Abnormal Metabolic Phenotypes Research Articles

An Experimental Study on The Oxidative Status and Inflammatory Levels of A Rat Model of Polycystic Ovary Syndrome Induced by Letrozole and A New High-Fat Diet.

Although there are numerous animal models of polycystic ovary syndrome (PCOS), they often fail to accurately replicate the reproductive and metabolic phenotypes associated with PCOS. The objective of this study is to assess oxidative status and inflammatory levels in a rat model of PCOS subjected to a new high-fat diet (HFD) in combination with letrozole. In this experimental study, mature, six-week-old female Sprague-Dawley rats (n=20) were divided into four groups: control (standard diet); letrozole (letrozole plus a standard diet); HFD; and letrozole+HFD. After 16 weeks, the rats underwent vaginal smear analysis, measurement of hormonal and lipid profiles, and an oral glucose tolerance test (OGTT). Ovarian tissue morphology, oxidative parameters, and inflammatory status were evaluated. The experimental groups exhibited anoestrus profiles in the vaginal smears and abnormal ovarian morphology, which was not observed in the control group. Steroid hormone levels were significantly higher in the letrozole+HFD group compared to the other groups (P=0.00). The experimental groups also showed abnormal glucose levels and lipid metabolism. The relative expression levels of inflammatory genes were significantly elevated in the experimental groups compared to the control group (P=0.00), and the letrozole+HFD group exhibited the highest expression level (P=0.00). The HFD, letrozole, and letrozole+HFD groups demonstrated significantly increased levels of malondialdehyde (MDA) and reactive oxygen species (ROS), while the levels of enzymatic antioxidants were significantly reduced compared to the control group (P=0.00). The combination of a new HFD and letrozole treatment induces inflammation and oxidative stress (OS) in a rat model of PCOS. This model accurately exhibits abnormal metabolic phenotypes and disruptions in hormonal profiles associated with PCOS.

CcpA-Knockout Staphylococcus aureus Induces Abnormal Metabolic Phenotype via the Activation of Hepatic STAT5/PDK4 Signaling in Diabetic Mice.

Catabolite control protein A (CcpA), an important global regulatory protein, is extensively found in S. aureus. Many studies have reported that CcpA plays a pivotal role in regulating the tricarboxylic acid cycle and pathogenicity. Moreover, the CcpA-knockout Staphylococcus aureus (S. aureus) in diabetic mice, compared with the wild-type, showed a reduced colonization rate in the tissues and organs and decreased inflammatory factor expression. However, the effect of CcpA-knockout S. aureus on the host's energy metabolism in a high-glucose environment and its mechanism of action remain unclear. S. aureus, a common and major human pathogen, is increasingly found in patients with obesity and diabetes, as recent clinical data reveal. To address this issue, we generated CcpA-knockout S. aureus strains with different genetic backgrounds to conduct in-depth investigations. In vitro experiments with high-glucose-treated cells and an in vivo model study with type 1 diabetic mice were used to evaluate the unknown effect of CcpA-knockout strains on both the glucose and lipid metabolism phenotypes of the host. We found that the strains caused an abnormal metabolic phenotype in type 1 diabetic mice, particularly in reducing random and fasting blood glucose and increasing triglyceride and fatty acid contents in the serum. In a high-glucose environment, CcpA-knockout S. aureus may activate the hepatic STAT5/PDK4 pathway and affect pyruvate utilization. An abnormal metabolic phenotype was thus observed in diabetic mice. Our findings provide a better understanding of the molecular mechanism of glucose and lipid metabolism disorders in diabetic patients infected with S. aureus.

CARDIOMETABOLIC RISK PREDICTION IN PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE COMBINED WITH SUBCLINICAL HYPOTHYROIDISM

One of the most common diseases of our time is non-alcoholic fatty liver disease (NAFLD). Recently published research results indicate that patients with NAFLD along with traditional risk factors for cardiovascular diseases (CVD) have "new" risk factors such as endothelial dysfunction (ED), carotid intima-media thickness (CIMT), an increase in the CRP level, as well as risk factors combined into the Framingham scale. It is also known that combination of NAFLD with subclinical hypothyroidism (SH) forms an abnormal metabolic phenotype, which is associated with cardiometabolic risk factors. The study of cardiometabolic predictors and vascular markers in patients with NAFLD in combination with SH will provide an opportunity to improve the strategy of cardiovascular events prevention in such comorbid patients.

Transgenerational inheritance of acquired epigenetic signatures at CpG islands in mice

Transgenerational epigenetic inheritance in mammals remains a debated subject. Here, we demonstrate that DNA methylation of promoter-associated CpG islands (CGIs) can be transmitted from parents to their offspring in mice. We generated DNA methylation-edited mouse embryonic stem cells (ESCs), in which CGIs of two metabolism-related genes, the Ankyrin repeat domain 26 and the low-density lipoprotein receptor, were specifically methylated and silenced. DNA methylation-edited mice generated by microinjection of the methylated ESCs exhibited abnormal metabolic phenotypes. Acquired methylation of the targeted CGI and the phenotypic traits were maintained and transmitted across multiple generations. The heritable CGI methylation was subjected to reprogramming in parental PGCs and subsequently reestablished in the next generation at post-implantation stages. These observations provide a concrete step toward demonstrating transgenerational epigenetic inheritance in mammals, which may have implications in our understanding of evolutionary biology as well as the etiology, diagnosis, and prevention of non-genetically inherited human diseases.

Are Women with Normal-Weight Obesity at Higher Risk for Cardiometabolic Disorders?

This study aimed to evaluate the cardiometabolic abnormalities in women with normal-weight obesity (NWO) in comparison with lean, overweight, and obese women. This cross-sectional study evaluated the assessment of cardiometabolic abnormalities of women with NWO compared to lean, overweight, and obese women. NWO was defined as a BMI < 25 kg.m-2 and a BFP higher than 30%. Anthropometric variables, cardiometabolic abnormality markers (fasting blood glucose (FBG), blood pressure (BP), lipid profile, insulin resistance, and high-sensitivity C-reactive protein (hs-CRP)), and liver enzymes were also examined. Significant differences were observed in HDL concentrations between NWO, lean, and obese participants (p < 0.05). There were no significant differences in FBG, insulin resistance, liver enzymes, or cholesterol between groups (p > 0.05). The prevalence of the abnormal metabolic phenotype was higher in NWO compared to the lean group (4.0% and 24.1%, respectively; p < 0.05). Women with type 2 and 3 obesity had abnormal metabolic profiles (60.9% and 73.9%, respectively) compared to NWO participants (p < 0.01). The NWO group had a significantly higher incidence of cardiometabolic abnormalities compared to the lean participants (p < 0.05), while the type 2 and 3 obese individuals had significantly higher incidences compared to the NWO group (p < 0.001 and p < 0.001, respectively). Individuals with NWO had a significantly higher incidence of cardiometabolic abnormalities when compared to lean participants. These abnormalities strongly relate to BFP and waist circumferences.

Identification of a Chromosome 1 Substitution Line B6-Chr1BLD as a Novel Hyperlipidemia Model via Phenotyping Screening.

Hyperlipidemia is a chronic disease that seriously affects human health. Due to the fact that traditional animal models cannot fully mimic hyperlipidemia in humans, new animal models are urgently needed for basic drug research on hyperlipidemia. Previous studies have demonstrated that the genomic diversity of the wild mice chromosome 1 substitution lines was significantly different from that of laboratory mice, suggesting that it might be accompanied by phenotypic diversity. We first screened the blood lipid-related phenotype of chromosome 1 substitution lines. We found that the male HFD-fed B6-Chr1BLD mice showed more severe hyperlipidemia-related phenotypes in body weight, lipid metabolism and liver lesions. By RNA sequencing and whole-genome sequencing results of B6-Chr1BLD, we found that several differentially expressed single nucleotide polymorphism enriched genes were associated with lipid metabolism-related pathways. Lipid metabolism-related genes, mainly including Aida, Soat1, Scly and Ildr2, might play an initial and upstream role in the abnormal metabolic phenotype of male B6-Chr1BLD mice. Taken together, male B6-Chr1BLD mice could serve as a novel, polygenic interaction-based hyperlipidemia model. This study could provide a novel animal model for accurate clinical diagnosis and precise medicine of hyperlipidemia.

Irisin reduces the abnormal reproductive and metabolic phenotypes of PCOS by regulating the activity of brown adipose tissue in mice†.

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disease in women, with clinical manifestations of anovulation and hyperandrogenaemia. The treatment of PCOS mainly focuses on improving clinical symptoms, such as insulin sensitivity or menstrual disorder, through drug treatment. However, due to the pathogenesis diversity of PCOS, there is still a lack of effective treatment in clinics. Metabolic disorder is the key factor in the occurrence of PCOS. Brown adipose tissue (BAT) is a special adipose tissue in the human body that can participate in metabolic balance by improving heat production. BAT has been demonstrated to be an important substance involved in the metabolic disorder of PCOS. Although increasing evidence indicates that BAT transplantation can improve the symptoms of PCOS, it is difficult to achieve BAT transplantation at present due to technical limitations. Stimulation of BAT activation by exogenous substances may be an effective alternative therapy for PCOS. In this study, we investigated the effects of Irisin on dehydroepiandrosterone (DHEA)-induced PCOS in mice and evaluated the effect of Irisin on serum hormone levels and changes in body temperature, body weight, and ovarian morphology. In our study, we found that Irisin can enhance the thermogenesis and insulin sensitivity of PCOS mice by activating the function of BAT. In addition, Irisin treatment can correct the menstrual cycle of PCOS mice, improve the serum steroid hormone disorder status, and reduce the formation of ovarian cystic follicles. In conclusion, our results showed that Irisin treatment significantly improved the metabolic disorder of PCOS and may provide a new and alternative therapy for the treatment of this pathology.

Abnormal Obesity Phenotype Is Associated with Reduced eGFR among Diabetes Mellitus and Hypertensive Patients in a Peri-Urban Community in Ghana.

Background Diabetes mellitus (DM) is a chronic disease characterized by hyperglycemia due to obesity and defects in insulin action. Significant complications of DM include kidney disease due to its association with hypertension and obesity. Thus, the contribution of the various obesity phenotypes to the kidney impairment observed among hypertensive and diabetes mellitus patients is of major concern. Aim The study assessed the association between obesity phenotypes and reduced glomerular filtration rate among diabetes mellitus and hypertensive patients. Methods Three hundred and ten (310) adult patients diagnosed with type 2 diabetes mellitus, hypertension, or both who attended the Presbyterian Hospital, Dormaa Ahenkro, from October 2016 to March 2017 were recruited for the study. Blood samples were collected to analyze biochemical parameters (fasting blood glucose (FBG), lipid profile, and creatinine). Questionnaires were used to collect sociodemographic information, and anthropometrics were appropriately measured. The estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI equation, and reduced eGFR was defined as eGFR <90 ml/min/1.73 m2. Results The prevalence of metabolically healthy nonobese (MHNO), metabolically healthy obese (MHO), metabolically abnormal nonobese (MANO), and metabolically abnormal obese (MAO) phenotypes among the study participants was 30.65%, 4.50%, 52.90%, and 11.94%, respectively. The highest prevalence of reduced eGFR (29/37 (78.38%)) was seen among the MAO group. This was followed by the MANO, MHO, and MHNO with a reduced eGFR prevalence of 62.20%, 57.64%, and 37.89%, respectively. After normalization with MHNO, the reduced eGFR was 1.51, 1.64, and 2.06 times expressed in MHO, MANO, and MAO. For the total samples, when MHNO was maintained as a reference, reduced eGFR was significantly associated with MANO (aOR = 3.07 (95% CI = 1.76–5.35), P < 0.001) and MAO (aOR = 5.67 (95% CI = 2.66–17.27), P < 0.001) even after adjusting for age, gender, smoking, and alcohol intake. This association was maintained among the female study participants when stratified by gender, and in addition, among the female participants, reduced eGFR was also associated with MHO (aOR = 4.19 (95% CI = 1.06–16.53), P=0.041). Conclusion There is a high prevalence of abnormal metabolic phenotypes among diabetes mellitus patients, and these were significantly associated with reduced eGFR among our study participants.

Association Between Indices of Body Composition and Metabolically Unhealthy Phenotype in China: A Cross-Sectional Study.

IntroductionBody composition is closely related to metabolic health status. Visceral adipose tissue (VAT) dysfunction contributes to metabolic syndrome. However, results regarding subcutaneous adipose tissue (SAT) and skeletal muscle are controversial. We aimed to determine the association of indices of body composition with abnormal metabolic phenotype in China.MethodsA total of 3, 954 subjects (age 50.2 ± 11.7 years) with body mass index (BMI) more than 18.5 kg/m2 from Pinggu Metabolic Disease Study were analyzed. Quantitative computed tomography (QCT) was performed to measure total adipose tissue (TAT), VAT, SAT area, and lumbar skeletal muscle area (SMA). Participants were divided into six groups on the basis of BMI category (normal weight/overweight/obesity) and metabolic status (healthy/unhealthy), as defined by the presence or absence of components of the metabolic syndrome by Chinese Diabetes Society criteria.Results63.4%, 39.5%, and 23.3% participants were classified as metabolically healthy phenotype in individuals with normal weight, overweight and obese, respectively. Individuals in the highest TAT, VAT, and VAT/TAT ratio category had higher risk of being metabolically unhealthy than individuals in the lowest group (all p<0.01). While, risk for metabolically unhealthy was reduced significantly in the highest SMA/TAT ratio category when compared with the lowest category in individuals with normal wight and overweight (both p<0.05). Risk for metabolically unhealthy was reduced significantly in the highest SAT category when compared with the lowest category (OR=0.555, 95%CI: 0.360-0.856, p=0.008) in individuals with obese after adjustment for age, sex and BMI. However, skeletal muscle index (SMI) showed no significant association with the metabolically healthy status in different BMI categories (p>0.05). The VAT and VAT/TAT ratio were better diagnostic values of indicators to differentiate metabolically unhealthy subjects from controls compared with other indicators, such as TAT, SAT, SMI, SMA/TAT ratio.ConclusionsHigher visceral adipose tissue was closely associated with metabolically unhealthy phenotype in Chinese adults. Subcutaneous adipose tissue might be a protective factor for metabolic health status only in obese individuals.

Activation of HIF1α Rescues the Hypoxic Response and Reverses Metabolic Dysfunction in the Diabetic Heart.

Type 2 diabetes (T2D) impairs hypoxia-inducible factor (HIF)1α activation, a master transcription factor that drives cellular adaptation to hypoxia. Reduced activation of HIF1α contributes to the impaired post-ischemic remodeling observed following myocardial infarction in T2D. Molidustat is an HIF stabilizer currently undergoing clinical trials for the treatment of renal anemia associated with chronic kidney disease; however, it may provide a route to pharmacologically activate HIF1α in the T2D heart. In human cardiomyocytes, molidustat stabilized HIF1α and downstream HIF target genes, promoting anaerobic glucose metabolism. In hypoxia, insulin resistance blunted HIF1α activation and downstream signaling, but this was reversed by molidustat. In T2D rats, oral treatment with molidustat rescued the cardiac metabolic dysfunction caused by T2D, promoting glucose metabolism and mitochondrial function, while suppressing fatty acid oxidation and lipid accumulation. This resulted in beneficial effects on post-ischemic cardiac function, with the impaired contractile recovery in T2D heart reversed by molidustat treatment. In conclusion, pharmacological HIF1α stabilization can overcome the blunted hypoxic response induced by insulin resistance. In vivo this corrected the abnormal metabolic phenotype and impaired post-ischemic recovery of the diabetic heart. Therefore, molidustat may be an effective compound to further explore the clinical translatability of HIF1α activation in the diabetic heart.

Reduction in endoplasmic reticulum stress activates beige adipocytes differentiation and alleviates high fat diet-induced metabolic phenotypes

Endoplasmic reticulum (ER) stress is closely associated with various metabolic diseases, such as obesity and diabetes. Development of beige/brite adipocytes increases thermogenesis and helps to reduce obesity. Although the relationship between ER stress and white adipocytes has been studied considerably, the possible role of ER stress and the unfolded protein response (UPR) induction in beige adipocytes differentiation remain to be investigated. In this study we investigated how ER stress affected beige adipocytes differentiation both in vitro and in vivo. Phosphorylation of eIF2α was transiently decreased in the early phase (day 2), whereas it was induced at the late phase with concomitant induction of C/EBP homologous protein (CHOP) during beige adipocytes differentiation. Forced expression of CHOP inhibited the expression of beige adipocytes markers, including Ucp1, Cox8b, Cidea, Prdm16, and Pgc-1α, following the induction of beige adipocytes differentiation. When ER stress was reduced by the chemical chaperone tauroursodeoxycholic acid (TUDCA), the expression of the beige adipocytes marker uncoupling protein 1 (UCP1) was significantly enhanced in inguinal white adipose tissue (iWAT) and high fat diet (HFD)-induced abnormal metabolic phenotype was improved. In summary, we found that ER stress and the UPR induction were closely involved in beige adipogenesis. These results suggest that modulating ER stress could be a potential therapeutic intervention against metabolic dysfunctions via activation of iWAT browning.

Valproate-Induced Epigenetic Upregulation of Hypothalamic Fto Expression Potentially Linked with Weight Gain.

Valproate (VPA), a widely-used antiepileptic drug, is a selective inhibitor of histone deacetylase (HDAC) that play important roles in epigenetic regulation. The patient with different diseases receiving this drug tend to exhibit weight gain and abnormal metabolic phenotypes, but the underlying mechanisms remain largely unknown. Here we show that VPA increases the Fto mRNA and protein expression in mouse hypothalamic GT1-7 cells. Interestingly, VPA promotes histone H3/H4 acetylation and the FTO expression which could be reversed by C646, an inhibitor for histone acetyltransferase. Furthermore, VPA weakens the FTO's binding and enhances the binding of transcription factor TAF1 to the Fto promoter, and C646 leads to reverse effect of the VPA, suggesting an involvement of the dynamic of histone H3/H4 acetylation in the regulation of FTO expression. In addition, the mice exhibit an increase in the food intake and body weight at the beginning of 2-week treatment with VPA. Simultaneously, in the hypothalamus of the VPA-treated mice, the FTO expression is upregulated and the H3/H4 acetylation is increased; further the FTO's binding to the Fto promoter is decreased and the TAF1's binding to the promoter is enhanced, suggesting that VPA promotes the assembly of the basal transcriptional machinery of the Fto gene. Finally, the inhibitor C646 could restore the effects of VPA on FTO expression, H3/H4 acetylation, body weight, and food intake; and loss of FTO could reverse the VPA-induced increase of body weight and food intake. Taken together, this study suggests an involvement of VPA in the epigenetic upregulation of hypothalamic FTO expression that is potentially associated with the VPA-induced weight gain.

Abnormal Metabolic Phenotypes Among Urban Chinese Children: Epidemiology and the Impact of DXA-Measured Body Composition.

This study aimed to describe the prevalence rates of abnormal metabolic phenotypes among urban Chinese children and to explore the impact of body composition as measured by dual-energy x-ray absorptiometry (DXA) on metabolic disorders. A total of 7,926 children aged 6 to 17years from seven cities across China were involved. Metabolically unhealthy was defined as having ≥2 risk factors (elevated blood pressure, high triglyceride levels, low levels of high-density lipoprotein cholesterol, and impaired fasting glucose [IFG]). Abnormal metabolic phenotypes were defined as metabolically unhealthy with normal weight (MUNW) and metabolically healthy with overweight or obesity (MHO). Overall prevalence rates of MUNW and MHO were 10.6% and 15.3%, respectively. The prevalence of MUNW increased with age in boys, whereas the prevalence in girls was statistically higher in 11- to 15-year-olds than in other age groups. The prevalence of MHO decreased with age in both genders. Among children with normal weight, the levels of body composition indices were positively correlated with metabolically unhealthy phenotype. Fat-free mass had a protective effect on IFG in children with normal weight. Among children with overweight or obesity, body composition was related to elevated blood pressure and dyslipidemia but not to IFG. The prevalence rates of abnormal metabolic phenotypes differed between genders and ages. Body composition could partly explain the different metabolic phenotypes at the same BMI status among children.

Giving a good start to a new life via maternal brain allostatic adaptations in pregnancy.

Successful pregnancy requires adjustments to multiple maternal homeostatic mechanisms, governed by the maternal brain to support and enable survival of the growing fetus and placenta. Such adjustments fit the concept of allostasis (stability through change) and have a cost: allostatic load. Allostasis is driven by ovarian, anterior pituitary, placental and feto-placental hormones acting on the maternal brain to promote adaptations that support the pregnancy and protect the fetus. Many women carry an existing allostatic load into pregnancy, from socio-economic circumstances, poor mental health and in 'developed' countries, also from obesity. These pregnancies have poorer outcomes indicating negative interactions (failing allostasis) between pre-pregnancy and pregnancy allostatic loads. Use of animal models, such as adult prenatally stressed female offspring with abnormal neuroendocrine, metabolic and behavioural phenotypes, to probe gene expression changes, and epigenetic mechanisms in the maternal brain in adverse pregnancies are discussed, with the prospect of ameliorating poor pregnancy outcomes.

Intrauterine exposure to hyperglycemia retards the development of brown adipose tissue.

Brown adipose tissue (BAT) is an exclusive tissue of nonshivering thermogenesis. It is fueled by lipids and glucose and involved in energy and metabolic homeostasis. Intrauterine exposure to hyperglycemia during gestational diabetes mellitus may result in abnormal fetal development and metabolic phenotypes in adulthood. However, whether intrauterine hyperglycemia influences the development of BAT is unknown. In this study, mouse embryos were exposed to the intrauterine hyperglycemia environment by injecting streptozocin into pregnant mice at 1 d post coitum (dpc). The structure of BAT was examined by hematoxylin and eosin staining and immunohistochemical analysis. The glucose uptake in BAT was measured in vivo by [18F]-fluoro-2-deoxyglucose-micro-positron emission tomography. The gene expression in BAT was determined by real-time PCR, and the 5'-C-phosphate-G-3' site-specific methylation was quantitatively analyzed. Intrauterine hyperglycemia exposure resulted in the impaired structure of BAT and decreased glucose uptake function in BAT in adulthood. The expressions of the genes involved in thermogenesis and mitochondrial respiratory chain in BAT, such as Ucp1, Cox5b, and Elovl3, were down-regulated by intrauterine hyperglycemia exposure at 18.5 dpc and at 16 wk of age. Furthermore, higher methylation levels of Ucp1, Cox5b, and Elovl3 were found in offspring of mothers with streptozotocin-induced diabetes. Our results provide the evidence for enduring inhibitory effects of intrauterine hyperglycemia on BAT development in offspring. Intrauterine hyperglycemia is associated with increased DNA methylation of the BAT specific genes in offspring, which support an epigenetic involvement.-Yu, D.-Q., Lv, P.-P., Yan, Y.-S., Xu, G.-X., Sadhukhan, A., Dong, S., Shen, Y., Ren, J., Zhang, X.-Y., Feng, C., Huang, Y.-T., Tian, S., Zhou, Y., Cai, Y.-T., Ming, Z.-H., Ding, G.-L., Zhu, H., Sheng, J.-Z., Jin, M., Huang, H.-F. Intrauterine exposure to hyperglycemia retards the development of brown adipose tissue.

DXA-measured visceral fat mass and lean body mass reflect abnormal metabolic phenotypes among some obese and nonobese Chinese children and adolescents

Background and aimThe exact constellation of body composition characteristics among metabolically unhealthy obese (MUO) and nonobese (MUNO) children and adolescents remains unclear. The purpose of this study was to identify the major body composition determinants of metabolically unhealthy phenotypes among Chinese children and adolescents. Methods and resultsWe used data from a cross-sectional survey in 2015 that included 1983 children and adolescents aged 6–18 years. Subjects were classified into two phenotypes based on a combination of body mass index (BMI) and metabolic syndrome components. Body composition was measured by dual-energy X-ray absorptiometry (DXA). Among all boys and among adolescent boys, those with MUNO phenotypes displayed significantly higher indices of body composition except for fat mass (FM) percentage and trunk-to-legs FM ratio compared with the metabolically healthy nonobese phenotype (all P < 0.05). MUO individuals had higher arm FM, lean body mass (LBM), and trunk lean mass compared to metabolically healthy obese individuals (all P < 0.05). Visceral fat mass (VFM) and BMI were the major independent determinants of MUNO (VFM, 6- to 9-year-old boys, OR = 1.02, 95% CI = 1.00–1.03, P = 0.021; BMI, 6- to 9-year-old girls, OR = 1.90, 95% CI = 1.31–2.84, P = 0.001; and adolescent boys, OR = 1.34, 95% CI = 1.23–1.44, P < 0.001). LBM was the major independent predictor of MUO among adolescent boys (OR = 1.90, 95% CI = 1.03–1.17, P = 0.003). ConclusionsAmong children and adolescents, the metabolically unhealthy phenotype was associated with excess of body composition, but with significant differences observed based on age and sex. VFM and LBM derived by DXA can predict the metabolically unhealthy phenotype effectively in specific sex and age groups.

Role of the abnormal HIF‐1α‐glycolysis‐aerobic oxidation pathway in non‐Hodgkin lymphoma and the intervention study

Introduction: Diffuse large B-cell lymphoma is a highly heterogeneous entity with varied clinical manifestation and prognosis. Although the immunochemotherapy improves treatment responses, approximately 40% of the patients still eventually endure refractory/relapsed diseases. So how can we identify patients who are unlikely to be cured with conventional therapy and thus to optimize the strategy have become extremely meaningful. The metabolic reprogramming is a remarkably distinct character of tumor cells and is linked to proliferation, drug resistance, survival advantages, and tumor progression. Malignant tumor cells prefer glycolysis rather than aerobic oxidation even under aerobic surroundings. Furthermore, this altered metabolism is an active adjustment regulated by hypoxia inducible factor 1α (HIF-1α) in a reversible manner. The aim of this study is to clarify the role of the balance between glycolysis and aerobic oxidation in DLBCL and to explore the potential of targeting abnormal metabolic phenotype for NHL. Methods: Expressions of HIF-1α, key enzymes of glycolysis pathway hexokinase II (HKII), and aerobic oxidation pathway succinate dehydrogenase (SDHA) in lymphoma samples from DLBCL patients were detected by immunohistochemistry, and the association between expression levels and clinical outcomes were analyzed. SU-DHL-4 cells and Raji cells were stably transfected with lentiviral vectors carried with short hairpin RNA targeting either HIF-1α gene or HKII gene and control vectors encoding a nonmammalian shRNA. Results: Retrospective analysis of the 83 newly diagnosed DLBCL patients showed that HIF-1α+, HKIIhigh and SDHAlow were significantly correlated with inferior PFS and OS. A small subset of patients was identified that the H-H-S group (HIF-1α+HKIIhighSDHAlow), representing that critical regulator and enzymes of glycolysis-aerobic oxidation pathway are all abnormaly expressed, had significantly inferior PFS (3-year PFS, 14.3% vs 78.3%, P = .001) and OS (3-year OS, 14.3% vs 89.9%, P < .001) compared to the non–H-H-S group. Prognostic factors such as LDH, Ki67, SUVmax, IPI, and non-GCB subtype significantly differed between H-H-S group and non–H-H-S group. Furthermore, H-H-S group was demonstrated as an independent prognostic factor. HKII gene silencing significantly suppressed proliferation and abnormal glycolytic metabolism of lymphoma cells as well as enhanced cell apoptosis and sensitivity to chemotherapeutic drugs. Same phenomena were found while HIF-1α was interfered by specific shRNA. Conclusions: The abnormal HIF-1α-glycolysis-aerobic oxidation pathway might act as a prognostic indicator in DLBCL. Knocking down either HIF-1α gene or HKII gene could rescue malignant biological phenotypes of lymphoma cells, suggesting that targeting malignant metabolic phenotype may be a promising approach for refractory/relapsed lymphoma. Keywords: diffuse large B-cell lymphoma (DLBCL); prognostic indices; R-CHOP

Association between Indices of Body Composition and Abnormal Metabolic Phenotype in Normal-Weight Chinese Adults.

We aimed to determine the association of indices of body composition with abnormal metabolic phenotype, and to examine whether the strength of association was differentially distributed in different age groups in normal-weight Chinese adults. A total of 3015 normal-weight adults from a survey of Chinese people encompassing health and basic physiological parameters was included in this cross-sectional study. We investigated the association of body composition measured by bioelectrical impedance analysis and conventional body indices with metabolically unhealthy normal-weight (MUHNW) adults, divided by age groups and gender. Associations were assessed by multiple logistic regression analysis. We found abnormal metabolism in lean Chinese adults to be associated with higher adiposity indices (body mass index, BMI), waist circumference, and percentage body fat), lower skeletal muscle %, and body water %. Body composition was differentially distributed in age groups within the metabolically healthy normal weight (MHNW)/MUHNW groups. The impact of factors related to MUHNW shows a decreasing trend with advancing age in females and disparities of factors (BMI, body fat %, skeletal muscle %, and body water %) associated with the MUHNW phenotype in the elderly was noticed. Those factors remained unchanged in males throughout the age range, while the association of BMI, body fat %, skeletal muscle %, and body water % to MUHNW attenuated and grip strength emerged as a protective factor in elderly females. These results suggest that increased adiposity and decreased skeletal muscle mass are associated with unfavorable metabolic traits in normal-weight Chinese adults, and that MUHNW is independent of BMI, while increased waist circumference appears to be indicative of an abnormal metabolic phenotype in elderly females.

Whole-genome sequencing identifies common-to-rare variants associated with human blood metabolites.

Genetic factors modifying the blood metabolome have been investigated through genome-wide association studies (GWAS) of common genetic variants and through exome sequencing. We conducted a whole-genome sequencing study of common, low-frequency and rare variants to associate genetic variations with blood metabolite levels using comprehensive metabolite profiling in 1,960 adults. We focused the analysis on 644 metabolites with consistent levels across three longitudinal data collections. Genetic sequence variations at 101 loci were associated with the levels of 246 (38%) metabolites (P ≤ 1.9 × 10-11). We identified 113 (10.7%) among 1,054 unrelated individuals in the cohort who carried heterozygous rare variants likely influencing the function of 17 genes. Thirteen of the 17 genes are associated with inborn errors of metabolism or other pediatric genetic conditions. This study extends the map of loci influencing the metabolome and highlights the importance of heterozygous rare variants in determining abnormal blood metabolic phenotypes in adults.

Association between Metabolite Profiles, Metabolic Syndrome and Obesity Status.

Underlying mechanisms associated with the development of abnormal metabolic phenotypes among obese individuals are not yet clear. Our aim is to investigate differences in plasma metabolomics profiles between normal weight (NW) and overweight/obese (Ov/Ob) individuals, with or without metabolic syndrome (MetS). Mass spectrometry-based metabolite profiling was used to compare metabolite levels between each group. Three main principal components factors explaining a maximum of variance were retained. Factor 1’s (long chain glycerophospholipids) metabolite profile score was higher among Ov/Ob with MetS than among Ov/Ob and NW participants without MetS. This factor was positively correlated to plasma total cholesterol (total-C) and triglyceride levels in the three groups, to high density lipoprotein -cholesterol (HDL-C) among participants without MetS. Factor 2 (amino acids and short to long chain acylcarnitine) was positively correlated to HDL-C and negatively correlated with insulin levels among NW participants. Factor 3’s (medium chain acylcarnitines) metabolite profile scores were higher among NW participants than among Ov/Ob with or without MetS. Factor 3 was negatively associated with glucose levels among the Ov/Ob with MetS. Factor 1 seems to be associated with a deteriorated metabolic profile that corresponds to obesity, whereas Factors 2 and 3 seem to be rather associated with a healthy metabolic profile.