Early Stages Of Obesity Research Articles

The association between the size of adipocyte-derived extracellular vesicles and fasting serum triglyceride-glucose index as proxy measures of adipose tissue insulin resistance in a rat model of early-stage obesity.

Obesity is a complex disease that predisposes individuals to cardiometabolic alterations. It leads to adipose tissue (AT) dysfunction, which triggers insulin resistance (IR). This suggests that people with obesity develop local IR first and systemic IR later. AT secretes extracellular vesicles, which may be physiopathologically associated with the development of IR. Our aim was to evaluate the effect of a high-fat diet on different parameters of adiposity in a rat model of early-stage obesity and to determine if these parameters are associated with markers of systemic IR. In addition, we sought to explore the relationship between fasting blood measures of IR (Triglycerides/High Density Lipoprotein-cholesterol [TAG/HDL-c] and Triglycerides-Glucose Index [TyG Index]) with the size of adipocyte-derived extracellular vesicles (adEV). We used a model of diet-induced obesity for ten weeks in Wistar rats exposed to a high-fat diet. Final weight gain was analyzed by Dual X-ray absorptiometry. Visceral obesity was measured as epididymal AT weight. IR was evaluated with fasting TyG Index & TAG/HDL-c, and adEV were isolated from mature adipocytes on ceiling culture. In the high-fat diet group, glucose and triglyceride blood concentrations were higher in comparison to the control group (Log2FC, 0.5 and 1.5 times higher, respectively). The values for TyG Index and adEV size were different between the control animals and the high-fat diet group. Multiple linear regression analyses showed that adEV size can be significantly associated with the TyG Index value, when controlling for epididymal AT weight. Our results show that lipid and glucose metabolism, as well as the size and zeta potential of adEV are already altered in early-stage obesity and that adEV size can be significantly associated with liver and systemic IR, estimated by TyG Index.

Obesity Induces Temporally Regulated Alterations in the Extracellular Matrix That Drive Breast Tumor Invasion and Metastasis.

Obesity is associated with increased incidence and metastasis of triple-negative breast cancer, an aggressive breast cancer subtype. The extracellular matrix (ECM) is a major component of the tumor microenvironment that drives metastasis. To characterize the temporal effects of age and high-fat diet (HFD)-driven weight gain on the ECM, we injected allograft tumor cells at 4-week intervals into mammary fat pads of mice fed a control or HFD, assessing tumor growth and metastasis and evaluating the ECM composition of the mammary fat pads, lungs, and livers. Tumor growth was increased in obese mice after 12 weeks on HFD. Liver metastasis increased in obese mice only at 4 weeks, and elevated body weight correlated with increased metastasis to the lungs but not the liver. Whole decellularized ECM coupled with proteomics indicated that early stages of obesity were sufficient to induce changes in the ECM composition. Obesity led to an increased abundance of the proinvasive ECM proteins collagen IV and collagen VI in the mammary glands and enhanced the invasive capacity of cancer cells. Cells of stromal vascular fraction and adipose stem and progenitor cells were primarily responsible for secreting collagen IV and collagen VI, not adipocytes. Longer exposure to HFD increased the invasive potential of ECM isolated from the lungs and liver, with significant changes in ECM composition found in the liver with short-term HFD exposure. Together, these data suggest that changes in the breast, lungs, and liver ECM underlie some of the effects of obesity on triple-negative breast cancer incidence and metastasis. Significance: Organ-specific extracellular matrix changes in the primary tumor and metastatic microenvironment are mechanisms by which obesity contributes to breast cancer progression.

Epigenetic modifications in obesity-associated diseases.

The global prevalence of obesity has reached epidemic levels, significantly elevating the susceptibility to various cardiometabolic conditions and certain types of cancer. In addition to causing metabolic abnormalities such as insulin resistance (IR), elevated blood glucose and lipids, and ectopic fat deposition, obesity can also damage pancreatic islet cells, endothelial cells, and cardiomyocytes through chronic inflammation, and even promote the development of a microenvironment conducive to cancer initiation. Improper dietary habits and lack of physical exercise are important behavioral factors that increase the risk of obesity, which can affect gene expression through epigenetic modifications. Epigenetic alterations can occur in early stage of obesity, some of which are reversible, while others persist over time and lead to obesity-related complications. Therefore, the dynamic adjustability of epigenetic modifications can be leveraged to reverse the development of obesity-associated diseases through behavioral interventions, drugs, and bariatric surgery. This review provides a comprehensive summary of the impact of epigenetic regulation on the initiation and development of obesity-associated cancers, type 2 diabetes, and cardiovascular diseases, establishing a theoretical basis for prevention, diagnosis, and treatment of these conditions.

Early macrophage-mediated Bdnf expression in white adipose tissue during high-fat diet feeding

The expression of brain-derived neurotrophic factor (BDNF) is observed not only in the brain, but also in peripheral tissues including white adipose tissues (WATs). Here, we showed that the mRNA expression of Bdnf in inguinal WAT (iWAT) and epididymal WAT (eWAT) increased within 2 weeks of feeding mice with a high-fat diet (HFD). In mice on a 2-week HFD, the induction of Bdnf expression in WATs was significantly correlated with increases in body weight, suggesting that Bdnf expression may increase at an early stage of obesity. The mRNA expression of hypoxia-inducible factor 1α and platelet-derived growth factor, which are involved in neovascularization and the subsequent expansion of adipose tissues, increased in the iWAT of mice on the 2-week HFD. We also found that the expression of macrophage marker F4/80 in iWAT increased under the HFD. Interestingly, HFD-induced Bdnf expression in iWAT was not observed when macrophages were removed by the administration of clodronate liposomes. Accordingly, mice receiving clodronate liposomes also exhibited a significant reduction in the HFD-induced increase in body weight. In conclusion, increased body weight in HFD-induced obese model mice was accompanied by the induction of Bdnf expression in iWAT and was probably mediated by macrophages. Our findings imply a novel function for BDNF in iWAT at an early stage of obesity.

Tissue and Circulating MicroRNAs 378 and 142 as Biomarkers of Obesity and Its Treatment Response.

Promising approaches to the treatment of obesity include increasing energy expenditure and slowing down fibrogenesis of adipose tissue. The neurotransmitter reuptake inhibitor sibutramine affects appetite and activates lipolysis in a catecholaminergic way. MicroRNAs (miRs) are considered as biomarkers of molecular genetic mechanisms underlying various processes. The profile of a number of miRs is altered in obesity, both in the circulation and in adipose tissue. The aim of this study was to assess the expression levels of miRs (hsa-miR-378a-3p, hsa-miR-142-3p) by real-time polymerase chain reaction in subcutaneous adipose tissue (SAT) and in plasma in patients with different degrees and duration of obesity and during sibutramine therapy. This study included 51 obese patients and 10 healthy subjects with normal weight who formed a control group. The study found that, before treatment, obese patients had no significant difference in the expression level of miR-378 in SAT and plasma compared to the control group, while the expression of miR-142 was significantly decreased in SAT and increased in plasma. A significant elevation in miR-378 expression level was noted in patients with first-degree obesity and duration of less than 10 years, and the decline in miR-142 increased with the duration of obesity. These data indicate a maximal increase in the expression of the adipogenesis inducer miR-378 in the early stages of obesity, a progressive decrease in the expression of the fibrogenesis inhibitor miR-142 in SAT with growth of duration of obesity and the likely presence of antifibrogenic effects of sibutramine realized through miR-142 activation.

Adaptation of a Mobile Interactive Obesity Treatment Approach for Early Severe Mental Illness: Protocol for a Mixed Methods Implementation and Pilot Randomized Controlled Trial

Background Obesity is common in individuals with severe mental illness (SMI), contributing to a significantly shortened lifespan when compared to the general population. Available weight loss treatments have attenuated efficacy in this population, underscoring the importance of prevention and early intervention. Objective Here, we describe a type 1 hybrid study design for adapting and pilot-testing an existing mobile health intervention for obesity prevention in individuals with early SMI and Class I or early-stage obesity, defined as a BMI of 30-35. Methods An existing, evidence-based interactive obesity treatment approach using low-cost, semiautomated SMS text messaging was selected for adaptation. Community mental health clinics and Clubhouse settings in Eastern Missouri and South Florida were identified to participate. This study has the following 3 aims. First, using the Enhanced Framework for Reporting Adaptations and Modifications to Evidence-based interventions, contextual aspects of the clinical and digital treatment environments are identified for adaptation, considering 5 main stakeholder groups (clinical administrators, prescribing clinicians, case managers, nurses, and patients). Following a 2-week trial of unadapted SMS text messaging, Innovation Corps methods are used to discover needed intervention adaptations by stakeholder group and clinical setting. Second, adaptations to digital functionality and intervention content will be made based on themes identified in aim 1, followed by rapid usability testing with key stakeholders. A process for iterative treatment adaptation will be developed for making unplanned modifications during the aim 3 implementation pilot study. Individuals working in partner community mental health clinics and Clubhouse settings will be trained in intervention delivery. Third, in a randomized pilot and feasibility trial, adults with 5 years or less of treatment for an SMI diagnosis will be randomized 2:1 to 6 months of an adapted interactive obesity treatment approach or to an attentional control condition, followed by a 3-month extension phase of SMS text messages only. Changes in weight, BMI, and behavioral outcomes, as well as implementation challenges, will be evaluated at 6 and 9 months. Results Institutional review board approval for aims 1 and 2 was granted on August 12, 2018, with 72 focus group participants enrolled; institutional review board approval for aim 3 was granted on May 6, 2020. To date, 52 participants have been enrolled in the study protocol. Conclusions In this type 1 hybrid study design, we apply an evidence-based treatment adaptation framework to plan, adapt, and feasibility test a mobile health intervention in real-world treatment settings. Resting at the intersection of community mental health treatment and physical health promotion, this study aims to advance the use of simple technology for obesity prevention in individuals with early-stage mental illness. Trial Registration ClinicalTrials.gov NCT03980743; https://clinicaltrials.gov/ct2/show/NCT03980743 International Registered Report Identifier (IRRID) DERR1-10.2196/42114

Enhanced mitochondrial oxidative metabolism in peripheral blood mononuclear cells is associated with fatty liver in obese young adults

Systemic inflammation underlies the association between obesity and nonalcoholic fatty liver disease (NAFLD). Here, we investigated functional changes in leukocytes’ mitochondria in obese individuals and their associations with NAFLD. We analyzed 14 obese male Japanese university students whose body mass index was > 30 kg/m2 and 15 healthy age- and sex-matched lean university students as controls. We observed that the mitochondrial oxidative phosphorylation (OXPHOS) capacity with complex I + II-linked substrates in peripheral blood mononuclear cells (PBMCs), which was measured using a high-resolution respirometry, was significantly higher in the obese group versus the controls. The PBMCs’ mitochondrial complex IV capacity was also higher in the obese subjects. All of the obese subjects had hepatic steatosis defined by a fatty liver index (FLI) score ≥ 60, and there was a positive correlation between their FLI scores and their PBMCs’ mitochondrial OXPHOS capacity. The increased PBMCs’ mitochondrial OXPHOS capacity was associated with insulin resistance, systemic inflammation, and higher serum levels of interleukin-6 in the entire series of subjects. Our results suggest that the mitochondrial respiratory capacity is increased in the PBMCs at the early stage of obesity, and the enhanced PBMCs’ mitochondrial oxidative metabolism is associated with hepatic steatosis in obese young adults.

A combined X-ray fluorescence and infrared microspectroscopy study for new insights into elemental-biomolecular obesity-induced changes in rat brain structures

The objective of our research was to determine the brain changes at the molecular and elemental levels typical of early-stage obesity. Therefore a combined approach using Fourier transform infrared micro-spectroscopy (FTIR-MS) and synchrotron radiation induced X-ray fluorescence (SRXRF) was introduced to evaluate some brain macromolecular and elemental parameters in high-calorie diet (HCD)- induced obese rats (OB, n = 6) and in their lean counterparts (L, n = 6). A HCD was found to alter the lipid- and protein- related structure and elemental composition of the certain brain areas important for energy homeostasis. The increased lipid unsaturation in the frontal cortex and ventral tegmental area, the increased fatty acyl chain length in the lateral hypothalamus and substantia nigra as well as the decreased both protein α helix to protein β- sheet ratio and the percentage fraction of β-turns and β-sheets in the nucleus accumbens were revealed in the OB group reflecting obesity-related brain biomolecular aberrations. In addition, the certain brain elements including P, K and Ca were found to differentiate the lean and obese groups at the best extent. We can conclude that HCD-induced obesity triggers lipid- and protein- related structural changes as well as elemental redistribution within various brain structures important for energy homeostasis. In addition, an approach applying combined X-ray and infrared spectroscopy was shown to be a reliable tool for identifying elemental-biomolecular rat brain changes for better understanding the interplay between the chemical and structural processes involved in appetite control.

The Importance of Uric Acid High-Density Lipoprotein Cholesterol Ratio As an Indicator of Visceral Adiposity

Objective: A number of anthropometric measurements are being developed to detect metabolic risks in overweight and obesity. Our purpose is to investigate the relationship of visceral adipocyte index (VAI), which is useful as a marker of adipocyte dysfunction with the ratio of uric acid to high-density lipoprotein ratio (UHR), an inflammatory marker, considering body mass index groups and accompanying metabolic syndrome (MetS). Material and Methods: In all, 509 female participants aged 18-60 years, admitted to the Outpatient Department of Endocrinology, Erzurum Training, and Research Hospital, were involved in this study. Our study group consisted of 409 patients (63 overweight, 202 obese, and 144 morbid obese) and 100 healthy controls. Anthropometric measurements, including height, weight, and waist circumferences, were measured, and VAI values were calculated for all participants. All subjects had been tested with biochemistry analysis for lipid profile tests and uric acid. Results: UHR level was significantly elevated in the patient group [10.9 (3.8-30.4%)] compared with the control group [7.29 (3.44-19.3 %)]. The highest UHR level was found in the morbid obese group, 12.3 (5.8-30 %), and the lowest UHR level was in the overweight group [8.63 (3.8-17 %)]. A moderately strong positive correlation was found between VAI and UHR in both patient and control groups, and the strongest correlation was found in the overweight group (r=0.586, R2=0.319). In addition, the UHR level was 12.2 (6-30%) in the patient group with MetS and 9.7 (3.8-23%) in the patients without MetS. Conclusion: Since the BMI is insufficient regarding prognosis and obesity-related mortality, it should be supported with VAI, a new anthropometric cardiometabolic risk indicator. UHR might be a sensitive and accurate indicator of visceral fat excess even in the early stages of obesity and MetS.

Combined spectroscopic, biochemical and chemometric approach toward finding of biochemical markers of obesity

BackgroundEarly-stage detection of subclinical obesity-driven systemic changes is a challenging area of medical diagnostics, where the most popular existing measures – such as body mass index – BMI – often fall short of providing a realistic estimate of adiposity and, therefore, of ongoing pathologies at the systemic, tissue and cellular level. In the quest for identifying new more robust diagnostic markers, whole-organ analysis of chemical elements is a promising approach for identifying candidate proxies of obesity status in the system. MethodsTotal Reflection X-ray fluorescence (TXRF) coupled with biochemical assays, chemometrics and statistical validation was used as a new integrated pipeline for marker identification in external ear samples of obese animals. The specimens were taken from obese animals fed a high calorie diet as well as from lean intact animals fed a standard diet. ResultsThe most significant differences in the content of K, Fe, Br, and Rb between the studied groups of the animals were identified. However, with the methodology applied Rb was found the most robust biochemical discriminator of early-stage obesity effects, as validated by the logistic regression model. We observed no relationship between the levels of the elements consumed by the animals and their apparent content in the earlobe tissue samples. ConclusionsOur preliminary study confirms that obesity alters tissue trace metal metabolism and shows the proposed new approach as an accurate and reliable methodology for detecting tissue elemental obesity-related alterations. General significanceThis result can be of practical significance for designing new point-of-care systems for obesity screening tests, taking advantage of direct/indirect Rb measurements.

Hypoxia induces stress fiber formation in adipocytes in the early stage of obesity

In obese adipose tissue (AT), hypertrophic expansion of adipocytes is not matched by new vessel formation, leading to AT hypoxia. As a result, hypoxia inducible factor-1⍺ (HIF-1⍺) accumulates in adipocytes inducing a transcriptional program that upregulates profibrotic genes and biosynthetic enzymes such as lysyl oxidase (LOX) synthesis. This excess synthesis and crosslinking of extracellular matrix (ECM) components cause AT fibrosis. Although fibrosis is a hallmark of obese AT, the role of fibroblasts, cells known to regulate fibrosis in other fibrosis-prone tissues, is not well studied. Here we have developed an in vitro model of AT to study adipocyte-fibroblast crosstalk in a hypoxic environment. Further, this in vitro model was used to investigate the effect of hypoxia on adipocyte mechanical properties via ras homolog gene family member A (RhoA)/Rho-associated coiled-coil kinases (ROCK) signaling pathways. We confirmed that hypoxia creates a diseased phenotype by inhibiting adipocyte maturation and inducing actin stress fiber formation facilitated by myocardin-related transcription factor A (MRTF-A/MKL1) nuclear translocation. This work presents new potential therapeutic targets for obesity by improving adipocyte maturation and limiting mechanical stress in obese AT.

4주 고지방식이 생쥐모델에서 트레드밀 운동이 지방조직의 변화 및 혈중 사이토카인에 미치는 영향

The purpose of this study was to observe the effect of exercise in the early stages of obesity through a 4 weeks high-fat diet and treadmill exercise using aging male mice. In the change of adipose tissue by region, in the genital and inguinal adipose tissue, the weight of adipose tissue increased significantly in the 4 weeks high-fat diet group compared to the control group, and the 4-week high-fat diet significantly decreased in the exercise group. There was no significant difference in the interscapular adipose tissue in all groups. In the morphological change of adipose tissue, it was confirmed that the size of fat droplets increased in the 4 weeks high-fat diet group compared to the control group in the genital and groin adipose tissue, and the size of the fat droplets decreased in the 4 weeks high-fat diet exercise group. In the change of blood cytokines, TNF-α showed a significant difference in all groups, and in IL-4/IL-13, the 4 weeks high-fat diet group significantly increased compared to the control group, and the 4 weeks high-fat diet exercise group showed a significant difference. and there was no significant difference. Therefore, it was confirmed that treadmill aerobic exercise reduces obesity treatment and inflammatory cytokines even in the early stages of obesity, which is expected to provide important basic data for the development of exercise treatment programs for each obesity period.

High-fat diet increases gliosis and immediate early gene expression in APOE3 mice, but not APOE4 mice

BackgroundAPOE4 is the strongest genetic risk factor for Alzheimer’s disease (AD), and obesity is a strong environmental risk factor for AD. These factors result in multiple central nervous system (CNS) disturbances and significantly increase chances of AD. Since over 20% of the US population carry the APOE4 allele and over 40% are obese, it is important to understand how these risk factors interact to affect neurons and glia in the CNS.MethodsWe fed male and female APOE3 and APOE4 knock-in mice a high-fat diet (HFD-45% kcal fat) or a "control" diet (CD-10% kcal fat) for 12 weeks beginning at 6 months of age. At the end of the 12 weeks, brains were collected and analyzed for gliosis, neuroinflammatory genes, and neuronal integrity.ResultsAPOE3 mice on HFD, but not APOE4 mice, experienced increases in gliosis as measured by GFAP and Iba1 immunostaining. APOE4 mice on HFD showed a stronger increase in the expression of Adora2a than APOE3 mice. Finally, APOE3 mice on HFD, but not APOE4 mice, also showed increased neuronal expression of immediate early genes cFos and Arc.ConclusionsThese findings demonstrate that APOE genotype and obesity interact in their effects on important processes particularly related to inflammation and neuronal plasticity in the CNS. During the early stages of obesity, the APOE3 genotype modulates a response to HFD while the APOE4 genotype does not. This supports a model where early dysregulation of inflammation in APOE4 brains could predispose to CNS damages from various insults and later result in the increased CNS damage normally associated with the APOE4 genotype.

New Insights of SF1 Neurons in Hypothalamic Regulation of Obesity and Diabetes.

Despite the substantial role played by the hypothalamus in the regulation of energy balance and glucose homeostasis, the exact mechanisms and neuronal circuits underlying this regulation remain poorly understood. In the last 15 years, investigations using transgenic models, optogenetic, and chemogenetic approaches have revealed that SF1 neurons in the ventromedial hypothalamus are a specific lead in the brain’s ability to sense glucose levels and conduct insulin and leptin signaling in energy expenditure and glucose homeostasis, with minor feeding control. Deletion of hormonal receptors, nutritional sensors, or synaptic receptors in SF1 neurons triggers metabolic alterations mostly appreciated under high-fat feeding, indicating that SF1 neurons are particularly important for metabolic adaptation in the early stages of obesity. Although these studies have provided exciting insight into the implications of hypothalamic SF1 neurons on whole-body energy homeostasis, new questions have arisen from these results. Particularly, the existence of neuronal sub-populations of SF1 neurons and the intricate neurocircuitry linking these neurons with other nuclei and with the periphery. In this review, we address the most relevant studies carried out in SF1 neurons to date, to provide a global view of the central role played by these neurons in the pathogenesis of obesity and diabetes.

Circadian clock dysfunction in human omental fat links obesity to metabolic inflammation

To unravel the pathogenesis of obesity and its complications, we investigate the interplay between circadian clocks and NF-κB pathway in human adipose tissue. The circadian clock function is impaired in omental fat from obese patients. ChIP-seq analyses reveal that the core clock activator, BMAL1 binds to several thousand target genes. NF-κB competes with BMAL1 for transcriptional control of some targets and overall, BMAL1 chromatin binding occurs in close proximity to NF-κB consensus motifs. Obesity relocalizes BMAL1 occupancy genome-wide in human omental fat, thereby altering the transcription of numerous target genes involved in metabolic inflammation and adipose tissue remodeling. Eventually, clock dysfunction appears at early stages of obesity in mice and is corrected, together with impaired metabolism, by NF-κB inhibition. Collectively, our results reveal a relationship between NF-κB and the molecular clock in adipose tissue, which may contribute to obesity-related complications.

Neurotensin differentially regulates bile acid metabolism and intestinal FXR-bile acid transporter axis in response to nutrient abundance.

Studies demonstrate a role for neurotensin (NT) in obesity and related comorbidities. Bile acid (BA) homeostasis alterations are associated with obesity. We determined the effect of NT on BA metabolism in obese and non-obese conditions. Plasma and fecal BA profiles were analyzed by LC-MS/MS in male and female NT+/+ and NT-/- mice fed low-fat (LFD) or high-fat diet (HFD) for 6weeks (early stage of obesity) or greater than 20weeks (late stage of obesity). The nuclear farnesoid X receptor (FXR) and BA transporter mRNA expression were assessed in ileum, mouse enteroids, and human cell lines. HFD decreased plasma primary and secondary BAs in NT+/+ mice; HFD-induced decrease of plasma BAs was improved in NT-deficient mice. In NT+/+ mice, HFD inhibited ileal FXR and BA transporter expression; HFD-decreased expression of FXR and BA transporters was prevented in NT-/- mice. Compared with LFD-fed NT+/+ mice, LFD-fed NT-/- mice had relatively lower levels of ileal FXR and BA transporter expression. Moreover, NT stimulates the expression of FXR and BA transporters in Caco-2 cells; however, stimulated expression of BA transporters was attenuated in NT-/- enteroids. Therefore, we demonstrate that HFD disrupts the BA metabolism and ileal FXR and BA transporter axis which are improved in the absence of NT, suggesting that NT contributes to HFD-induced disruption of BA metabolism and plays an inhibitory role in the regulation of ileal FXR and BA transporter signaling under obese conditions. Conversely, NT positively regulates the expression of ileal FXR and BA transporters under non-obese conditions. Therefore, NT plays a dual role in obese and non-obese conditions, suggesting possible therapeutic strategies for obesity control.

Diet-Induced Obesity Promotes the Upregulation of Fas Expression on T-cells.

Simple SummaryObesity is associated with the development of metabolic disorders and alterations in immune responses. Notably, obesity-induced inflammation promotes the chronic activation of T-cells, which may result in the aberrant expression of their regulatory markers. Programmed cell death -1 (PD-1) and Fas (CD95) are some of the important modulators of T-cell function. Although it is apparent that their expression is dysregulated in obesity, it remains unclear whether the eventual T-cell dysfunction is due to the upregulation or downregulation of these markers. Therefore, this study aimed to assess the expression of PD-1 and Fas in T-cells in metabolic disorders.This study was conducted to assess the expression of Fas (CD95) and programmed cell death-1 (PD-1) on circulating T-cells in obesity using a diet-induced obesity mouse model. Furthermore, we aimed to determine if there are any associations between metabolic disorders and the expression of T-cell regulatory markers. A total of 12 male C57BL/6 mice were randomized into either a high-fat diet (HFD) or low-fat diet (LFD) group for 8 weeks (n = 6/group). Changes in body weights were monitored on a weekly basis. The lipid, glucose, and hematological profiles, as well as Fas and PD1 expression on the T-cell immunophenotype, were measured after 8 weeks of feeding. The HFD-fed group had a higher percentage weight gain (29.17%) in comparison with the LFD-fed group (21.74%) after the 8-week period. In addition, the HFD group had increased fasting glucose and glucose excursion following a 2-h postprandial period. The levels of total cholesterol were elevated in the HFD group when compared with the LFD group (p < 0.05). Notably, the absolute white cell count (p = 0.0096), neutrophil count (p = 0.0022, lymphocytes (p = 0.0155), and monocyte count (p = 0.0015) were elevated in the HFD group when compared with the LFD-fed group. However, the platelets (0.0680), red cell counts (0.3575), and their indices (p > 0.05) were comparable between the two groups. Interestingly, HFD feeding was associated with elevated expression of Fas on T-cells (p < 0.0001), which positively correlated with body weights (r = 0.93, p = 0.0333). No associations were found between Fas expression and dyslipidemia or fasting blood glucose levels (p > 0.05). The multivariant regression analysis showed that the association between the levels of Fas on T-cells and body weights (coefficient: −1.00, t-value: 19.27, p = 0.0330) was independent of fasting blood glucose, total cholesterol, and lymphocyte count. Lastly, the expression of PD-1 on T-cells was comparable between the two diet groups (p = 0.1822). In all, immune activation, dyslipidemia, and poor glucose control in the early stages of obesity may drive the pathogenesis of metabolic T-cell disorders. Importantly, T-cell dysfunction in obesity is partially mediated by an upregulation of Fas which is independent of dyslipidemia and hyperglycemia.

The gap between overweight and obesity status in children - (STROBE-compliant article)

Overweight might represent only the early stage of obesity or it might act as a trigger of self-awareness turning into an ideal chance for preventing further obesity development.The aim of this study was to assess the differences between overweight and obese children in terms of anthropometric, low-grade systemic inflammation, liver impairment and atherosclerotic risk.We performed a study on 132 children aged between 5 and 18 years, divided according to the BMI into 2 groups: group 1 to 76 obese children, and group 2 to 56 overweight children, assessing anthropometric, laboratory and elastography parameters.We obtained significantly higher values of anthropometric parameters in obese children versus overweight ones. We found higher levels of leukocytes, lymphocytes, AST, ALT, and E median (P = .0345, P = .0103, P < .0001, P = .0008 and P < .0001) in the obese group as compared to the overweight one. BMI was positively correlated with neutrophils, NLR, ESR, glycemia, anthropometric parameters, and E median (P = .0007/<.0001/.0018/.0044/<.0001/<.0001/<.0001/<.0001/<.0001/.0204); and negatively with lymphocytes and HDL-cholesterol (r = −0.2747/−0.2181, P = .0116/.0120).Our study underlined significant differences between overweight and obese children in terms of inflammatory status and liver impairment suggesting that the risk is directly related to the increase in BMI.

Does Proteomic Mirror Reflect Clinical Characteristics of Obesity?

Obesity is a frightening chronic disease, which has tripled since 1975. It is not expected to slow down staying one of the leading cases of preventable death and resulting in an increased clinical and economic burden. Poor lifestyle choices and excessive intake of “cheap calories” are major contributors to obesity, triggering type 2 diabetes, cardiovascular diseases, and other comorbidities. Understanding the molecular mechanisms responsible for development of obesity is essential as it might result in the introducing of anti-obesity targets and early-stage obesity biomarkers, allowing the distinction between metabolic syndromes. The complex nature of this disease, coupled with the phenomenon of metabolically healthy obesity, inspired us to perform data-centric, hypothesis-generating pilot research, aimed to find correlations between parameters of classic clinical blood tests and proteomic profiles of 104 lean and obese subjects. As the result, we assembled patterns of proteins, which presence or absence allows predicting the weight of the patient fairly well. We believe that such proteomic patterns with high prediction power should facilitate the translation of potential candidates into biomarkers of clinical use for early-stage stratification of obesity therapy.

Redox Imbalance and Methylation Disturbances in Early Childhood Obesity.

Obesity is increasing worldwide in prepubertal children, reducing the age of onset of associated comorbidities, including type 2 diabetes. Sulfur-containing amino acids, methionine, cysteine, and their derivatives play important roles in the transmethylation and transsulfuration pathways. Dysregulation of these pathways leads to alterations in the cellular methylation patterns and an imbalanced redox state. Therefore, we tested the hypothesis that one-carbon metabolism is already dysregulated in prepubertal children with obesity. Peripheral blood was collected from 64 children, and the plasma metabolites from transmethylation and transsulfuration pathways were quantified by HPLC. The cohort was stratified by BMI z-scores and HOMA-IR indices into healthy lean (HL), healthy obese (HO), and unhealthy obese (UHO). Fasting insulin levels were higher in the HO group compared to the HL, while the UHO had the highest. All groups presented normal fasting glycemia. Furthermore, high-density lipoprotein (HDL) was lower while triglycerides and lactate levels were higher in the UHO compared to HO subjects. S-adenosylhomocysteine (SAH) and total homocysteine levels were increased in the HO group compared to HL. Additionally, glutathione metabolism was also altered. Free cystine and oxidized glutathione (GSSG) were increased in the HO as compared to HL subjects. Importantly, the adipocyte secretory function was already compromised at this young age. Elevated circulating leptin and decreased adiponectin levels were observed in the UHO as compared to the HO subjects. Some of these alterations were concomitant with alterations in the DNA methylation patterns in the obese group, independent of the impaired insulin levels. In conclusion, our study informs on novel and important metabolic alterations in the transmethylation and the transsulfuration pathways in the early stages of obesity. Moreover, the altered secretory function of the adipocyte very early in life may be relevant in identifying early metabolic markers of disease that may inform on the increased risk for specific future comorbidities in this population.