A non-coding variant linked to metabolic obesity with normal weight affects actin remodelling in subcutaneous adipocytes.

Recent large-scale genomic association studies found evidence for a genetic link between increased risk of type 2 diabetes and decreased risk for adiposity-related traits, reminiscent of metabolically obese normal weight (MONW) association signatures. However, the target genes and cellular mechanisms driving such MONW associations remain to be identified. Here, we systematically identify the cellular programmes of one of the top-scoring MONW risk loci, the 2q24.3 risk locus, in subcutaneous adipocytes. We identify a causal genetic variant, rs6712203, an intronic single-nucleotide polymorphism in the COBLL1 gene, which changes the conserved transcription factor motif of POU domain, class 2, transcription factor 2, and leads to differential COBLL1 gene expression by altering the enhancer activity at the locus in subcutaneous adipocytes. We then establish the cellular programme under the genetic control of the 2q24.3 MONW risk locus and the effector gene COBLL1, which is characterized by impaired actin cytoskeleton remodelling in differentiating subcutaneous adipocytes and subsequent failure of these cells to accumulate lipids and develop into metabolically active and insulin-sensitive adipocytes. Finally, we show that perturbations of the effector gene Cobll1 in a mouse model result in organismal phenotypes matching the MONW association signature, including decreased subcutaneous body fat mass and body weight along with impaired glucose tolerance. Taken together, our results provide a mechanistic link between the genetic risk for insulin resistance and low adiposity, providing a potential therapeutic hypothesis and a framework for future identification of causal relationships between genome associations and cellular programmes in other disorders.

Inflammation biomarkers and inflammatory genes expression in metabolically healthy obese patients.

BACKGROUND AND AIMS: Obesity without metabolic alterations (Metabolically Healthy Obesity, MHO) is a condition with a risk of death and cardiovascular disease lower than that of obesity associated with metabolic alterations (Metabolically Unhealthy Obesity, MUO) and similar to that of healthy non obese individuals. Inflammation is considered as a key risk factor mediating the adverse health outcomes in obesity. METHODS AND RESULTS: We compared circulating levels of thirteen major cytokines and adipokines and the expression profiles of fifteen pro-inflammatory and two anti-inflammatory genes in visceral and subcutaneous adipose tissue in a series of 16 MHO patients and in 32 MUO patients that underwent bariatric surgery. MHO was defined according to the most applied definition in current literature. Serum levels of a large set of major cytokines and adipokines did not differ between MHO and MUO patients (p ≥ 0.15). Analyses of the expression profile of pro-inflammatory and anti-inflammatory genes in subcutaneous and visceral adipose tissue failed to show differences between MHO and MUO patients (p ≥ 0.07). Sensitivity analyses applying two additional definitions of MHO confirmed the results of the primary analysis. CONCLUSION: In a series of metabolically healthy obese patients neither circulating levels of major cytokines and adipokines nor the gene expression profile of a large set of pro-inflammatory and anti-inflammatory genes in subcutaneous and visceral fat differed from those in metabolically unhealthy obese patients.

Associations of metabolic heterogeneity of obesity with frailty progression: Results from two prospective cohorts.

BACKGROUND: Previous studies indicated that obesity would accelerate frailty progression. However, obesity is heterogeneous by different metabolic status. The associations of metabolic heterogeneity of obesity with frailty progression remain unclear. METHODS: A total of 6730 participants from the China Health and Retirement Longitudinal Study (CHARLS) and 4713 from the English Longitudinal Study of Ageing (ELSA) were included at baseline. Metabolic heterogeneity of obesity was evaluated based on four obesity and metabolic phenotypes as metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy overweight/obesity (MHOO), and metabolically unhealthy overweight/obesity (MUOO). Frailty status was assessed by the frailty index (FI) ranging from 0 to 100 and frailty was defined as FI ≥ 25. Linear mixed-effect models were used to analyse the associations of metabolic heterogeneity of obesity with frailty progression. RESULTS: In the CHARLS, MUOO and MUNW presented the accelerated FI progression with additional annual increases of 0.284 (95% CI: 0.155 to 0.413, P < 0.001) and 0.169 (95% CI: 0.035 to 0.303, P = 0.013) as compared with MHNW. MHOO presented no accelerated FI progression (ß: -0.011, 95% CI: -0.196 to 0.173, P = 0.904) as compared with MHNW. In the ELSA, the accelerated FI progression was marginally significant for MUOO (ß: 0.103, 95% CI: -0.005 to 0.210, P = 0.061) and MUNW (ß: 0.157, 95% CI: -0.011 to 0.324, P = 0.066), but not for MHOO (ß: -0.047, 95% CI: -0.157 to 0.062, P = 0.396) in comparison with MHNW. The associations of MUOO and MUNW with the accelerated FI progression were stronger after excluding the baseline frail participants in both cohorts. The metabolic status changed over time. When compared with stable MHNW, participants who changed from MHNW to MUNW presented the accelerated FI progression with additional annual increases of 0.356 (95% CI: 0.113 to 0.599, P = 0.004) and 0.255 (95% CI: 0.033 to 0.477, P = 0.024) in the CHARLS and ELSA, respectively. The accelerated FI progression was also found in MHOO participants who transitioned to MUOO (CHARLS, ß: 0.358, 95% CI: 0.053 to 0.663, P = 0.022; ELSA, ß: 0.210, 95% CI: 0.049 to 0.370, P = 0.011). CONCLUSIONS: Metabolically unhealthy overweight/obesity and normal weight, but not metabolically healthy overweight/obesity, accelerated frailty progression as compared with metabolically healthy normal weight. Regardless of obesity status, transitions from healthy metabolic status to unhealthy metabolic status accelerated frailty progression as compared with stable metabolically healthy normal weight. Our findings highlight the important role of metabolic status in frailty progression and recommend the stratified management of obesity based on metabolic status.

Sleep duration and metabolic body size phenotypes among Chinese young workers.

The evidence linking sleep duration and metabolic body size phenotypes is limited, especially in young adulthood. In this study, we aimed to examine the association between sleep duration and metabolic body size phenotypes among Chinese young workers and investigate whether discrepancies exist among shift and non-shift workers. A cross-sectional study was performed between 2018 and 2019 in Wuhan, China and 7,376 young adults aged 20-35 years were included. Self-reported sleep duration was coded into four groups: <7, 7-8, 8-9, and ≥9 h per day. Participants were classified into four metabolic body size phenotypes according to their body mass index and metabolic health status: metabolically healthy normal weight, metabolically unhealthy normal weight, metabolically healthy overweight/obesity (MHO), and metabolically unhealthy overweight/obesity (MUO). Multinomial logistic regression models were used to explore the associations between sleep duration and metabolic body phenotypes. Compared with those who slept 7-8 h each night, those with sleep duration <7 h per day had higher odds of MHO (OR 1.27, 95% CI: 1.02-1.56) and MUO (OR 1.22, 95% CI: 1.03-1.43), irrespective of multiple confounders. Stratification analyses by shift work showed that the association between short nighttime sleep and increased odds of MUO was only observed in shift workers (OR 1.26, 95% CI 1.03-1.54). Sleep duration is independently associated with metabolic body size phenotypes among Chinese young adults, while shift work could possibly modulate the association. These results may provide evidence for advocating adequate sleep toward favorable metabolic body size phenotypes in young workers.

Distinct whole-blood transcriptome profile of children with metabolic healthy overweight/obesity compared to metabolic unhealthy overweight/obesity.

BACKGROUND: Youth populations with overweight/obesity (OW/OB) exhibit heterogeneity in cardiometabolic health phenotypes. The underlying mechanisms for those differences are still unclear. This study aimed to analyze the whole-blood transcriptome profile (RNA-seq) of children with metabolic healthy overweight/obesity (MHO) and metabolic unhealthy overweight/obesity (MUO) phenotypes. METHODS: Twenty-seven children with OW/OB (10.1 ± 1.3 years, 59% boys) from the ActiveBrains project were included. MHO was defined as having none of the following criteria for metabolic syndrome: elevated fasting glucose, high serum triglycerides, low high-density lipoprotein-cholesterol, and high systolic or diastolic blood pressure, while MUO was defined as presenting one or more of these criteria. Inflammatory markers were additionally determined. Total blood RNA was analyzed by 5'-end RNA-sequencing. RESULTS: Whole-blood transcriptome analysis revealed a distinct pattern of gene expression in children with MHO compared to MUO children. Thirty-two genes differentially expressed were linked to metabolism, mitochondrial, and immune functions. CONCLUSIONS: The identified gene expression patterns related to metabolism, mitochondrial, and immune functions contribute to a better understanding of why a subset of the population remains metabolically healthy despite having overweight/obesity. IMPACT: A distinct pattern of whole-blood transcriptome profile (RNA-seq) was identified in children with metabolic healthy overweight/obesity (MHO) compared to metabolic unhealthy overweight/obesity (MUO) phenotype. The most relevant genes in understanding the molecular basis underlying the MHO/MUO phenotypes in children could be: RREB1, FAM83E, SLC44A1, NRG1, TMC5, CYP3A5, TRIM11, and ADAMTSL2. The identified whole-blood transcriptome profile related to metabolism, mitochondrial, and immune functions contribute to a better understanding of why a subset of the population remains metabolically healthy despite having overweight/obesity.

Increased AHR Transcripts Correlate With Pro-inflammatory T-Helper Lymphocytes Polarization in Both Metabolically Healthy Obesity and Type 2 Diabetic Patients.

Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor whose transcription activity is regulated by small compounds provided by diet, xenobiotics, and metabolism. It has been proven to be involved in energy homeostasis and inflammation in most recent years. Epidemiologically, exposure to xenobiotic AHR ligands contributes to obesity and type 2 diabetes (T2D). AHR is also the critical transcription factor determining the lineage commitment of pro-inflammatory Th17 and Th22 cells from naïve CD4+ T lymphocytes. It has been well-illustrated in animal models that IL-22, the major effector cytokine of Th17 and Th22 cells, played a major role in the interaction of metabolism and gut microbiota. But there were still missing links between gut microbiota, IL-22, and metabolism in humans. Our previous findings indicated that elevated circulating levels of IL-22 and frequencies of Th22 cells were associated with insulin resistance in both patients with obesity and T2D. Additionally, the hyperactive Th17 and Th22 cells phenotype also correlate with islets ß-cell dysfunction in T2D. In this study, we made efforts to determine AHR expressions in peripheral blood mononuclear cells (PBMCs) from patients with T2D and metabolically healthy obesity (MHO). Correlation analyses were conducted to assess the possible link between AHR and the metabolic and inflammatory context. We revealed that mRNA expression of AHR was up-regulated and correlated with the percentage of Th17, Th22 as well as Th1 cells. Elevated plasma levels of IL-22 and IL-17 also correlated with increased AHR transcripts in PBMCs from both MHO and T2D patients. The transcription factor AHR may thus have a plausible role in the interaction between metabolism and pro-inflammatory status of patients in the development of obesity and T2D.

Association Metabolic Obesity Phenotypes with Cardiometabolic Index, Atherogenic Index of Plasma and Novel Anthropometric Indices: A Link of FTO-rs9939609 Polymorphism.

BACKGROUND: The role of metabolic states in cardiovascular risks among individuals with varying degrees of obesity is unknown. The study aimed to compare cardiometabolic index (CMI), atherogenic index of plasma (AIP), lipid accumulation product (LAP) and novel anthropometric indices in metabolic and non-metabolically obese individual with regard to the role of FTO gene in Iranian adults. METHODS: In total, 165 individuals were recruited into this cross-sectional study. Individuals grouped into four groups: metabolic healthy normal-weight (MHNW) individuals, metabolically unhealthy normal-weight (MUNW) individuals, metabolically healthy obese (MHO) individuals and metabolic unhealthy obese (MUO) individuals. The dietary intake was evaluated by food frequency questionnaire (FFQ). The cardiovascular indices (CMI, AIP and LAP) were calculated. A variety of anthropometric indices were calculated, including body adiposity Index (BAI), weight-adjusted-waist index (WWI), A body shape index (ABSI) and waist-height ratio (WHR). The genotypes of FTO-rs9939609 subjects were detected by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: The individuals with metabolically unhealthy phenotypes (MUO, MUNW) have higher levels of triglyceride and cardiovascular indices (AIP, LAP and CMI) than the individuals with metabolic healthy phenotypes (MHO, MHNW). With a similar degree of obesity, the anthropometric indices (BAI, WWI and WHR) levels were higher in metabolic unhealthy groups than metabolically healthy groups. The highest frequency of obesity-risk allele AA of FTO gene was observed in MUO, MHO, MUNW and MHNW, respectively. CONCLUSION: Normal-weight individuals with metabolic unhealthy status are at higher risk for cardiovascular diseases than obese individuals with metabolically healthy status. The genotype frequencies of obesity-risk allele AA of FTO gene were higher in obesity phenotypes than metabolic phenotypes.

Lack of association between FTO gene variations and metabolic healthy obese (MHO) phenotype: Tehran Cardio-metabolic Genetic Study (TCGS).

BACKGROUND: Obesity is currently an international epidemic and metabolic derangements pose these individuals at greater risk for future morbidity and mortality. Genetics and environmental factors have undeniable effects and among genetic risk factors, FTO/CETP genes are important. The current study examines the interaction between obesity phenotypes and FTO/CETP SNPs and their effects on lipid profile changes. MATERIALS AND METHODS: We selected 954 adult subjects from TCGS (47.9% male). Participants were stratified according to their BMI and presence of metabolic syndrome according to the Joint Interim Statement (JIS) definition. Nine selected polymorphisms from FTO/CETP genes were genotyped using Tetra ARMS-PCR method. After age and sex adjustment the interaction of 9 markers with lipid profiles among phenotypes were tested by PASW. RESULTS: In three main groups, HDL_C level had a strong significant association with CETP markers: (rs3764261, ß(95% CI) - 0.48(- 0.61 to - 0.35), P = 1.0 × 10-11), (rs1800775, ß(95% CI) 0.5(0.36;0.65), P = 1.0 × 10-6) and (rs1864163, ß(95% CI) 0.3(0.16;0.43), P = 9.1 × 10-5). This association was also seen in rs7202116 within the total population. In only unhealthy metabolic obese (MUHO) subgroups four new FTO markers (rs1421085, rs1121980, rs1558902 and rs8050136) (P value < 0.01) demonstrated significant association, even after lipid profile adjustment. CONCLUSION: In the present study, we investigated the association between obesity phenotypes and some variations in FTO/CETP genes for the first time. Our study showed that four markers in the first intron of the FTO gene should be the risk marker in MUHO participants. LEVEL OF EVIDENCE: Level III, case-control study.

Identification of Novel Causal Blood Biomarkers Linking Metabolically Favorable Adiposity With Type 2 Diabetes Risk.

OBJECTIVE: Observations of a metabolically unhealthy normal weight phenotype suggest that a lack of favorable adiposity contributes to an increased risk of type 2 diabetes. We aimed to identify causal blood biomarkers linking favorable adiposity with type 2 diabetes risk for use in cardiometabolic risk assessments. RESEARCH DESIGN AND METHODS: A weighted polygenic risk score (PRS) underpinning metabolically favorable adiposity was validated in the UK Biobank (n = 341,872) and the Outcome Reduction With Initial Glargine Intervention (ORIGIN Trial) (n = 8,197) and tested for association with 238 blood biomarkers. Associated biomarkers were investigated for causation with type 2 diabetes risk using Mendelian randomization and for its performance in predictive models for incident major adverse cardiovascular events (MACE). RESULTS: Of the 238 biomarkers tested, only insulin-like growth factor-binding protein (IGFBP)-3 concentration was associated with the PRS, where a 1 unit increase in PRS predicted a 0.28-SD decrease in IGFBP-3 blood levels (P < 0.05/238). Higher IGFBP-3 levels causally increased type 2 diabetes risk (odds ratio 1.26 per 1 SD genetically determined IGFBP-3 level [95% CI 1.11-1.43]) and predicted a higher incidence of MACE (hazard ratio 1.13 per 1 SD IGFBP-3 concentration [95% CI 1.07-1.20]). Adding IGFBP-3 concentrations to the standard clinical assessment of metabolic health enhanced the prediction of incident MACE, with a net reclassification improvement of 11.5% in normal weight individuals (P = 0.004). CONCLUSIONS: We identified IGFBP-3 as a novel biomarker linking a lack of favorable adiposity with type 2 diabetes risk and a predictive marker for incident cardiovascular events. Using IGFBP-3 blood concentrations may improve the risk assessment of cardiometabolic diseases.

Sleep duration and apolipoprotein B in metabolically healthy and unhealthy overweight/obese phenotypes: a cross-sectional study in Chinese adults.

OBJECTIVES: Short sleep duration is independently associated with an increased risk of developing cardiovascular disease; however, the association has not yet been examined in obese populations. We assessed the associations between sleep duration, metabolic phenotype and apolipoprotein variables in a nationally representative Chinese population with overweight/obesity. STUDY DESIGN: Cross-sectional study. SETTINGS: The study conducted in nine provinces of China that vary substantially in geography and economic development. PATIENTS: Data were obtained from 4149 adults with overweight/obesity aged 18 to 94 years from the 2009 China Health and Nutrition Survey. Sleep duration was categorised as ≤6, 7-8 or ≥9 hour. Phenotypes were determined based on body mass index and metabolic health status and categorised as metabolically healthy overweight/obesity (MHOO) and metabolically unhealthy overweight/obesity (MUOO). MAIN OUTCOME MEASURE: The outcome variables were elevated apolipoproteins. RESULTS: Compared with MHOO phenotype, MUOO phenotypes were more likely to report shorter sleep duration (12.2%vs9%). In the MUOO group, the multivariate-adjusted OR (95% CI) for elevated apolipoprotein B (apoB) was 1.66 (1.23 to 2.23) for those with ≤6 hours of sleep and 1.12 (0.86 to 1.45) for those with ≥9 hours of sleep, using 7-8 hours of sleep as a reference. Similar results were obtained in the subgroup of subjects who were ≥45 or<45 years old, but shorter sleep duration was more strongly associated with elevated apoB in those <45 years (p interaction=0.023). However, no association was observed in the MHOO phenotype. CONCLUSIONS: The high prevalence of short sleep duration and its strong association with elevated apoB in adults who are metabolically unhealthy overweight/obese suggest an increased risk of cardiovascular disease in this population. The differences in sleep sufficiency among obese phenotypes may account for the disparities in their cardiovascular outcomes.

Using genetics to understand the causal influence of higher BMI on depression.

BACKGROUND: Depression is more common in obese than non-obese individuals, especially in women, but the causal relationship between obesity and depression is complex and uncertain. Previous studies have used genetic variants associated with BMI to provide evidence that higher body mass index (BMI) causes depression, but have not tested whether this relationship is driven by the metabolic consequences of BMI nor for differences between men and women. METHODS: We performed a Mendelian randomization study using 48 791 individuals with depression and 291 995 controls in the UK Biobank, to test for causal effects of higher BMI on depression (defined using self-report and Hospital Episode data). We used two genetic instruments, both representing higher BMI, but one with and one without its adverse metabolic consequences, in an attempt to 'uncouple' the psychological component of obesity from the metabolic consequences. We further tested causal relationships in men and women separately, and using subsets of BMI variants from known physiological pathways. RESULTS: Higher BMI was strongly associated with higher odds of depression, especially in women. Mendelian randomization provided evidence that higher BMI partly causes depression. Using a 73-variant BMI genetic risk score, a genetically determined one standard deviation (1 SD) higher BMI (4.9 kg/m2) was associated with higher odds of depression in all individuals [odds ratio (OR): 1.18, 95% confidence interval (CI): 1.09, 1.28, P = 0.00007) and women only (OR: 1.24, 95% CI: 1.11, 1.39, P = 0.0001). Meta-analysis with 45 591 depression cases and 97 647 controls from the Psychiatric Genomics Consortium (PGC) strengthened the statistical confidence of the findings in all individuals. Similar effect size estimates were obtained using different Mendelian randomization methods, although not all reached P < 0.05. Using a metabolically favourable adiposity genetic risk score, and meta-analysing data from the UK biobank and PGC, a genetically determined 1 SD higher BMI (4.9 kg/m2) was associated with higher odds of depression in all individuals (OR: 1.26, 95% CI: 1.06, 1.50], P = 0.010), but with weaker statistical confidence. CONCLUSIONS: Higher BMI, with and without its adverse metabolic consequences, is likely to have a causal role in determining the likelihood of an individual developing depression.

Genes that make you fat, but keep you healthy.

Obesity prevalence continues to rise worldwide, posing a substantial burden on people's health. However, up to 45% of obese individuals do not suffer from cardiometabolic complications, also called the metabolically healthy obese (MHO). Concurrently, up to 30% of normal-weight individuals demonstrate cardiometabolic risk factors that are generally observed in obese individuals, the metabolically obese normal weight (MONW). Besides lifestyle, environmental factors and demographic factors, innate biological mechanisms are known to contribute to the aetiology of the MHO and MONW phenotypes, as well. Experimental studies in animal models have shown that adipose tissue expandability, fat distribution, adipogenesis, adipose tissue vascularization, inflammation and fibrosis, and mitochondrial function are the main mechanisms that uncouple adiposity from its cardiometabolic comorbidities. We reviewed current genetic association studies to expand insights into the biology of MHO/MONW phenotypes. At least four genetic loci were identified through genome-wide association studies for body fat percentage (BF%) of which the BF%-increasing allele was associated with a protective effect on glycemic and lipid outcomes. For some, this association was mediated through favourable effects on body fat distribution. Other studies that characterized the genetic susceptibility of insulin resistance found that a higher susceptibility was associated with lower overall adiposity due to less fat accumulation at hips and legs, suggesting that an impaired capacity to store fat subcutaneously or a preferential storage in the intra-abdominal cavity may be metabolically harmful. Clearly, more work remains to be done in this field, first through gene discovery and subsequently through functional follow-up of identified genes.

Evidence of genetic predisposition for metabolically healthy obesity and metabolically obese normal weight.

Obesity has evolved into a global pandemic that constitutes a major threat to public health. The majority of obesity-related health care costs are due to cardiometabolic complications, such as insulin resistance, dyslipidemia, and hypertension, which are risk factors for Type 2 diabetes and cardiovascular disease. However, many obese individuals, often called metabolically healthy obese (MHO), seem to be protected from these cardiometabolic complications. Conversely, there is a group of individuals who suffer from cardiometabolic complications despite being of normal weight; a condition termed metabolically obese normal weight (MONW). Recent large-scale genomic studies have provided evidence that a number of genetic variants show an association with increased adiposity but a favorable cardiometabolic profile, an indicator for the genetic basis of the MHO and MONW phenotypes. Many of these loci are located in or near genes that implicate pathways involved in adipogenesis, fat distribution, insulin signaling, and insulin resistance. It has been suggested that a threshold for subcutaneous adipose tissue expandability may be at play in the manifestation of MHO and MONW, where expiry of adipose tissue storage capacity could lead to ectopic lipid accumulation in non-adipose tissues such as liver, muscle, heart, and pancreatic beta cells. Understanding the genetic aspects of the mechanisms that underpin MHO and MONW is crucial to define appropriate public health action points and to develop effective intervention measures.

Role of adiponectin gene variants, adipokines and hydrometry-based percent body fat in metabolically healthy and abnormal obesity.

OBJECTIVE: Metabolically healthy obesity (MHO) subjects have better metabolic parameters than metabolically abnormal obesity (MAO) subjects, but the possible mechanisms underlying this remain unknown. Our study was designed to investigate the interrelationships among genes, adipokines, body fat and its distribution in MHO and MAO. METHODS: From 2007 to 2009, 103 males and 131 females aged 18-50 years were enrolled by an intention-to-treat design in a weight management clinic. Participants were divided into MHO and MAO groups. Percent body fat (PBF) was measured by a deuterium oxide dilution method. Four polymorphic variants, including PPARγ2 (Pro12Ala and C1431T) and adiponectin (T45G and G276T) genes, and three adipokines (adiponectin, leptin and resistin) were obtained. RESULTS: Of the 234 obese subjects, 130 (55.6%) were MHO. In the univariate analysis, the MAO group has significantly higher anthropometric, metabolic indices and leptin levels than the MHO group. Logistic regression analysis revealed that age, male gender, the T allele of adiponectin T45G polymorphism, leptin and PBF were positively associated with MAO. ANCOVA analysis revealed that the T allele of adiponectin T45G polymorphism was associated with higher fasting and postprandial glucose levels. We further found that TT genotype has a lower high molecular weight (HMW)/low molecular weight (LMW) adiponectin ratio than GG genotype. CONCLUSIONS: The factors associated with MAO are age, male gender, the T allele of adiponectin T45G polymorphism, leptin, and PBF. The net effects of T45G polymorphism on the MAO phenotype may be achieved by changes in the adiponectin oligomer ratio and glucose levels.

Metabolically healthy obese women have longer telomere length than obese women with metabolic syndrome.

INTRODUCTION: Obesity is the principal component in the Metabolic Syndrome (MetS) that determines the progression of metabolic complications. Metabolically healthy obese (MHO) individuals seem to be protected against those complications. Telomere length (TL) as a novel marker of cellular aging had a complex relationship to the MetS. The principal aim of this study was to investigate the TL in MHO, and to study the association between TL and the worsening of the metabolic condition. MATERIAL AND METHODS: We have determined the absolute TL (aTL) in 400 women (mean age of 46.76 ± 15.47 years; range: 18-86 years), grouped according to the metabolic condition in three groups: metabolically healthy non-obese women (MHNO), MHO and obese women with MetS (MSO); and grouped according to the number of components of MetS. RESULTS: We found that MHO displays significantly higher aTL than MSO (p = 0.033; r = -4.63; 95% CI r = -8.89 / -0.37), but did not differ from MHNO. A decrease in aTL with the progressive increase in the number of MetS components was also observed (p < 0.001; r = -2.06; 95% CI r = -3.13 / -0.99). In this way, our results indicate that aTL is influenced by the presence of MetS, but it is not affected by the presence of obesity. DISCUSSION: We found that shorter aTL is not associated with MHO, but is related to MetS and with the increased number of metabolic abnormalities.

Factor XIII-A transglutaminase deficient mice show signs of metabolically healthy obesity on high fat diet.

F13A1 gene, which encodes for Factor XIII-A blood clotting factor and a transglutaminase enzyme, was recently identified as a potential causative gene for obesity in humans. In our previous in vitro work, we showed that FXIII-A regulates preadipocyte differentiation and modulates insulin signaling via promoting plasma fibronectin assembly into the extracellular matrix. To understand the role of FXIII-A in whole body energy metabolism, here we have characterized the metabolic phenotype of F13a1-/- mice. F13a1-/- and F13a1+/+ type mice were fed chow or obesogenic, high fat diet for 20 weeks. Weight gain, total fat mass and fat pad mass, glucose handling, insulin sensitivity, energy expenditure and, morphological and biochemical analysis of adipose tissue was performed. We show that mice lacking FXIII-A gain weight on obesogenic diet, similarly as wild type mice, but exhibit a number of features of metabolically healthy obesity such as protection from developing diet-induced insulin resistance and hyperinsulinemia. Mice also show normal fasting glucose levels, larger adipocytes, decreased extracellular matrix accumulation and inflammation of adipose tissue, as well as decreased circulating triglycerides. This study reveals that FXIII-A transglutaminase can regulate whole body insulin sensitivity and may have a role in the development of diet-induced metabolic disturbances.

The Frequencies of Haplotypes of FTO Gene Variants and Their Association with the Distribution of Body Fat in Non-Obese Poles.

BACKGROUND: The minor allele frequencies (MAFs) of the FTO gene vary substantially among different ethnic groups, and this variation may explain, to some degree, the differences between estimates of the effects of these alleles on body fat distribution indicators. OBJECTIVES: The aim of this study was to investigate the prevalence of fat mass and obesity associated (FTO) gene variants characterizing the structure of FTO haplotypes in a large Polish population, and to examine the influence of FTO gene variants on body fat distribution among metabolically obese normal weight (MONW) individuals, i.e. those with a normal BMI and visceral obesity. MATERIAL AND METHODS: A total of 854 non-obese individuals aged from 20 to 40 years, residing in three different regions in Poland, were studied. All the patients from this group were genotyped for four FTO gene variants (rs9939609, rs9930506, rs1421085 and rs1121980). Simultaneous identification of all single nucleotide polymorphisms (SNPs) was conducted using the minisequencing method with a pair of designed specific primers. RESULTS: Over 90% of the diplotypes contain only the two most common haplotypes, in three combinations of haplotype pairs: CTAT/CTAT comprised 26.9% in women and 30.9% in men; CTAT/TCGA comprised 45.0% in women and 44.4% in men; and TCGA/TCGA comprised 19.3% in woman and 14.8% in men. The analysis of the variance in body fat distribution parameters shows no statistically significant differences between the three common haplotype pairs in either men or women. CONCLUSIONS: The young Polish population is characterized by two disparate haplotypes of common FTO gene variants: TCGA (a risk SNP haplotype), and CTAT (a protective haplotype). No significant differences were found between fat distribution indicators in relation to haplotypes in either women and men.

Identification of Genetic and Environmental Factors Predicting Metabolically Healthy Obesity in Children: Data From the BCAMS Study.

CONTEXT: Available data related to the metabolically healthy obesity (MHO) phenotype are mainly derived from studies in adults because studies during childhood are very limited to date. OBJECTIVE: The objective of the study was to determine the prevalence of MHO in Chinese children and to investigate environmental and genetic factors impacting on MHO status. DESIGN: This was a cross-sectional study. PARTICIPANTS: A total of 1213 children with a body mass index at the 95th percentile or greater aged 6­18 years were included in this study. Participants were classified as MHO or of metabolically unhealthy obesity based on insulin resistance (IR) or cardiometabolic risk (CR) factors (blood pressure, lipids, and glucose). Twenty-two genetic variants previously reported from genome-wide association studies of obesity and diabetes plus the environmental factors of lifestyle, socioeconomic status, and birth weight was assessed. RESULTS: The prevalence of MHO-IR and MHO-CR were 27.1% and 37.2%, respectively. Waist circumference was an independent predictor of MHO, regardless of definitions, whereas walking to school and KCNQ1-rs2237897 were independent predictors of MHO-CR. Acanthosis nigricans, birth weight, the frequency of soft drink consumption, the mother's education status, and KCNQ1-rs2237892 were independent predictors of MHO-IR. Multiplicative interaction effects were found between KCNQ1-rs2237897 and walking to school on MHO-CR (odds ratio 1.31 [95% confidence interval 1.05­1.63]) and between rs2237892 and consumption of soft drinks on MHO-IR (odds ratio 0.80 [95% confidence interval 0.68­0.94]). CONCLUSIONS: Approximately one-third of Chinese obese children can be classified as MHO. Both genetic predisposition and environment factors and their interaction contribute to the prediction of MHO status. This study provides novel insights into the heterogeneity of obesity and has the potential to impact the optimization of the intervention options and regimens in the management of pediatric obesity.

Gene expression profiling reveals key genes and pathways related to the development of non-alcoholic fatty liver disease.

UNLABELLED:  Background. This study aims to identify key genes and pathways involved in non-alcoholic fatty liver disease (NAFLD). MATERIAL AND METHODS: The dataset GSE48452 was downloaded from Gene Expression Omnibus, including 14 control liver samples, 27 healthy obese samples, 14 steatosis samples and 18 nonalcoholic steatohepatitis (NASH) samples. Differentially expressed genes (DEGs) between controls and other samples were screened through LIMMA package. Then pathway enrichment analysis for DEGs was performed by using DAVID, and alterations of enriched pathways were determined. Furthermore, protein-protein interaction (PPI) networks were constructed based on the PPI information from HPRD database, and then, networks were visualized through Cytoscape. Additionally, interactions between microRNAs (miRNAs) and pathways were analyzed via Fisher's exact test. RESULTS: A total of 505, 814 and 783 DEGs were identified for healthy obese, steatosis and NASH samples in comparison with controls, respectively. DEGs were enriched in ribosome (RPL36A, RPL14, etc.), ubiquitin mediated proteolysis (UBE2A, UBA7, etc.), focal adhesion (PRKCA, EGFR, CDC42, VEGFA, etc.), Fc?R-mediated phagocytosis (PRKCA, CDC42, etc.), and so on. The 27 enriched pathways gradually deviated from baseline (namely, controls) along with the changes of obese-steatosis-NASH. In PPI networks, PRKCA interacted with EGFR and CDC42. Besides, hsa-miR-330-3p and hsa-miR-126 modulated focal adhesion through targeting VEGFA and CDC42. CONCLUSIONS: The identified DEGs (PRKCA, EGFR, CDC42, VEGFA), disturbed pathways (ribosome, ubiquitin mediated proteolysis, focal adhesion, Fc?R-mediated phagocytosis, etc.) and miRNAs (hsa-miR-330-3p, hsa-miR-126, etc.) might be closely related to NAFLD progression. These results might contribute to understanding NAFLD mechanism, conducting experimental researches, and designing clinical practices.