The Kynurenine Pathway Metabolites in Cord Blood Positively Correlate With Early Childhood Adiposity

Context The kynurenine pathway generates metabolites integral to energy metabolism, neurotransmission, and immune function. Circulating kynurenine metabolites positively correlate with adiposity in children and adults, yet it is not known whether this relationship is present already at birth. Objective In this prospective longitudinal study, we investigate the relationship between cord blood kynurenine metabolites and measures of adiposity from birth to 4.5 years. Methods Liquid chromatography-tandem mass spectrometry was used to quantify cord blood kynurenine metabolites in 812 neonates from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) study. Fat percentage was measured by air displacement plethysmography and abdominal adipose tissue compartment volumes; superficial (sSAT) and deep subcutaneous (dSAT) and internal adipose tissue were quantified by magnetic resonance imaging at early infancy in a smaller subset of neonates, and again at 4 to 4.5 years of age. Results Cord blood kynurenine metabolites appeared to be higher in female newborns, higher in Indian newborns compared with Chinese newborns, and higher in infants born by cesarean section compared with vaginal delivery. Kynurenine, xanthurenic acid, and quinolinic acid were positively associated with birthweight, but not with subsequent weight during infancy and childhood. Quinolinic acid was positively associated with sSAT at birth. Kynurenic acid and quinolinic acid were positively associated with fat percentage at 4 years. Conclusion Several cord blood kynurenine metabolite concentrations were positively associated with birthweight, with higher kynurenic acid and quinolinic acid correlating to higher percentage body fat in childhood, suggesting these cord blood metabolites as biomarkers of early childhood adiposity.Peer reviewe

Retrospective techniques for segmentation of structural and functional MR brain images

In this thesis, we focus on several segmentation problems arising in the area of structural and functional neuroimaging. Our solutions to these problems are based on a retrospective framework, wherein a complex segmentation procedure is divided into two simpler steps, initial segmentation and incorporation of prior information. While combining these steps might potentially lead to an optimal solution, we show that the simpler two-step approach can either be made equivalent to a combined procedure or achieve superior performance, due to simpler optimization. We first consider the problem of detecting activated regions in functional Magnetic Resonance Imaging (fMRI). While activated regions are typically large, smaller spurious activations caused by noise are likely to appear in the segmentation. These can be removed by cluster size thresholding. Though cluster size thresholding can be regarded as a method to reduce false positives, it affects the smaller true activations. We show that in the context of Markov Random Field (MRF) based segmentation, simple removal of small regions after the segmentation is not optimal. We propose a retrospective correction approach that allows the regions to grow before they are eliminated based on the cluster size. This approach finds the best modification (removal or growth) and achieves superior performance to that of the standard MRF-based segmentation. The second and the main problem considered in this thesis is skull stripping, i.e., the problem of separating the brain tissues (white matter, grey matter, cerebral spinal fluid) from the non-brain tissues (skull, scalp, eye sockets, neck tissues, etc.). Skull stripping performance suffers from the problem of narrow connections between brain and non-brain structures which usually results in preservation of significant amount of non-brain tissues. Many popular methods rely on iterative surface deformation to fit the brain boundary and tend to leave residual dura. We first approach the problem in a general framework of narrow connection removal. Here, we show that of all existing approaches, isoperimetric algorithm performs the best but can be sensitive to initialization. Instead, we propose a novel approach based on graph cuts that has beneficial features - global optimality, speed, and possibility of fully automated implementation for many applications. We also show that incorporating intensity information into graph weight assignment can further improve performance. In the case of skull stripping, compared to the Hybrid Watershed Algorithm (HWA), our approach achieves an additional 10-30% of dura removal without incurring further brain tissue erosion. When used in conjunction with HWA, our approach substantially decreases and often fully avoids cortical surface overestimation in subsequent segmentation. Lastly, we address the problem of skull stripping in multimodal images (combinations of T1-weighted and T2-weighted images). T1W and T2W images have different contrast properties and we show that the combined use of this information can help to further differentiate dura from brain structures, compared to using only T1W modality. We employ the graph cuts based skull stripping approach with suitably modified thresholding and post-processing procedures to suit multimodal images. The results obtained show significant decrease in the amount of dura in the resultant brain mask when using multimodal images.DOCTOR OF PHILOSOPHY (SCE

Sex differences in glucose and fatty acid metabolism in Asians who are nonobese

Context - The prevalence of diabetes is increasing throughout Asia, even in the absence of obesity, and is lower in women than in men. The underlying mechanisms are not well understood. Objective - To evaluate the sex differences in glucose and fatty acid metabolism in Asians who are nonobese. Design - Cross-sectional study. Setting - Clinical Nutrition Research Centre, Singapore. Participants - Healthy Asian men (n = 32; body mass index, 21.8 ± 1.5 kg/m2; age, 42 ± 14 years) and women (n = 28; body mass index, 21.4 ± 2.0 kg/m2; age, 41 ± 13 years). Main Outcome Measures - Insulin sensitivity (insulin-mediated glucose uptake normalized for steady-state insulin; hyperinsulinemic-euglycemic clamp), postprandial glucose, insulin and fatty acid concentrations, insulin secretion (mixed meal tolerance test with mathematical modeling), insulin clearance, body composition and fat distribution (dual-energy X-ray absorptiometry, MRI, and spectroscopy), cardiorespiratory fitness (maximal oxygen uptake; graded exercise test), and handgrip strength (dynamometry). Results - Women had more total body fat but less visceral fat than men; liver and muscle lipid contents were not different. Maximal oxygen uptake and handgrip strength were lower in women than men. The postprandial glucose concentrations were ~8% lower, the insulin-mediated glucose uptake was ~16% greater, and the meal-induced suppression of fatty acid concentrations was significantly greater in women than in men (P < 0.05 for all). However, muscle insulin sensitivity was not different between the sexes. No differences were found in postprandial insulin secretion and clearance rates; however, the steady-state insulin clearance was ~17% lower in women. Conclusions - Asian women who are nonobese are more insulin-sensitive than men at the level of adipose tissue but not skeletal muscle. Therefore, sex differences in glucose tolerance are likely the result of sexual dimorphism in hepatic insulin action.Agency for Science, Technology and Research (A*STAR)The present study was supported by the Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore (Award BMSI/16-07803C-R20H)

A 12-week aerobic exercise intervention results in improved metabolic function and lower adipose tissue and ectopic fat in high-fat diet fed rats

10.1042/BSR20201707BIOSCIENCE REPORTS41

Brown adipose tissues mediate the metabolism of branched chain amino acids during the transitioning from hyperthyroidism to euthyroidism (TRIBUTE)

Both hyperthyroidism and elevated plasma branched chain amino acids (BCAA) are associated with insulin resistance. BCAA utilization and clearance relative to thyroid status changes remains unclear. We investigate amino acids changes, specifically BCAA, during the transition from hyperthyroidism to euthyroidism, and the impact of active brown adipose tissue (BAT) on the metabolic effects of BCAA. Newly diagnosed Graves' disease participants were recruited. Hyperthyroidism was treated via a titration dosing regimen of thionamide anti-thyroid drug to establish euthyroidism over 12-24 weeks. All underwent energy expenditure (EE) measurement within a chamber calorimeter, 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomography/magnetic resonance (PET/MR) imaging and plasma amino acids measurement during hyperthyroidism and euthyroidism. PET BAT maximum standardized uptake value (SUVmax), SUVmean and MR supraclavicular fat fraction (FF) quantified BAT activity. Twenty-two patients completed the study. Plasma BCAA level was significantly reduced in BAT-positive but not in BAT-negative patients during the transition from hyperthyroidism to euthyroidism. Plasma valine but not leucine and isoleucine correlated positively with insulin and HOMA-IR in hyperthyroidism. Plasma valine, leucine and isoleucine correlated with insulin and HOMA-IR in euthyroidism. Plasma valine correlated with insulin and HOMA-IR in BAT-negative but not in BAT-positive participants in both hyperthyroid and euthyroid state. However, the change (i.e. decrease) in plasma valine concentration from hyperthyroid to euthyroid state was affected by BAT-status. BAT utilizes and promotes BCAA plasma clearance from hyperthyroid to euthyroid state. Active BAT can potentially reduce circulating BCAA and may help to ameliorate insulin resistance and improve metabolic health.Clinical trial registration: The trial was registered at clinicaltrials.gov as NCT03064542.National Medical Research Council (NMRC)Published versionThe study was supported by the National Medical Research Council Award grant. Grant number: NMRC/ CSA-INV/0003/2015

Clinical and imaging features of women with polygenic partial lipodystrophy: a case series

Abstract Background Familial partial lipodystrophy (FPLD) is an inherited disorder of white adipose tissue that causes premature cardiometabolic disease. There is no clear diagnostic criteria for FPLD, and this may explain the under-detection of this condition. Aim This pilot study aimed to describe the clinical features of women with FPLD and to explore the value of adipose tissue measurements that could be useful in diagnosis. Methods In 8 women with FPLD and 4 controls, skinfold measurements, DXA and whole-body MRI were undertaken. Results Whole genome sequencing was negative for monogenic metabolic causes, but polygenic scores for partial lipodystrophy were elevated in keeping with FPLD type 1. The mean age of diagnosis of DM was 31 years in the FPLD group. Compared with controls, the FPLD group had increased HOMA-IR (10.3 vs 2.9, p = 0.028) and lower mean thigh skinfold thickness (19.5 mm vs 48.2 mm, p = 0.008). The FPLD group had lower percentage of leg fat and an increased ratio of trunk to leg fat percentage on DXA. By MRI, the FPLD group had decreased subcutaneous adipose tissue (SAT) volume in the femoral and calf regions (p < 0.01); abdominal SAT, visceral adipose tissue, and femoral and calf muscle volumes were not different from controls. Conclusion Women with FPLD1 in Singapore have significant loss of adipose but not muscle tissue in lower limbs and have early onset of diabetes. Reduced thigh skinfold, and increased ratio of trunk to leg fat percentage on DXA are potentially clinically useful markers to identify FPLD1

Automated segmentation of visceral and subcutaneous (deep and superficial) adipose tissues in normal and overweight men

10.1002/jmri.24655Journal of Magnetic Resonance Imaging414924-93

Branched-Chain Amino Acid Supplementation Does Not Preserve Lean Mass or Affect Metabolic Profile in Adults with Overweight or Obesity in a Randomized Controlled Weight Loss Intervention

10.1093/jn/nxaa414JOURNAL OF NUTRITION1514911-920complete