Suppressed bone turnover in obesity: a link to energy metabolism? A case-control study

CONTEXT\nObservations in rodents suggest that osteocalcin (OC) participates in glucose metabolism. Based on human studies, it remains unclear whether circulating OC is simply a bone turnover marker (BTM) or also a mediator in interactions between the skeleton and glucose homeostasis.\nOBJECTIVE\nThe objective of the study was to determine the responses of BTMs, including OC, to oral glucose tolerance test (OGTT) in a case-control setting.\nDESIGN AND PATIENTS\nThirty-four normoglycemic young adults [mean age 19 y (SD 2.3)] with severe childhood-onset obesity and their gender- and age-matched nonobese controls underwent a standard 2-hour OGTT.\nMAIN OUTCOME MEASURES\nGlucose, insulin, and six BTMs including total and carboxylated OC (cOC) were determined at baseline and at 30, 60, 90, and 120 minutes during OGTT.\nRESULTS\nThe obese and control subjects were similar in height; the mean body mass indices were 40.4 and 21.9 kg/m(2), respectively. The homeostasis model assessment index was 2.7 times greater in the obese subjects. All BTMs, except bone-specific alkaline phophatase, were lower in the obese subjects compared with the controls: the differences at baseline were 40%, 35%, 17%, 31%, and 32% for N-terminal propeptides of type I collagen, cross-linked telopeptides of type I collagen, tartrate-resistant acid phosphatase, total OC, and carboxylated OC (P &lt; .05 for all) after adjusting for whole-body bone area. All BTMs decreased during OGTT. The relative values for the OGTT responses for total, but not for cOC (measured as area under the curve) differed between the two groups (P = .029 and P = .139, respectively): the decrease in total OC during the OGTT was less pronounced in the obese subjects. Responses in other BTMs were similar between the groups. No associations were observed between glucose metabolism and OCs during OGTT with linear regression.\nCONCLUSIONS\nBone turnover markers were substantially lower in obese subjects compared with controls. Total OC and cOC showed less pronounced decrease during the OGTT in obese subjects compared with controls, whereas other BTMs responded similarly in the two groups. The role of OC, if anything, in glucose homeostasis is indirect and may be mediated via other factors than glucose or insulin.</p

Identification of plasma lipid biomarkers for prostate cancer by lipidomics and bioinformatics

Background: Lipids have critical functions in cellular energy storage, structure and signaling. Many individual lipid molecules have been associated with the evolution of prostate cancer; however, none of them has been approved to be used as a biomarker. The aim of this study is to identify lipid molecules from hundreds plasma apparent lipid species as biomarkers for diagnosis of prostate cancer. Methodology/Principal Findings: Using lipidomics, lipid profiling of 390 individual apparent lipid species was performed on 141 plasma samples from 105 patients with prostate cancer and 36 male controls. High throughput data generated from lipidomics were analyzed using bioinformatic and statistical methods. From 390 apparent lipid species, 35 species were demonstrated to have potential in differentiation of prostate cancer. Within the 35 species, 12 were identified as individual plasma lipid biomarkers for diagnosis of prostate cancer with a sensitivity above 80%, specificity above 50% and accuracy above 80%. Using top 15 of 35 potential biomarkers together increased predictive power dramatically in diagnosis of prostate cancer with a sensitivity of 93.6%, specificity of 90.1% and accuracy of 97.3%. Principal component analysis (PCA) and hierarchical clustering analysis (HCA) demonstrated that patient and control populations were visually separated by identified lipid biomarkers. RandomForest and 10-fold cross validation analyses demonstrated that the identified lipid biomarkers were able to predict unknown populations accurately, and this was not influenced by patient's age and race. Three out of 13 lipid classes, phosphatidylethanolamine (PE), ether-linked phosphatidylethanolamine (ePE) and ether-linked phosphatidylcholine (ePC) could be considered as biomarkers in diagnosis of prostate cancer. Conclusions/Significance: Using lipidomics and bioinformatic and statistical methods, we have identified a few out of hundreds plasma apparent lipid molecular species as biomarkers for diagnosis of prostate cancer with a high sensitivity, specificity and accuracy

BCAA catabolism in brown fat controls energy homeostasis through SLC25A44.

Branched-chain amino acid (BCAA; valine, leucine and isoleucine) supplementation is often beneficial to energy expenditure; however, increased circulating&nbsp;levels of BCAA are linked to obesity and diabetes. The mechanisms of this paradox remain unclear. Here we report that, on cold exposure, brown adipose tissue (BAT) actively utilizes BCAA in the mitochondria for thermogenesis and promotes systemic BCAA clearance in mice and humans. In turn, a BAT-specific defect in BCAA catabolism attenuates systemic BCAA clearance, BAT fuel oxidation and thermogenesis, leading to diet-induced obesity and glucose intolerance. Mechanistically, active BCAA catabolism in BAT is mediated by SLC25A44, which transports BCAAs into mitochondria. Our results suggest that BAT serves as a key metabolic filter that controls BCAA clearance via SLC25A44, thereby contributing to the improvement of metabolic health

Plasma lysophosphatidylcholine levels are reduced in obesity and type 2 diabetes

BACKGROUND: Obesity and type 2 diabetes (T2DM) are associated with increased circulating free fatty acids and triacylglycerols. However, very little is known about specific molecular lipid species associated with these diseases. In order to gain further insight into this, we performed plasma lipidomic analysis in a rodent model of obesity and insulin resistance as well as in lean, obese and obese individuals with T2DM. METHODOLOGY/PRINCIPAL FINDINGS: Lipidomic analysis using liquid chromatography coupled to mass spectrometry revealed marked changes in the plasma of 12 week high fat fed mice. Although a number of triacylglycerol and diacylglycerol species were elevated along with of a number of sphingolipids, a particularly interesting finding was the high fat diet (HFD)-induced reduction in lysophosphatidylcholine (LPC) levels. As liver, skeletal muscle and adipose tissue play an important role in metabolism, we next determined whether the HFD altered LPCs in these tissues. In contrast to our findings in plasma, only very modest changes in tissue LPCs were noted. To determine when the change in plasma LPCs occurred in response to the HFD, mice were studied after 1, 3 and 6 weeks of HFD. The HFD caused rapid alterations in plasma LPCs with most changes occurring within the first week. Consistent with our rodent model, data from our small human cohort showed a reduction in a number of LPC species in obese and obese individuals with T2DM. Interestingly, no differences were found between the obese otherwise healthy individuals and the obese T2DM patients. CONCLUSION: Irrespective of species, our lipidomic profiling revealed a generalized decrease in circulating LPC species in states of obesity. Moreover, our data indicate that diet and adiposity, rather than insulin resistance or diabetes per se, play an important role in altering the plasma LPC profile

Collateral fattening in body composition autoregulation: its determinants and significance for obesity predisposition

Collateral fattening refers to the process whereby excess fat is deposited as a result of the body’s attempt to counter a deficit in lean mass through overeating. Its demonstration and significance to weight regulation and obesity can be traced to work on energy budget strategies in growing mammals and birds, and to men recovering from experimental starvation. The cardinal features of collateral fattening rests upon (i) the existence of a feedback system between lean tissue and appetite control, with lean tissue deficit driving hyperphagia, and (ii) upon the occurrence of a temporal desynchronization in the recovery of body composition, with complete recovery of fat mass preceeding that of lean mass. Under these conditions, persistent hyperphagia driven by the need to complete the recovery of lean tissue will result in the excess fat deposition (hence collateral fattening) and fat overshooting. After reviewing the main lines of evidence for the phenomenon of collateral fattening in body composition autoregulation, this article discusses the causes and determinants of the desynchronization in fat and lean tissue recovery leading to collateral fattening and fat overshooting, and points to their significance in the mechanisms by which dieting, developmental programming and sedentariness predispose to obesity

Association of size at birth with adolescent hormone levels, body size and age at menarche: relevance for breast cancer risk

Birth size has been positively associated with age at menarche and height in adolescence and adulthood, but the relevant biological mechanisms remain unclear. Among 262 Norwegian term-born singleton girls, birth size measures (weight, length, ponderal index, head circumference and subscapular skin-fold thickness) were analysed in relation to adolescent hormone levels (oestradiol, prolactin, dehydroepiandrosterone sulphate, androstenedione and free testosterone index), age at menarche and adolescent (ages 12.7–15.5 years) and body size (height, weight, body mass index and waist-to-hip ratio) using survival analysis and general linear modelling. The results were adjusted for gestational age at birth, age and menarcheal status at measurement in adolescence and maternal age at menarche. Birth weight, birth length and head circumference were positively associated with adolescent weight and height, and small birth size was associated with earlier age at menarche. Subscapular skin-fold thickness at birth was not associated with adolescent body size, but low fold-thickness was associated with earlier age at menarche. Measures of birth size were inversely related to circulating levels of dehydroepiandrosterone sulphate in adolescence, but there was no clear association with other hormones. These results suggest that physical and sexual development in puberty and adolescence is influenced by prenatal factors, and in combination, these factors may influence health and disease later in life

Obesity Impact on the Attentional Cost for Controlling Posture

International audienceBACKGROUND: This study investigated the effects of obesity on attentional resources allocated to postural control in seating and unipedal standing. METHODS: Ten non obese adults (BMI = 22.4±1.3, age = 42.4±15.1) and 10 obese adult patients (BMI = 35.2±2.8, age = 46.2±19.6) maintained postural stability on a force platform in two postural tasks (seated and unipedal). The two postural tasks were performed (1) alone and (2) in a dual-task paradigm in combination with an auditory reaction time task (RT). Performing the RT task together with the postural one was supposed to require some attentional resources that allowed estimating the attentional cost of postural control. 4 trials were performed in each condition for a total of 16 trials. FINDINGS: (1) Whereas seated non obese and obese patients exhibited similar centre of foot pressure oscillations (CoP), in the unipedal stance only obese patients strongly increased their CoP sway in comparison to controls. (2) Whatever the postural task, the additional RT task did not affect postural stability. (3) Seated, RT did not differ between the two groups. (4) RT strongly increased between the two postural conditions in the obese patients only, suggesting that body schema and the use of internal models was altered with obesity. INTERPRETATION: Obese patients needed more attentional resources to control postural stability during unipedal stance than non obese participants. This was not the case in a more simple posture such as seating. To reduce the risk of fall as indicated by the critical values of CoP displacement, obese patients must dedicate a strong large part of their attentional resources to postural control, to the detriment of non-postural events. Obese patients were not able to easily perform multitasking as healthy adults do, reflecting weakened psycho-motor abilities

Birth size and gestational age in opposite-sex twins as compared to same-sex twins: An individual-based pooled analysis of 21 cohorts

It is well established that boys are born heavier and longer than girls, but it remains unclear whether birth size in twins is affected by the sex of their co-twin. We conducted an individual-based pooled analysis of 21 twin cohorts in 15 countries derived from the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins), including 67,850 dizygotic twin individuals. Linear regression analyses showed that boys having a co-twin sister were, on average, 31 g (95% CI 18 to 45) heavier and 0.16 cm (95% CI 0.045 to 0.274) longer than those with a co-twin brother. In girls, birth size was not associated (5 g birth weight; 95% CI -8 to -18 and -0.089 cm birth length; 95% CI -0.202 to 0.025) with the sex of the co-twin. Gestational age was slightly shorter in boy-boy pairs than in boy-girl and girl-girl pairs. When birth size was standardized by gestational age, the magnitude of the associations was attenuated in boys, particularly for birth weight. In conclusion, boys with a co-twin sister are heavier and longer at birth than those with a co-twin brother. However, these differences are modest and partly explained by a longer gestation in the presence of a co-twin sister

Genetic and environmental factors affecting birth size variation: a pooled individual-based analysis of secular trends and global geographical differences using 26 twin cohorts

Background: The genetic architecture of birth size may differ geographically and over time. We examined differences in the genetic and environmental contributions to birthweight, length and ponderal index (PI) across geographical-cultural regions (Europe, North America and Australia, and East Asia) and across birth cohorts, and how gestational age modifies these effects. Methods: Data from 26 twin cohorts in 16 countries including 57 613 monozygotic and dizygotic twin pairs were pooled. Genetic and environmental variations of birth size were estimated using genetic structural equation modelling. Results: The variance of birthweight and length was predominantly explained by shared environmental factors, whereas the variance of PI was explained both by shared and unique environmental factors. Genetic variance contributing to birth size was small. Adjusting for gestational age decreased the proportions of shared environmental variance and increased the propositions of unique environmental variance. Genetic variance was similar in the geographical-cultural regions, but shared environmental variance was smaller in East Asia than in Europe and North America and Australia. The total variance and shared environmental variance of birth length and PI were greater from the birth cohort 1990-99 onwards compared with the birth cohorts from 1970-79 to 1980-89. Conclusions: The contribution of genetic factors to birth size is smaller than that of shared environmental factors, which is partly explained by gestational age. Shared environmental variances of birth length and PI were greater in the latest birth cohorts and differed also across geographical-cultural regions. Shared environmental factors are important when explaining differences in the variation of birth size globally and over time

Association between birthweight and later body mass index: an individual-based pooled analysis of 27 twin cohorts participating in the CODATwins project

Background: There is evidence that birthweight is positively associated with body mass index (BMI) in later life, but it remains unclear whether this is explained by genetic factors or the intrauterine environment. We analysed the association between birthweight and BMI from infancy to adulthood within twin pairs, which provides insights into the role of genetic and environmental individual-specific factors. Methods: This study is based on the data from 27 twin cohorts in 17 countries. The pooled data included 78 642 twin individuals (20 635 monozygotic and 18 686 same-sex dizygotic twin pairs) with information on birthweight and a total of 214 930 BMI measurements at ages ranging from 1 to 49 years. The association between birthweight and BMI was analysed at both the individual and within-pair levels using linear regression analyses. Results: At the individual level, a 1-kg increase in birthweight was linearly associated with up to 0.9 kg/m 2 higher BMI ( P  < 0.001). Within twin pairs, regression coefficients were generally greater (up to 1.2 kg/m 2 per kg birthweight, P  < 0.001) than those from the individual-level analyses. Intra-pair associations between birthweight and later BMI were similar in both zygosity groups and sexes and were lower in adulthood. Conclusions: These findings indicate that environmental factors unique to each individual have an important role in the positive association between birthweight and later BMI, at least until young adulthood