteins were preserved in the cells that were co-treated with oxLDL and the 4-PBA. Consistent with this result we found that blockade of ER stress activation alleviated the loss of insulin synthesis and abolished apoptosis evoked by oxLDL. However incubation of the cells with 4-PBA did not prevent impairment of insulin secretion elicited by oxLDL, indicating that ER stress is not responsible for the oxLDL-mediated defect of insulin secretion. Co-incubation of the cells with HDL mimicked the effects of 4-PBA on the expression of IB1 and Blc2 and thereby counteracted oxLDL attacks on insulin synthesis and cell survivals. We found that HDL efficiently inhibited activation of the ER stress mediated by oxLDL: These data highlight the contribution of the ER stress in the defects of insulin synthesis and cell survivals induced by oxLDL and emphasize the potent role of HDL to counter activation of the oxLDL-mediated ER-stress activation:

Body taping for contour surgery.

BACKGROUND: Preoperative marking is of primary importance in body contouring and when precise simulation of skin excisions is difficult. Because the "cut as you go" principle can be delicate, especially in patients after massive weight loss, a simple and quick method is needed for preoperative planning. We suggest an approach that helps visualize the optimal skin incision lines and simulates the postoperative result by body taping. METHODS: Twelve patients who underwent abdominal contouring, including classic and vertical abdominoplasties as well as dog ear and scar revision, were prospectively analyzed. The skin to be excised was preoperatively folded, taped, and then marked. The area marked was measured and compared with the actual intraoperatively resected area and the postoperative result was evaluated after 1 year by the patients and three surgeons. RESULTS: With body taping, an 83% congruence between the preoperative planning and the surgery was obtained and only two patients had additional skin resected. No wound dehiscence and flap necrosis occurred and patients as well as surgeons scored the final body contour positively. CONCLUSION: Body taping is a simple, quick, and economic method for planning contour surgery with high accuracy as demonstrated by the low rate of intraoperative changes of the planned resection and low complication rate.

Loss of Prestress, Camber, and Deflection of Non-Composite and Composite Structures Using Different Weight Concretes, HR-137, 1970

General equations are presented for predicting loss of prestress and camber of both composite and non- composite prestressed concrete structures. Continuous time functins of all parameters needed to solve the equations are given, and sample results included. Computed prestress loss and camber are compared with experimental data for normal weight and lightweight concrete. Methods are also presented for predicting the effect of non-prestressed tension steel in reducing time-dependent loss of prestress and camber, and for the determination of short-time deflections of uncracked and cracked prestressed members. Comparisons with experimental results are indicated for these partially prestressed methods.

Reference values of fat-free and fat masses by bioelectrical impedance analysis in 3393 healthy subjects.

Determination of fat-free mass (FFM) and fat mass (FM) is of considerable interest in the evaluation of nutritional status. In recent years, bioelectrical impedance analysis (BIA) has emerged as a simple, reproducible method used for the evaluation of FFM and FM, but the lack of reference values reduces its utility to evaluate nutritional status. The aim of this study was to determine reference values for FFM, FM, and %FM by BIA in a white population of healthy subjects, to observe the changes in these values with age, and to develop percentile distributions for these parameters. Whole-body resistance of 1838 healthy white men and 1555 women, aged 15-64 y, was determined by using four skin electrodes on the right hand and foot. FFM and FM were calculated according to formulas validated for the subject groups and analyzed for age decades. This is the first study to present BIA-determined age- and sex-specific percentiles for FFM, FM, and %FM for healthy subjects, aged 15-64 y. Mean FM and %FM increased progressively in men and after age 45 y in women. The results suggest that any weight gain noted with age is due to a gain in FM. In conclusion, the data presented as percentiles can serve as reference to evaluate the normality of body composition of healthy and ill subject groups at a given age.

Reproductive performance of Santa Inês ewes fed protected fat diet

The objective of this work was to evaluate the reproductive performance of Santa Inês ewes fed a diet supplemented with protected fat. Intervals from lambing to first clinical estrus and to conception, conception rate, prolificacy, live weight and body condition were determined. After lambing, 60 ewes and their offsprings were weighted and randomly assigned to three treatments, based on age, body weight and number of born lambs. Treatments consisted of: control diet, or control diet plus 30 g of protected fat, from lambing to day 25 of post-lambing (Sup25), or to day 60 of post-lambing (Sup60). Out of 60 evaluated ewes, 93.3% returned to estrus, and 74.5% got pregnant, with 73.53% lambing rate and 196.5 days lambing interval. The average periods from lambing to first estrus were 32.4, 27.2 and 35.5 days for ewes fed the control diet, Sup25, and Sup60, respectively. The intervals from lambing to conception were 45.2, 46.5 and 45.2 days, and the supplemented diets did not show differences in comparison to the control diet. Supplementation with protected fat to well-nourished Santa Inês ewes does not improve their reproductive performance.

Optimal stop-loss reinsurance: a dependence analysis

The stop-loss reinsurance is one of the most important reinsurance contracts in the insurance market. From the insurer point of view, it presents an interesting property: it is optimal if the criterion of minimizing the variance of the cost of the insurer is used. The aim of the paper is to contribute to the analysis of the stop-loss contract in one period from the point of view of the insurer and the reinsurer. Firstly, the influence of the parameters of the reinsurance contract on the correlation coefficient between the cost of the insurer and the cost of the reinsurer is studied. Secondly, the optimal stop-loss contract is obtained if the criterion used is the maximization of the joint survival probability of the insurer and the reinsurer in one period.

Different transcriptional control of metabolism and extracellular matrix in visceral and subcutaneous fat of obese and rimonabant treated mice.

BACKGROUND: The visceral (VAT) and subcutaneous (SCAT) adipose tissues play different roles in physiology and obesity. The molecular mechanisms underlying their expansion in obesity and following body weight reduction are poorly defined. METHODOLOGY: C57Bl/6 mice fed a high fat diet (HFD) for 6 months developed low, medium, or high body weight as compared to normal chow fed mice. Mice from each groups were then treated with the cannabinoid receptor 1 antagonist rimonabant or vehicle for 24 days to normalize their body weight. Transcriptomic data for visceral and subcutaneous adipose tissues from each group of mice were obtained and analyzed to identify: i) genes regulated by HFD irrespective of body weight, ii) genes whose expression correlated with body weight, iii) the biological processes activated in each tissue using gene set enrichment analysis (GSEA), iv) the transcriptional programs affected by rimonabant. PRINCIPAL FINDINGS: In VAT, "metabolic" genes encoding enzymes for lipid and steroid biosynthesis and glucose catabolism were down-regulated irrespective of body weight whereas "structure" genes controlling cell architecture and tissue remodeling had expression levels correlated with body weight. In SCAT, the identified "metabolic" and "structure" genes were mostly different from those identified in VAT and were regulated irrespective of body weight. GSEA indicated active adipogenesis in both tissues but a more prominent involvement of tissue stroma in VAT than in SCAT. Rimonabant treatment normalized most gene expression but further reduced oxidative phosphorylation gene expression in SCAT but not in VAT. CONCLUSION: VAT and SCAT show strikingly different gene expression programs in response to high fat diet and rimonabant treatment. Our results may lead to identification of therapeutic targets acting on specific fat depots to control obesity.

Sequencing of Lp-PLA2-encoding PLA2G7 gene in 2000 Europeans reveals several rare loss-of-function mutations.

Elevated plasma levels of lipoprotein-associated phospholipase A(2) (Lp-PLA2) activity have been shown to be associated with increased risk of coronary heart disease and an inhibitor of this enzyme is under development for the treatment of that condition. A Val279Phe null allele in this gene, that may influence patient eligibility for treatment, is relatively common in East Asians but has not been observed in Europeans. We investigated the existence and functional effects of low frequency alleles in a Western European population by re-sequencing the exons of PLA2G7 in 2000 samples. In all, 19 non-synonymous single-nucleotide polymorphisms (nsSNPs) were found, 14 in fewer than four subjects (minor allele frequency <0.1%). Lp-PLA2 activity was significantly lower in rare nsSNP carriers compared with non-carriers (167.8±63.2 vs 204.6±41.8, P=0.01) and seven variants had enzyme activities consistent with a null allele. The cumulative frequency of these null alleles was 0.25%, so <1 in 10,000 Europeans would be expected to be homozygous, and thus not potentially benefit from treatment with an Lp-PLA2 inhibitor.

Beneficial effects of combinatorial micronutrition on body fat and atherosclerosis in mice.

AIMS: More than two billion people worldwide are deficient in key micronutrients. Single micronutrients have been used at high doses to prevent and treat dietary insufficiencies. Yet the impact of combinations of micronutrients in small doses aiming to improve lipid disorders and the corresponding metabolic pathways remains incompletely understood. Thus, we investigated whether a combination of micronutrients would reduce fat accumulation and atherosclerosis in mice. METHODS AND RESULTS: Lipoprotein receptor-null mice fed with an original combination of micronutrients incorporated into the daily chow showed reduced weight gain, body fat, plasma triglycerides, and increased oxygen consumption. These effects were achieved through enhanced lipid utilization and reduced lipid accumulation in metabolic organs and were mediated, in part, by the nuclear receptor PPARα. Moreover, the micronutrients partially prevented atherogenesis when administered early in life to apolipoprotein E-null mice. When the micronutrient treatment was started before conception, the anti-atherosclerotic effect was stronger in the progeny. This finding correlated with decreased post-prandial triglyceridaemia and vascular inflammation, two major atherogenic factors. CONCLUSION: Our data indicate beneficial effects of a combination of micronutritients on body weight gain, hypertriglyceridaemia, liver steatosis, and atherosclerosis in mice, and thus our findings suggest a novel cost-effective combinatorial micronutrient-based strategy worthy of being tested in humans.

Urate-induced acute renal failure and chronic inflammation in liver-specific Glut9 knockout mice.

Plasma urate levels are higher in humans than rodents (240-360 vs. â^¼30 μM) because humans lack the liver enzyme uricase. High uricemia in humans may protect against oxidative stress, but hyperuricemia also associates with the metabolic syndrome, and urate and uric acid can crystallize to cause gout and renal dysfunctions. Thus, hyperuricemic animal models to study urate-induced pathologies are needed. We recently generated mice with liver-specific ablation of Glut9, a urate transporter providing access of urate to uricase (LG9KO mice). LG9KO mice had moderately high uricemia (â^¼120 μM). To further increase their uricemia, here we gavaged LG9KO mice for 3 days with inosine, a urate precursor; this treatment was applied in both chow- and high-fat-fed mice. In chow-fed LG9KO mice, uricemia peaked at 300 μM 2 h after the first gavage and normalized 24 h after the last gavage. In contrast, in high-fat-fed LG9KO mice, uricemia further rose to 500 μM. Plasma creatinine strongly increased, indicating acute renal failure. Kidneys showed tubule dilation, macrophage infiltration, and urate and uric acid crystals, associated with a more acidic urine. Six weeks after inosine gavage, plasma urate and creatinine had normalized. However, renal inflammation, fibrosis, and organ remodeling had developed despite the disappearance of urate and uric acid crystals. Thus, hyperuricemia and high-fat diet feeding combined to induce acute renal failure. Furthermore, a sterile inflammation caused by the initial crystal-induced lesions developed despite the disappearance of urate and uric acid crystals.

Loss of egg yolk genes in mammals and the origin of lactation and placentation

Embryonic development in nonmammalian vertebrates depends entirely on nutritional reserves that are predominantly derived from vitellogenin proteins and stored in egg yolk. Mammals have evolved new resources, such as lactation and placentation, to nourish their developing and early offspring. However, the evolutionary timing and molecular events associated with this major phenotypic transition are not known. By means of sensitive comparative genomics analyses and evolutionary simulations, we here show that the three ancestral vitellogenin-encoding genes were progressively lost during mammalian evolution (until around 30-70 million years ago, Mya) in all but the egg-laying monotremes, which have retained a functional vitellogenin gene. Our analyses also provide evidence that the major milk resource genes, caseins, which have similar functional properties as vitellogenins, appeared in the common mammalian ancestor approximately 200-310 Mya. Together, our data are compatible with the hypothesis that the emergence of lactation in the common mammalian ancestor and the development of placentation in eutherian and marsupial mammals allowed for the gradual loss of yolk-dependent nourishment during mammalian evolution