Obese Phenotype Research Articles

Metabolically healthy/unhealthy obesity and breast cancer: A possible role of plasma-derived extracellular vesicles on the cancerous behavior of triple-negative breast cancer

PurposeObesity has known detrimental effects on breast cancer (BC) development and progression. However, it's essential to consider the obesity phenotype based on metabolic health. This study aims to evaluate the impact of circulating extracellular vesicles (EVs) from women with metabolically healthy or unhealthy normal weight, overweight, and obesity on MDA-MB-231 cell migration, invasion, and apoptosis. MethodsPlasma EVs were isolated from different obesity phenotypes in women. EVs were characterized and EVs uptake by MDA-MB-231 cells was assessed. MDA-MB-231 cell lines were treated with EVs obtained from various studied groups, and migration, invasion, MMP-2 and MMP-9 activity, Bax and Bcl-2 mRNA expression, p-53 and Thr55 p-p53 protein expression, and apoptosis were assessed. ResultsEVs from obese individuals, regardless of phenotype, increased invasion and MMP-2 activity compared to healthy normal-weight EVs. Normal-weight EVs led to higher invasion under unhealthy conditions. BC cell migration was enhanced by EVs from healthy obese individuals compared to healthy normal-weight EVs. EVs from unhealthy obese women exhibited significantly lower p53/p-p53 levels and reduced apoptosis compared to healthy obese groups. ConclusionIt appears that EVs from both normal-weight women with unhealthy conditions and those with obesity or overweight, irrespective of metabolic status, worsened the cancerous behavior of TNBC cells. Therefore, considering metabolic health, in addition to BMI, is crucial for understanding obesity-related disorders.

Smith-Magenis syndrome protein RAI1 regulates body weight homeostasis through hypothalamic BDNF-producing neurons and neurotrophin downstream signalling.

Retinoic acid-induced 1 (RAI1) haploinsufficiency causes Smith-Magenis syndrome (SMS), a genetic disorder with symptoms including hyperphagia, hyperlipidemia, severe obesity, and autism phenotypes. RAI1 is a transcriptional regulator with a pan-neural expression pattern and hundreds of downstream targets. The mechanisms linking neural Rai1 to body weight regulation remain unclear. Here we find that hypothalamic brain-derived neurotrophic factor (BDNF) and its downstream signalling are disrupted in SMS (Rai1+/-) mice. Selective Rai1 loss from all BDNF-producing cells or from BDNF-producing neurons in the paraventricular nucleus of the hypothalamus (PVH) induced obesity in mice. Electrophysiological recordings revealed that Rai1 ablation decreased the intrinsic excitability of PVHBDNF neurons. Chronic treatment of SMS mice with LM22A-4 engages neurotrophin downstream signalling and delayed obesity onset. This treatment also partially rescued disrupted lipid profiles, insulin intolerance, and stereotypical repetitive behaviour in SMS mice. These data argue that RAI1 regulates body weight and metabolic function through hypothalamic BDNF-producing neurons and that targeting neurotrophin downstream signalling might improve associated SMS phenotypes.

Smith–Magenis syndrome protein RAI1 regulates body weight homeostasis through hypothalamic BDNF-producing neurons and neurotrophin downstream signalling

Retinoic acid-induced 1 (RAI1) haploinsufficiency causes Smith–Magenis syndrome (SMS), a genetic disorder with symptoms including hyperphagia, hyperlipidemia, severe obesity, and autism phenotypes. RAI1 is a transcriptional regulator with a pan-neural expression pattern and hundreds of downstream targets. The mechanisms linking neural Rai1 to body weight regulation remain unclear. Here we find that hypothalamic brain-derived neurotrophic factor (BDNF) and its downstream signalling are disrupted in SMS (Rai1+/-) mice. Selective Rai1 loss from all BDNF-producing cells or from BDNF-producing neurons in the paraventricular nucleus of the hypothalamus (PVH) induced obesity in mice. Electrophysiological recordings revealed that Rai1 ablation decreased the intrinsic excitability of PVHBDNF neurons. Chronic treatment of SMS mice with LM22A-4 engages neurotrophin downstream signalling and delayed obesity onset. This treatment also partially rescued disrupted lipid profiles, insulin intolerance, and stereotypical repetitive behaviour in SMS mice. These data argue that RAI1 regulates body weight and metabolic function through hypothalamic BDNF-producing neurons and that targeting neurotrophin downstream signalling might improve associated SMS phenotypes.

The relationship between diabetes, obesity and cardiovascular disease phenotypes: a UK Biobank cohort study

Abstract Background Obesity and diabetes mellitus (DM) frequently co-exist, yet their individual contributions to cardiovascular risk remain debated. Purpose We explored cardiovascular disease biomarkers, events and mortality in a large cohort stratified by body mass index (BMI) and DM. We hypothesised that DM with normal BMI is associated with a cardiovascular phenotype and event rate comparable to obesity without DM. Methods 451,355 UK Biobank participants were stratified by ethnicity-specific BMI categories (normal, overweight, obese) and DM status. We examined cardiovascular biomarkers including: carotid intima-media thickness (CIMT); arterial stiffness; left ventricular ejection fraction (LVEF) and cardiac contractility index (CCI). Poisson regression models estimated adjusted incidence rate ratios (IRR) for myocardial infarction, ischaemic stroke and cardiovascular death, with normal weight non-DM as comparator. Correlation matrices of Poisson model’s coefficients were used to assess correlations between covariates. Results 5% of participants had DM (10% normal weight, 34% overweight and 55% obese; versus 34%, 43% and 23%, respectively, in non-DM). In the non-DM group, overweight/obesity was associated with higher CIMT, arterial stiffness and CCI, and lower LVEF (p<0.05); these relationships were diminished in the DM group. Within BMI classes, DM was associated with adverse cardiovascular phenotype (p<0.05), particularly in the normal weight group. After 5,323,190 person-years follow-up, incident myocardial infarction, ischaemic stroke and cardiovascular mortality all rose across increasing BMI categories in the DM and non-DM groups (p<0.05). However, normal weight DM had higher cardiovascular mortality than obese non-DM (IRR 2.81 [95% confidence interval: 2.24-3.54] vs IRR 1.84 [1.70-1.98]). Pairwise correlation analysis demonstrated the strongest correlates of cardiovascular parameters were markers of adiposity; this was apparent in the DM and non-DM groups, although these remained modest with Pearson’s correlation coefficients of no more than 0.25. Conclusions Obesity and DM are additively associated with adverse cardiovascular biomarkers and mortality risk. Whilst adiposity metrics are more strongly correlated with cardiovascular biomarkers than diabetes-oriented metrics, both correlate weakly, suggesting other factors underpin the high cardiovascular risk of normal-weight diabetes. Ideal target range for metrics of adiposity may therefore be lower than currently proposed in people with DM.Table 1:Adjusted IRR of CV deathFigure 1:KM Curve for CV death

Holo-omics analysis reveals the influence of gut microbiota on obesity indicators in Jinhua pigs

BackgroundThe mechanisms behind obesity are complex and multi-faceted, involving the interplay of both host genomics and gut microbiome. In recent years, research has largely focused on these factors separately, but rarely from the viewpoint of holo-omics, which considers the host and microbiome as an integrated entity. To address this gap in knowledge, the present study aimed to investigate the holo-omics basis of obesity in Jinhua pigs, a Chinese indigenous breed known for its high degree of fat deposition and superior meat quality.MethodsSix pigs with extreme obesity phenotype were selected from a larger cohort of eighteen Jinhua pigs, and the contents of the jejunum, cecum, and colon regions were collected after slaughter at 240 days of age. The data obtained was processed, denoised, and annotated using QIIME2, with expression differences being analyzed using edgeR software.ResultsThe results showed significant differences in jejunal microbial diversity and composition between the two groups, with gut transcriptomics also indicating that differentially expressed genes in the jejunum were enriched in lipid metabolism pathways. These findings provide further evidence of the influence of the gut microbiome and host gene expression on fat deposition in Jinhua pigs.ConclusionsThis study provides valuable insights into the mechanisms of fat deposition in Jinhua pigs from the viewpoint of holo-omics. The integration of host transcriptomics and microbiome data helps shed light on the complex interactions between the host and gut microbiome, and highlights the importance of considering both factors in our understanding of obesity.

From Metabolically Healthy Obesity to Metabolically Unhealthy Obesity Populations: Decreased Bone Turnover Bioactivity.

A bone turnover marker reflects bone bioactivity. The effects of metabolically healthy compared with metabolically unhealthy obesity phenotypes on bone metabolism are not well understood. The aim of the study was to evaluate differences of bone transformation indexes in these two obesity phenotypes. A total of 419 obese subjects were recruited, 64 with metabolically healthy obesity (MHO) and 351 with metabolically unhealthy obesity (MuHO). BTMs and clinical parameters were measured. Bone metabolism indexes, including tartrate resistant acid phosphatase (TRACP, p < 0.05), β carboxyl terminal peptide of collagen (β-CTX, p < 0.01), and bone alkaline phosphatase (BAP, p < 0.01), were higher in subjects with MHO than MuHO, but parathyroid hormone (PTH) was lower (p < 0.05). The between-group difference in serum calcium was not significant. Low bone turnover activity was associated with significant hyperglycemia, insulin resistance, and body fat index (p < 0.05). Multivariate logistic regression found that TRACP, β-CTX, and BAP were independently associated with the presence of MHO. Receiver operating characteristic curve analysis found that the maximum area under the curve value for the definition of MHO was (0.8221) and was obtained when sex, age, body mass index (BMI), TRACP, β-CTX and BAP were included simultaneously, resulting in a sensitivity of 81.25% and specificity: 72.3%. The MHO group had significantly increased circulating TRACP and β-CTX compared with the MuHO group and BAP levels were within the physiological range. Obesity with the metabolically healthy phenotype had slightly increased bone turnover activity that may be an early compensatory response of skeletal metabolism to the increased BMI.

Longitudinal association of serum 25-hydroxyvitamin D levels with metabolically healthy body size transition in children and adolescents: A prospective cohort study with 2 years of follow-up

Background and aimsAlthough the associations of vitamin D with obesity and metabolic abnormalities have been reported, the role of vitamin D in the transition of obesity phenotype remains unclear but is highly desired since it is crucial to identify potential methods for obesity management. Therefore, we aimed to investigate the relationship between vitamin D and the risk for metabolically unhealthy obesity (MUO) or metabolically healthy obesity (MHO) in metabolically healthy children with 2 years of follow-up. MethodsData were collected from a population-based cohort consisting of 6424 metabolically healthy children aged 6–16 years at baseline. Metabolic abnormalities including hypertension, high triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C), hyperglycemia, and hyperuricemia were assessed both at baseline and follow-up. Baseline serum 25-hydroxyvitamin D (25[OH]D) concentrations were measured as exposure. The obesity phenotype transition was evaluated by weight status with the combination of metabolic health status from baseline to follow-up. ResultsDuring a 2-year follow-up, 889 (13.8 %) incident MUO cases occurred. For participants with obesity, each 10 nmol/L increment in 25(OH)D concentrations was associated with a 21 % (95%CI: 13 %∼43 %) and a 7 % (95%CI: 1 %∼14 %) decreased risk in high TG and hyperuricemia, respectively. A 51 % (95%CI: 22 %∼69 %) lower risk of MUO was observed in participants with sufficient vitamin D levels (≥50 nmol/L) compared to those with vitamin D deficiency (<30 nmol/L). Besides, among children who were MHO at baseline, those with sufficient vitamin D levels (≥50 nmol/L) were more likely to transition to metabolically healthy normal weight (MHNW) than vitamin D deficient individuals (<30 nmol/L). ConclusionsVitamin D may prevent the development of MUO and help increase the transition from MHO to MHNW. The findings highlight that vitamin D might be an effective nutrient for obesity management.

Semaglutide in Patients With Obesity and Heart Failure Across Mildly Reduced or Preserved Ejection Fraction.

Many therapies for heart failure (HF) have shown differential impact across the spectrum of left ventricular ejection fraction (LVEF). In this prespecified analysis, the authors assessed the effects of semaglutide across the baseline LVEF strata in patients with the obesity phenotype of HF with preserved ejection fraction (HFpEF) in the STEP-HFpEF (Semaglutide Treatment Effect in People with obesity and HFpEF) trial. STEP-HFpEF randomized 529 patients (263 semaglutide; 266 placebo). For this prespecified analysis, patients were categorized into 3 groups based on LVEF: 45% to 49% (n=85), 50% to 59% (n=215), and≥60% (n=229). At 52weeks, semaglutide improved the dual primary endpoints of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (estimated treatment difference: EF [ejection fraction] 45%-49%: 5.0 points [95%CI:-2.7 to 12.8 points], EF 50%-59%: 9.8 points [95%CI: 5.0 to 14.6 points], and EF≥60%: 7.4 points [95%CI: 2.8 to 12.0 points]; P interaction=0.56) and body weight (EF: 45%-49%:-7.6 [95%CI:-10.7 to-4.4], EF 50%-59%:-10.6 [95%CI:-12.6 to-8.6] and EF≥60%:-11.9 [95%CI:-13.8 to-9.9]; P interaction=0.08), to a similar extent across LVEF categories. Likewise, LVEF did not influence the benefit of semaglutide on confirmatory secondary endpoints: 6-minute walk distance (P interaction=0.19), hierarchal composite endpoint (P interaction=0.43), and high-sensitivity C-reactive protein (P interaction=0.26); or exploratory endpoint of N-terminal pro-brain natriuretic peptide (Pinteraction=0.96). Semaglutide was well-tolerated across LVEF categories. In patients with HFpEF and obesity, semaglutide 2.4mg improved symptoms, physical limitations, and exercise function, and reduced inflammation and body weight to a similar extent across LVEF categories. These data support treatment with semaglutide in patients with the obesity phenotype of HFpEF regardless of LVEF. (Research Study to Investigate How Well Semaglutide Works in People Living With HeartFailure and Obesity [STEP-HFpEF]; NCT04788511).

Risk of incident chronic kidney disease in metabolically healthy obesity and metabolically unhealthy normal weight: A systematic review and meta-analysis.

Studies have reported inconsistent results about the risk of incident chronic kidney disease (CKD) in people with metabolically healthy obesity (MHO). We designed this systematic review and meta-analysis to evaluate the risk of developing CKD in people with MHO and metabolically unhealthy normal weight (MUNW). We used a predefined search strategy to retrieve eligible studies from multiple databases up to June 20, 2022. Random-effects model meta-analyses were implied to estimate the overall hazard ratio (HR) of incident CKD in obesity phenotypes. Eight prospective cohort studies, including approximately 5 million participants with a median follow-up ranging between 3 and 14 years, were included in this meta-analysis. Compared to the metabolically healthy normal weight (MHNW), the mean differences in cardiometabolic and renal risk factors in MHO, MUNW, and metabolically unhealthy obesity (MUO) were evaluated with overall HR of 1.42, 1.49, and 1.84, respectively. Compared to MHNW, the mean estimated glomerular filtration rate (eGFR) and high-density lipoprotein (HDL) were significantly lower, and low-density lipoprotein (LDL), blood pressure, blood glucose, and triglycerides were higher in MHO and MUNW. In conclusion, MHO and MUNW are not benign conditions and pose a higher risk for incident CKD. Obesity, whether in the presence or absence of metabolic health, is a risk factor for CKD.

The short- and long-term readmission of four major categories of digestive system cancers: does obesity or metabolic disorder matter?

Patients with digestive system cancers (DSCs) are at a high risk for hospitalizations; however, the risk factors for readmission remain unknown. Here, we established a retrospective cohort study to assess the association between metabolic obesity phenotypes and readmission risks of DSC. A total of 142,753 and 74,566 patients at index hospitalization were ultimately selected from the Nationwide Readmissions Database (NRD) 2018 to establish the 30-day and 180-day readmission cohorts, respectively. The study population was classified into four groups: metabolically healthy non-obese (MHNO), metabolically healthy obese (MHO), metabolically unhealthy non-obese (MUNO), and metabolically unhealthy obese (MUO). Multivariate Cox regression analysis was used to estimate the effect of metabolic obesity phenotypes on DSC readmission. The MUNO phenotype had 1.147-fold (95% CI: 1.066, 1.235; p < 0.001) increased 180-day readmission risks in patients with neoplasm of the upper digestive tract. The MUNO phenotype had 1.073-fold (95% CI: 1.027, 1.121; p = 0.002) increased 30-day readmission risks and 1.067-fold (95% CI: 1.021, 1.115; p = 0.004) increased 180-day readmission risks in patients with neoplasm of the lower digestive tract. The MUNO and MUO phenotypes were independent risk factors of readmission in patients with liver or pancreatic neoplasm. Metabolic obesity status was independently associated with a high risk of severe and unplanned hospitalization within 30 days or 180 days. Both obesity and metabolic abnormalities are associated with a high risk for the poor prognosis of DSC patients. The effect of metabolic categories on the short- or long-term readmission of liver or pancreas cancers may be stronger than that of obesity.

Discovering the Individualized Factors Associated with Sarcopenia and Sarcopenic Obesity Phenotypes-A Machine Learning Approach.

The literature shows how sarcopenia often occurs along with different phenotypes based either on the concomitant presence of adipose tissue excess (i.e., sarcopenic obesity, SO), or osteopenia/osteoporosis (osteosarcopenia, OS), or the combination of the two conditions, so-called osteosarcopenic obesity (OSO). This research aimed to assess the prevalence of sarcopenia phenotypes (SO, OS, OSO), their associated risk factors and their health impact in a population of out- and inpatients living in the North of Italy. Male and female subjects aged ≥18 years were enrolled for the study. A blood sample was collected to measure targeted blood makers. A comprehensive anthropometric clinical assessment (height, weight, Body Mass Index, BMI and Dual Energy X-ray Absorptiometry, DXA) was performed to measure ponderal, bone, fat, and muscle status. A total of 1510 individuals participated to the study (females, n = 1100; 72.85%). Sarcopenia was the most prevalent phenotype (17%), followed by osteosarcopenia (14.7%) and sarcopenic obesity. Only 1.9% of the sample was affected by OSO. According to logistic regression analysis, sarcopenia was associated with age, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) (positively) and BMI, Iron (Fe), Total Cholesterol, albumin (%), albumin (g), and gamma proteins (negatively). Sarcopenic obesity was associated with age, ferritin, ESR, CRP (positively) and BMI, Fe, and albumin (%) (negatively). Osteosarcopenia was associated with age, ESR (positively) and BMI, Total Cholesterol, albumin (%), albumin (g), and Ca (negatively). Osteosarcopenic obesity was associated with glycemia and gamma-glutamyl transferase (gGT) (positively). According to random forest analysis, a higher BMI was the most important protective factor for sarcopenia, for sarcopenic obesity (along with Iron) and for osteosarcopenia (along with albumin). Moreover, osteosarcopenic obesity was positively associated with GgT and glycaemia. The possibility of gaining such information, especially in the younger population, could help to prevent the onset of such diseases and best fit the patient's needs, according to a precision-medicine approach.

Muscle fiber phenotype: a culprit of abnormal metabolism and function in skeletal muscle of humans with obesity.

The proportion of the different types of fibers in a given skeletal muscle contributes to its overall metabolic and functional characteristics. Greater proportion of type I muscle fibers is associated with favorable oxidative metabolism and function of the muscle. Humans with obesity have a lower proportion of type I muscle fibers. We discuss how lower proportion of type I fibers in skeletal muscle of humans with obesity may explain metabolic and functional abnormalities reported in these individuals. These include lower muscle glucose disposal rate, mitochondrial content, protein synthesis, and quality/contractile function, as well as increased risk for heart disease, lower levels of physical activity, and propensity for weight gain/resistance to weight loss. We delineate future research directions and the need to examine hybrid muscle fiber populations, which are indicative of a transitory state of fiber phenotype within skeletal muscle. We also describe methodologies for precisely characterizing muscle fibers and gene expression at the single muscle fiber level to enhance our understanding of the regulation of muscle fiber phenotype in obesity. By contextualizing research in the field of muscle fiber type in obesity, we lay a foundation for future advancements and pave the way for translation of this knowledge to address impaired metabolism and function in obesity.

Prognosis of a malignant phenotype of obesity defined by a cardiac biomarker in hypertension: the Japan Morning Surge-Home Blood Pressure study.

Obesity with increased high-sensitive cardiac troponin T (hs-cTnT) has been reported to be more likely to progress cardiovascular disease (CVD) events, which suggests that hs-cTnT may identify a "malignant" phenotype of obesity. We classified 3513 hypertensive patients from the Japan Morning Surge-Home Blood Pressure (J-HOP) study into groups based on body mass index (BMI) (normal weight: <25 kg/m2, overweight: 25-29.9 kg/m2, obesity: ≥30 kg/m2) and elevations in biomarker levels (hs-cTnT ≥3 ng/mL: 51.3%, 54.9%, 53.3%, and N-terminal pro-brain natriuretic peptide [NT-ProBNP] ≥55 pg/mL: 51.1%, 40.7%, 36.0% in each BMI category). We evaluated the independent and combined associations of BMI and each hs-cTnT/NT-proBNP or both with CVD events (fatal and nonfatal coronary artery disease, stroke, and hospitalized heart failure). During the mean 6.4 ± 3.9-year follow-up, 232 CVD events occurred. Obesity with elevated hs-cTnT was associated with a risk of CVD events compared to normal weight without elevated hs-cTnT (hazard ratio 3.22, 95% confidence interval: 1.83-5.68). A similar pattern of results was also observed across the status of obesity and elevated NT-proBNP. There was a significant interaction between hs-cTnT and CVD events according to the obesity status (p = 0.039), while this association was marginal in NT-proBNP (p = 0.060). The magnitude of the mediation of hs-cTnT for the association between obesity and CVD risk was 41.2%, and that for NT-proBNP was 8.1%. In this Japanese hypertensive population, the elevation of hs-cTnT identified obese patients at particularly high risk for developing CVD events, suggesting that hs-cTnT may identify a 'malignant' phenotype of obesity.

Correlation analysis of obesity phenotypes with leptin and adiponectin

Obesity can be categorized as metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO). However, individuals with MHO are characterized by the absence of metabolic syndrome (MS) and appear to have lower inflammation levels compared to MUO. This study aimed to investigate the association of obesity phenotypes with leptin (LEP) and adiponectin (ADP). According to the inclusion and exclusion criteria, we selected 178 subjects from the previous cross-sectional survey. Based on the body mass index (BMI) and diagnostic criteria of MS, we divided the individuals into three groups, including healthy control group (HC group), metabolically healthy obesity group (MHO group) and metabolically unhealthy obesity group (MUO group). The concentrations of LEP and ADP in serum were measured, and the association of these two cytokines with different obesity phenotypes were subsequently analyzed. Compared to both the HC and MHO groups, the MUO group showed significantly higher BMI, waist circumference (WC), waist-hip ratio (WHR), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG), homeostasis model assessment of insulin resistance (Homa-IR) and blood pressure (P < 0.05). In contrast, serum high-density lipoprotein cholesterol (HDL-C) was notably lower in the MUO group (P < 0.05). ADP was found to have a positive correlation with systolic blood pressure (SBP) and a negative correlation with FPG in the MHO group. In the MUO group, LEP demonstrated a positive correlation with fasting insulin (FINS) and Homa-IR, while ADP showed a positive correlation with TC and SBP. Linear regression analysis further indicated that SBP (β = 0.234, P = 0.043), TG (β = − 0.292, P = 0.001) and LDL-C (β = 0.626, P = 0.000) were independently correlated with ADP, and BMI (β = 0.398, P = 0.002) was independently correlated with LEP in obese individuals. In conclusion, ADP and LEP were closely related with glucose and lipid metabolism in obese individuals, these two cytokines might play critical roles in obesity-associated metabolic disorders.

Rare Variants of Obesity-Associated Genes in Young Adults with Abdominal Obesity.

The increase in the prevalence of overweight, obesity and associated diseases is a serious problem. The aim of the study was to identify rare variants in obesity-associated genes in young adults with abdominal obesity in our population and to analyze information about these variants in other populations. Targeted high-throughput sequencing of obesity-associated genes was performed (203 young adults with an abdominal obesity phenotype). In our study, all of the 203 young adults with abdominal obesity had some rare variant in the genes associated with obesity. The widest range of rare and common variants was presented in ADIPOQ, FTO, GLP1R, GHRL, and INS genes. The use of targeted sequencing and clinical criteria makes it possible to identify carriers of rare clinically significant variants in a wide range of obesity-associated genes and to investigate their influence on phenotypic manifestations of abdominal obesity.

ПЕРСПЕКТИВЫ ИСПОЛЬЗОВАНИЯ ЛИПИДОМНОГО АНАЛИЗА В ДИАГНОСТИКЕ МЕТАБОЛИЧЕСКИХ НАРУШЕНИЙ

Lipid metabolism disorders play an important role in the development of a number of diseases associated with obesity. However, not all obese people have the traditional abnormal clinical plasma lipid levels, which is especially common in children and adolescents. Given this controversial relationship it is necessary to clarify the new lipid biomarkers in obesity. From this point of view, of particular interest is lipidomics, which allows identifying the diversity of different types of lipids presented in a cell, tissue, biological fluid or in the entire body using tandem mass spectrometry. The human lipidomic profile reflects lipid metabolism, including the early phase of pathophysiological changes associated with the formation of the obesity phenotype. Studying the connection between the lipidome and metabolic plasticity can provide new insight into the biological mechanisms of the development of obesity and its complications, the relationship between fat and carbohydrate metabolism in the development of insulin resistance, disruption of the functioning of intestinal incretins (cholecystokinin, glucagon-like peptide 1 and 2 etc.). From a public health perspective, a thorough understanding of the pathophysiological changes that lead to obesity at the earliest stage will have far-reaching promise for slowing the enormous global incidence of obesity and type 2 diabetes mellitus. This bibliographical review was conducted using the PubMed, Google Scholar and Cyberleninka databases through 2013-2023 sources.

Effects of myostatin gene knockout on white fat browning and related gene expression in type 2 diabetic mice.

Myostatin (Mstn) plays an important role in adipocyte growth, differentiation and metabolism, leading to the development of obesity. We aimed to explore the effect of Mstn on white fat browning in a mouse model of type 2 diabetes mellitus (T2DM). Twelve wild-type (WT), 12 heterozygous (Mstn(+/-)) and 12 homozygous (Mstn(-/-)) male mice were randomly divided into 6 groups: WT, Mstn(+/-), Mstn(-/-), WT+DM, Mstn(+/-)+DM, and Mstn(-/-)+DM. The first 3 groups were fed normal chow, while the last 3 were fed high-fat diet and administered streptozotocin to generate T2DM. Subsequently, body mass, length, and white and brown fat masses were measured, after which Lee's index, white-brown ratio and fat index were calculated. The serum free fatty acid (FFA) levels were detected using enzyme-linked immunosorbent assay (ELISA). Hematoxylin and eosin (H&E) staining was used to analyze white and brown fat cell morphology. The relative expression levels of peroxisome proliferator-activated receptor-gamma (PPARγ), peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α), uncoupling protein 1 (UCP1), and cluster of differentiation 137 (CD137) protein were determined with western blotting. The Mstn(-/-) group displayed higher levels of PPARγ, PGC-1α and CD137 proteins in white and brown fat compared to the WT and Mstn(+/-) groups, while the expression level of UCP1 protein in the Mstn(-/-) group was higher than in the WT group. The expression levels of PPARγ, PGC-1α, UCP1, and CD137 proteins in the WT+DM group were lower than in the WT group. Moreover, PPARγ, PGC-1α, UCP1, and CD137 proteins were more highly expressed in the Mstn(-/-)+DM group compared to the WT+DM and Mstn(+/-)+DM groups. The Mstn gene inhibition antagonizes obesity phenotypes, such as white fat accumulation and lipid metabolism derangement caused by T2DM, thus promoting white fat browning.

Metabolically healthy obese individuals are still at high risk for diabetes: Application of the marginal structural model.

To assess the effect of obesity phenotype on the incidence of diabetes, considering phenotype as a time-varying exposure. We used community-based cohort data from the Korean Genome and Epidemiology Study, with a 16-year follow-up period. Obesity phenotype was determined using body mass index and metabolic syndrome criteria. The influence of obesity phenotype on the occurrence of diabetes was evaluated using a Cox proportional hazard model and a marginal structural model (MSM). Obesity phenotypes were defined in 6265 individuals, with diabetes identified in 903 (14.4%) during the follow-up period. Individuals with metabolically healthy obesity (MHO) exhibited a higher risk of diabetes compared to those with metabolically healthy normal weight (MHNW), with a hazard ratio (HR) of 1.48 (95% confidence interval [CI] 1.15-1.90). This association remained significant after applying the MSM (HR 1.49, 95% CI 1.01-2.20). Moreover, various sensitivity analyses consistently demonstrated a higher risk of diabetes in individuals with MHO compared to those with MHNW. Even when obesity phenotype was treated as a time-varying exposure, individuals with MHO were still at higher risk for developing diabetes than those with MHNW. Consequently, such individuals should aim to avoid transitioning to a metabolically unfavourable state and strive to reduce their body weight to a normal range.

Dietary Behavior of Spanish Schoolchildren in Relation to the Polygenic Risk of Obesity

Several precedents support an association between single nucleotide genetic polymorphisms (SNPs), the obese phenotype, and eating behavior in the infant-juvenile population. This study aims to study this aspect in depth, analyzing the eating behavior of a sample of schoolchildren from Madrid in regard to their genetic predisposition to obesity. A total of 258 schoolchildren, aged 6 to 16 years, were evaluated through the Children’s Eating Behaviour Questionnaire (CEBQ) and the genotyping of 32 SNPs. Associations were observed between the total genetic risk score and eating behaviors related to emotional eating and food responsiveness. Individually, different SNPs were associated with eating behaviors, primarily those related to pro-eating behaviors or increased risk of developing obesity. However, diverse results are obtained, depending on the SNP. These results highlighted the strongest associations between the rs1801725 SNP risk allele (CASR) and increased enjoyment of food by 1846-fold. Likewise, the satiety response was associated with SNP rs11676272 (ADCY3) 2.39 and SNP rs7566605 (INSIG2), increasing this response by 2.39 and 1.63 times, respectively. Emotional anti-ingesting behaviors were inversely associated with SNP rs1421085 (FTO) and SNP rs987237 (TFAP2B). In contrast, SNP rs55915917 (CRHR1) increased the risk of these behaviors. SNPs rs4788099 (SH2B1), rs6857 (NECTIN2), and rs180172 (ADCY3) were associated with slow feeding. In conclusion, associations were found between most of the analyzed SNPs and the CEBQ items. This suggests that feeding behavior exists as a mediator between genotype and obesity phenotype, beginning in childhood.

Exosomes isolated from metabolically unhealthy normal weight and overweight phenotypes deteriorate the ER/PR positive breast cancer behavior.

Obesity has been linked to a higher risk of postmenopausal breast cancer Yet, research indicates an opposite correlation between obesity and premenopausal breast cancer risk. Various obesity phenotypes based on metabolic health could play a significant part. This study aims to assess how plasma exosomes taken from women with varying obesity phenotypes impact MCF-7 cell migration, matrix metalloproteinase-2 activity, and apoptosis. The characterization of isolated exosomes and their internalization into MCF-7 cells was evaluated. The treatment of MCF-7 cells with exosomes isolated from different groups was done. Migration, the activity of MMP-2, mRNA expression of Bax and Bcl-2, protein expression of p-53 and Thr55 p-p53, and apoptosis were assessed. Isolated exosomes from unhealthy obese individuals increase MCF-7 cell migration. Regarding MMP activities, unhealthy normal weight and overweight and healthy obese groups isolated exosomes increase the MMP-2 activity than the treated group with exosomes isolated from counterpart groups. Furthermore, unhealthy normal weight and overweight and healthy obese obtained exosomes decrease apoptosis compared to counterpart groups. Altogether, plasma exosomes derived from both unhealthy individuals with normal weight and overweight status, as well as those with unhealthy obesity, negatively impacted the behavior of estrogen/progesterone receptor-positive breast cancer cells. The online version contains supplementary material available at 10.1007/s40200-023-01295-1.