Obesity-associated Metabolic Complications Research Articles

Deletion of CD44 promotes adipogenesis by regulating PPARγ and cell cycle-related pathways.

CD44, a cell surface adhesion receptor and stem cell biomarker, is recently implicated in chronic metabolic diseases. Ablation of CD44 ameliorates adipose tissue inflammation and insulin resistance in obesity. Here, we investigated cell type-specific CD44 expression in human and mouse adipose tissue and further studied how CD44 in preadipocytes regulates adipocyte function. Using Crispr Cas9-mdediated gene deletion and lentivirus-mediated gene re-expression, we discovered that deletion of CD44 promotes adipocyte differentiation and adipogenesis, whereas re-expression of CD44 abolishes this effect and decreases insulin responsiveness and adiponectin secretion in 3T3-L1 cells. Mechanistically, CD44 does so via suppressing Pparg expression. Using quantitative proteomics analysis, we further discovered that cell cycle-regulated pathways were mostly decreased by deletion of CD44. Indeed, re-expression of CD44 moderately restored expression of proteins involved in all phases of the cell cycle. These data were further supported by increased preadipocyte proliferation rates in CD44-deficient cells and re-expression of CD44 diminished this effect. Our data suggest that CD44 plays a crucial role in regulating adipogenesis and adipocyte function possibly through regulating PPARγ and cell cycle-related pathways. This study provides evidence for the first time that CD44 expressed in preadipocytes plays key roles in regulating adipocyte function outside immune cells where CD44 is primarily expressed. Therefore, targeting CD44 in (pre)adipocytes may provide therapeutic potential to treat obesity-associated metabolic complications.

The potential efficacy of Artemisia anuua L. extract nanoparticles in mitigating obesity-related-metabolic complications in hypercaloric diet-fed rats

ABSTRACT Obesity-related health problems are worsening in various societies worldwide. Artemisia anuua L. (AA) has distinctive health benefits, including anti-inflammatory, antioxidant, and insulin-sensitizing properties. Nanoformulation of herbal extracts is a new approach to enhance the bioavailability of natural products. This study aimed to evaluate the efficacy of AA extract, either the conventional extract (AAE) or its nano-form (AAEN), in modulating obesity-related metabolic complications in hypercaloric (high-fat/high-sucrose) diet-induced obese rats. Forty-eight rats were divided into two groups fed either a basal or hypercaloric diet for twelve weeks. Starting from the eighth week, each main group was subdivided into three subgroups and treated orally with either saline, AAE, or AAEN until the end of the experiment. Both AAE and AAEN exerted antiadipogenic effects. They reduced body weight and epididymal fat, mitigated dyslipidemia, improved glucose utilization and insulin resistance, reduced hyperleptinemia, increased serum adiponectin, and decreased oxidative stress and inflammatory markers. These results were mediated by regulating SIRT-1, PGC-1α, SREBP-1, PPAR-γ, FAS, LPL, IRS 1, and GLUT4 gene expression, suggesting an effect of AA on de novo lipogenesis and glucose utilization. The AAEN produced more expressive ameliorating effects than the conventional extract. AAE administration ameliorated the obesity-associated metabolic complications induced by feeding a hypercaloric diet, implying that this extract may be used as a complementary treatment option for obesity and its metabolic consequences. The antiadipogenic effectiveness of AAE was enhanced by its nanoformulation, suggesting that the nanoparticle system can be applied to boost other herbal medicine effectiveness.

Therapeutic Effects of Curcumin Derivatives against Obesity and Associated Metabolic Complications: A Review of In Vitro and In Vivo Studies.

Obesity is a major cause of morbidity and mortality globally, increasing the risk for chronic diseases. Thus, the need to identify more effective anti-obesity agents has spurred significant interest in the health-promoting properties of natural compounds. Of these, curcumin, the most abundant and bioactive constituent of turmeric, possesses a variety of health benefits including anti-obesity effects. However, despite its anti-obesity potential, curcumin has demonstrated poor bioavailability, which limits its clinical applicability. Synthesizing curcumin derivatives, which are structurally modified analogs of curcumin, has been postulated to improve bioavailability while maintaining therapeutic efficacy. This review summarizes in vitro and in vivo studies that assessed the effects of curcumin derivatives against obesity and its associated metabolic complications. We identified eight synthetic curcumin derivatives that were shown to ameliorate obesity and metabolic dysfunction in diet-induced obese animal models, while five of these derivatives also attenuated obesity and associated metabolic complications in cell culture models. These curcumin derivatives modulated adipogenesis, lipid metabolism, insulin resistance, steatosis, lipotoxicity, inflammation, oxidative stress, endoplasmic reticulum stress, apoptosis, autophagy, fibrosis, and dyslipidemia to a greater extent than curcumin. In conclusion, the findings from this review show that compared to curcumin, synthetic curcumin derivatives present potential candidates for further development as therapeutic agents to modulate obesity and obesity-associated metabolic complications.

Obesity-induced and weight-loss-induced physiological factors affecting weight regain.

Weight regain after successful weight loss resulting from lifestyle interventions is a major challenge in the management of overweight and obesity. Knowledge of the causal mechanisms for weight regain can help researchers and cliniciansto find effective strategies to tackle weight regainand reduce obesity-associated metabolic and cardiovascular complications. This Review summarizes the current understanding of a number of potential physiological mechanisms underlying weight regain after weight loss, including: the role of adipose tissue immune cells; hormonal and neuronal factors affecting hunger, satiety and reward; resting energy expenditure and adaptive thermogenesis; and lipid metabolism (lipolysis and lipid oxidation). We describe and discuss obesity-associated changes in these mechanisms, their persistence during weight loss and weight regain and their association with weight regain. Interventions to prevent or limit weight regain based on these factors, such as diet, exercise, pharmacotherapyand biomedical strategies, and current knowledge on the effectiveness of these interventions are also reviewed.

Microphysiological system recapitulating the pathophysiology of adipose tissue in obesity.

A growing body of evidence has indicated that white adipose tissue (AT) remodeling is a major trigger for obesity-associated metabolic complications. However, the scarcity of translational models is an obstacle to the development of medicines that act on adipose restoration. Here, we describe a microphysiological system (MPS) that emulates the unique features of reprogrammed AT as a new in vitro tool for studying AT pathophysiology in obesity. The AT MPS contained mature adipocytes embedded in an extracellular matrix (ECM) hydrogel interfaced with AT microvascular endothelium, which was constantly perfused with fresh media. The unique biochemical signals due to the remodeled ECM in obesity were recapitulated using a decellularized AT ECM (AT dECM) hydrogel, which preserves the features of altered ECM composition in obesity. The mature adipocytes embedded in the AT dECM hydrogel maintained their function and morphology for a week without dedifferentiation. Using the AT MPS, we successfully modeled inflammation-induced AT microvascular dysfunction, the recruitment of immune cells due to the upregulation of cell adhesion molecules, and higher cancer cell adhesion as an indicator of metastasis, which are observed in obese individuals. The AT MPS may therefore represent a promising platform for understanding the dynamic cellular interplay in obesity-induced AT remodeling and validating the efficacy of drugs targeting AT in obesity. STATEMENT OF SIGNIFICANCE: The lack of translational in vitro white adipose tissue (AT) models is one of the main obstacles for understanding the obesity-induced reprogramming and the development of medicines. We report herein the AT microphysiological system (MPS), which recapitulates obesity and normal conditions and yields cell- and AT dECM-derived signals, thereby allowing accurate comparative in vitro analyses. Using the AT MPS, we successfully modeled reprogrammed AT in obesity conditions, including inflammation-induced AT vascular dysfunction, the recruitment of immune cells, and higher cancer cell metastasis, which are observed in obese individuals. Our proposed adipose tissue model providing physiological relevance and complexity may therefore enhance the understanding of obesity-associated disorders and be used to investigate their underlying molecular mechanisms to develop pharmacologic treatment strategies.

Set7 Deletion Prevents Glucose Intolerance and Improves the Recovery of Cardiac Function After Ischemia and Reperfusion in Obese Female Mice.

An obesogenic diet (high fat and sugar, low fiber) is associated with an increased risk for metabolic and cardiovascular disorders. Previous studies have demonstrated that epigenetic changes can modify gene transcription and protein function, playing a key role in the development of several diseases. The methyltransferase Set7 methylates histone and non-histone proteins, influencing diverse biological and pathological processes. However, the functional role of Set7 in obesity-associated metabolic and cardiovascular complications is unknown. Wild type and Set7 knockout female mice were fed a normal diet or an obesogenic diet for 12 weeks. Body weight gain and glucose tolerance were measured. The 3T3-L1 cells were used to determine the role of Set7 in white adipogenic differentiation. Cardiac morphology and function were evaluated by histology and echocardiography. An ex vivo Langendorff perfusion system was used to model cardiac ischemia/reperfusion (I/R). Here, we report that Set7 protein levels were enhanced in the heart and perigonadal adipose tissue (PAT) of female mice fed an obesogenic diet. Significantly, loss of Set7 prevented obesogenic diet-induced glucose intolerance in female mice although it did not affect the obesogenic diet-induced increase in body weight gain and adiposity in these animals, nor did Set7 inhibition change white adipogenic differentiation in vitro. In addition, loss of Set7 prevented the compromised cardiac functional recovery following ischemia and reperfusion (I/R) injury in obesogenic diet-fed female mice; however, deletion of Set7 did not influence obesogenic diet-induced cardiac hypertrophy nor the hemodynamic and echocardiographic parameters. These data indicate that Set7 plays a key role in obesogenic diet-induced glucose intolerance and compromised myocardial functional recovery after I/R in obese female mice.

High Hydrostatic Pressure Extract of Mulberry Leaf Attenuated Obesity-Induced Inflammation in Rats.

Low-grade inflammation might be a link between obesity and obesity-associated metabolic dysfunction, including diabetes, hepatic steatosis, and other health complications. This study investigated whether the supplementation of high hydrostatic pressure extract of mulberry (Morus alba L.) leaves (HML) to obese rats could counteract obesity-related inflammation. Three-week-old male Sprague-Dawley rats were separated into three groups as follows: (a) a normal diet, (b) 45% high-fat (HF) diet, and HF diet containing 0.4% HML (c) or 0.8% HML (d) (IACUC No. 17-033). After 14 weeks of HML supplementation, adipose tissue mass, mRNA expression of adipogenic genes, such as aP2, peroxisome proliferator-activated receptor γ (PPARγ), and sterol regulatory element binding protein 1c (SREBP1c), and macrophage recruitment were significantly decreased in HF-fed obese rats. Serum concentrations of nitric oxide and mRNA levels of arginase1 (Arg1), CD11c, and inducible nitric oxide synthase (iNOS) involved in adipose tissue macrophage M1 polarization were also significantly reduced by HML. Moreover, HML alleviated the serum and hepatic lipid profiles and reduced hepatic lipogenic gene expression of acetyl-CoA carboxylase (ACC), cluster of differentiation 36 (CD36), CPT1, fatty acid synthase (FAS), stearoyl-CoA desaturase (SCD1), and SREBP1c, and inflammation-associated genes, including IL1β, interleukin 6 (IL6), and tumor necrosis factor α (TNFα). Serum IL6 and TNFα levels were remarkedly suppressed in the 0.8% HML group. These results suggested that the favorable effect of HML on obesity-associated inflammation might be related in part to the decrease in adipose tissue and hepatic fat deposition and inflammation.

Obesity Due to Steroid Receptor Coactivator-1 Deficiency Is Associated With Endocrine and Metabolic Abnormalities.

ContextGenetic variants affecting the nuclear hormone receptor coactivator steroid receptor coactivator, SRC-1, have been identified in people with severe obesity and impair melanocortin signaling in cells and mice. As a result, obese patients with SRC-1 deficiency are being treated with a melanocortin 4 receptor agonist in clinical trials.ObjectiveHere, our aim was to comprehensively describe and characterize the clinical phenotype of SRC-1 variant carriers to facilitate diagnosis and clinical management.MethodsIn genetic studies of 2462 people with severe obesity, we identified 23 rare heterozygous variants in SRC-1. We studied 29 adults and 18 children who were SRC-1 variant carriers and performed measurements of metabolic and endocrine function, liver imaging, and adipose tissue biopsies. Findings in adult SRC-1 variant carriers were compared to 30 age- and body mass index (BMI)-matched controls.ResultsThe clinical spectrum of SRC-1 variant carriers included increased food intake in children, normal basal metabolic rate, multiple fractures with minimal trauma (40%), persistent diarrhea, partial thyroid hormone resistance, and menorrhagia. Compared to age-, sex-, and BMI-matched controls, adult SRC-1 variant carriers had more severe adipose tissue fibrosis (46.2% vs 7.1% respectively, P = .03) and a suggestion of increased liver fibrosis (5/13 cases vs 2/13 in controls, odds ratio = 3.4), although this was not statistically significant.Conclusion SRC-1 variant carriers exhibit hyperphagia in childhood, severe obesity, and clinical features of partial hormone resistance. The presence of adipose tissue fibrosis and hepatic fibrosis in young patients suggests that close monitoring for the early development of obesity-associated metabolic complications is warranted.

Impact of Bariatric Surgery on Adipose Tissue Biology.

Bariatric surgery (BS) procedures are actually the most effective intervention to help subjects with severe obesity achieve significant and sustained weight loss. White adipose tissue (WAT) is increasingly recognized as the largest endocrine organ. Unhealthy WAT expansion through adipocyte hypertrophy has pleiotropic effects on adipocyte function and promotes obesity-associated metabolic complications. WAT dysfunction in obesity encompasses an altered adipokine secretome, unresolved inflammation, dysregulated autophagy, inappropriate extracellular matrix remodeling and insufficient angiogenic potential. In the last 10 years, accumulating evidence suggests that BS can improve the WAT function beyond reducing the fat depot sizes. The causal relationships between improved WAT function and the health benefits of BS merits further investigation. This review summarizes the current knowledge on the short-, medium- and long-term outcomes of BS on the WAT composition and function.

Coelogin ameliorates metabolic dyshomeostasis by regulating adipogenesis and enhancing energy expenditure in adipose tissue

Obesity and associated metabolic disorders are heading up with an alarming rate in developing nations. One of highly sought solution for metabolic disorders is to identify natural molecule with an ability to reduce obesity and increase insulin sensitivity. Coelogin (CLN) is a phenanthrene derivative isolated from the ethanolic extract of Coelogyne cristata. In our constant efforts to identify novel anti-dyslipidemic and anti-adipogenic compounds using CFPMA (common feature pharmacophore model using known anti-adipogenic compounds) model, predicted possible anti-adipogenic activity of CLN. In vitro results showed significant inhibition of adipogenesis in 3T3-L1 and C3H10T1/2 cell by CLN. It arrests the cell cycle in G1 phase of interphase and inhibits mitotic clonal expansion to regulate adipogenesis. CLN elicits insulin sensitizing effect in mature adipocytes. During extracellular flux assessment studies, it increases oxidative respiration and energy expenditure in adipocytes. In vivo, CLN reversed HFD-induced dyslipidemia as well as insulin resistance in C57BL/6 mice. It promoted the expression of genes involved in improved mitochondrial function and fatty acid oxidation in eWAT. CLN restored energy expenditure and increased the capacity of energy utilization in HFD fed mice. Taken together, the study indicated beneficial effects of CLN in combating obesity-associated metabolic complications.

Nutritional management of individuals with obesity and COVID-19: ESPEN expert statements and practical guidance

The COVID-19 pandemics has created unprecedented challenges and threats to patients and healthcare systems worldwide. Acute respiratory complications that require intensive care unit (ICU) management are a major cause of morbidity and mortality in COVID-19 patients. Among other important risk factors for severe COVID-19 outcomes, obesity has emerged along with undernutrition-malnutrition as a strong predictor of disease risk and severity. Obesity-related excessive body fat may lead to respiratory, metabolic and immune derangements potentially favoring the onset of COVID-19 complications. In addition, patients with obesity may be at risk for loss of skeletal muscle mass, reflecting a state of hidden malnutrition with a strong negative health impact in all clinical settings. Also importantly, obesity is commonly associated with micronutrient deficiencies that directly influence immune function and infection risk. Finally, the pandemic-related lockdown, deleterious lifestyle changes and other numerous psychosocial consequences may worsen eating behaviors, sedentarity, body weight regulation, ultimately leading to further increments of obesity-associated metabolic complications with loss of skeletal muscle mass and higher non-communicable disease risk. Therefore, prevention, diagnosis and treatment of malnutrition and micronutrient deficiencies should be routinely included in the management of COVID-19 patients in the presence of obesity; lockdown-induced health risks should also be specifically monitored and prevented in this population. In the current document, the European Society for Clinical Nutrition and Metabolism (ESPEN) aims at providing clinical practice guidance for nutritional management of COVID-19 patients with obesity in various clinical settings.

Vitamin D Inhibits Adipokine Production and Inflammatory Signaling Through the Vitamin D Receptor in Human Adipocytes.

The purpose of this study was to investigate the effects of vitamin D on adipokine expression and inflammation in human adipose tissues and adipocytes and evaluate the molecular mechanisms involved. Omental and abdominal subcutaneous human adipose tissues were treated with 1,25-dihydroxyvitamin D3 (1,25(OH)2 D3 ), and adipokine levels were measured. Vitamin D effects were measured with or without dexamethasone because glucocorticoids are known to affect vitamin D actions. Using RNA interference, we examined whether the vitamin D receptor (VDR) mediated vitamin D actions on adipokine expression and inflammatory signaling pathways in human adipocytes. mRNA levels and secretion of leptin and IL-6 were suppressed by 1,25(OH)2 D3 in omental adipose tissues. Cotreatment with dexamethasone did not affect these inhibitory actions but partially blocked CYP24A1 induction. Similar results were observed in the subcutaneous depot. In addition, 1,25(OH)2 D3 suppressed leptin and IL-6 expression as well as nuclear factor-κB and extracellular signal-regulated kinase-1/2 phosphorylation in human adipocytes. Adipokine expression also was decreased by 25-hydroxyvitamin D3 (25(OH)D3 ), but not vitamin D3 . Knockdown of VDR increased the inflammatory signaling activity in the control condition and blocked the inhibitory effects of 1,25(OH)2 D3 on adipokine and inflammatory signaling pathways. Vitamin D acts through VDR to inhibit inflammatory pathways and adipokine expression in human adipocytes. Increasing vitamin D status may ameliorate obesity-associated metabolic complications by decreasing adipose tissue inflammation.

Lipidomic Analysis of Adipose-Derived Extracellular Vesicles Reveals Their Potential as Lipid Mediators of Obesity-Associated Metabolic Complications

Lipidomic Analysis of Adipose-Derived Extracellular Vesicles Reveals Their Potential as Lipid Mediators of Obesity-Associated Metabolic Complications

Defective FXR-SHP Regulation in Obesity Aberrantly Increases miR-802 Expression, Promoting Insulin Resistance and Fatty Liver.

Aberrantly elevated expression in obesity of microRNAs (miRNAs), including the miRNA miR-802, contributes to obesity-associated metabolic complications, but the mechanisms underlying the elevated expression are unclear. Farnesoid X receptor (FXR), a key regulator of hepatic energy metabolism, has potential for treatment of obesity-related diseases. We examined whether a nuclear receptor cascade involving FXR and FXR-induced small heterodimer partner (SHP) regulates expression of miR-802 to maintain glucose and lipid homeostasis. Hepatic miR-802 levels are increased in FXR-knockout (KO) or SHP-KO mice and are decreased by activation of FXR in a SHP-dependent manner. Mechanistically, transactivation of miR-802 by aromatic hydrocarbon receptor (AHR) is inhibited by SHP. In obese mice, activation of FXR by obeticholic acid treatment reduced miR-802 levels and improved insulin resistance and hepatosteatosis, but these beneficial effects were largely abolished by overexpression of miR-802. In patients with nonalcoholic fatty liver disease (NAFLD) and in obese mice, occupancy of SHP is reduced and that of AHR is modestly increased at the miR-802 promoter, consistent with elevated hepatic miR-802 expression. These results demonstrate that normal inhibition of miR-802 by FXR-SHP is defective in obesity, resulting in increased miR-802 levels, insulin resistance, and fatty liver. This FXR-SHP-miR-802 pathway may present novel targets for treating type 2 diabetes and NAFLD.

Identification of SCARA3 with potential roles in metabolic disorders.

Obesity is characterized by the expansion of adipose tissue which is partially modulated by adipogenesis. In the present study, we identified five differentially expressed genes by incorporating two adipogenesis-related datasets from the GEO database and their correlation with adipogenic markers. However, the role of scavenger receptor class A member 3 (SCARA3) in obesity-related disorders has been rarely reported. We found that Scara3 expression in old adipose tissue-derived mesenchymal stem cells (Ad-MSCs) was lower than it in young Ad-MSCs. Obese mice caused by deletion of the leptin receptor gene (db/db) or by a high-fat diet both showed reduced Scara3 expression in inguinal white adipose tissue. Moreover, hypermethylation of SCARA3 was observed in patients with type 2 diabetes and atherosclerosis. Data from the CTD database indicated that SCARA3 is a potential target for metabolic diseases. Mechanistically, JUN was predicted as a transcriptional factor of SCARA3 in different databases which is consistent with our further bioinformatics analysis. Collectively, our study suggested that SCARA3 is potentially associated with age-related metabolic dysfunction, which provided new insights into the pathogenesis and treatment of obesity as well as other obesity-associated metabolic complications.

Plasma glucagon levels are associated with obesity, insulin resistance and metabolic syndrome in a general population cohort

Rationale: Glucagon is a well- and long-recognized key regulator of hepatic glucose production playing a major role in plasma glucose control in both type 1 and type 2 diabetes. Experimental models have recently identified a role of glucagon in the regulation of energy balance and intermediate metabolism but potential associations between plasma glucagon, obesity and obesity-associated metabolic complications insulin resistance and metabolic syndrome in general population cohorts is largely unknown.

Macrophage-derived thrombospondin 1 promotes obesity-associated non-alcoholic fatty liver disease.

Background & AimsThrombospondin 1 (TSP1) is a multifunctional matricellular protein. We previously showed that TSP1 has an important role in obesity-associated metabolic complications, including inflammation, insulin resistance, cardiovascular, and renal disease. However, its contribution to obesity-associated non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD or NASH) remains largely unknown; thus, we aimed to determine its role.MethodsHigh-fat diet or AMLN (amylin liver NASH) diet-induced obese and insulin-resistant NAFLD/NASH mouse models were utilised, in addition to tissue-specific Tsp1-knockout mice, to determine the contribution of different cellular sources of obesity-induced TSP1 to NAFLD/NASH development.ResultsLiver TSP1 levels were increased in experimental obese and insulin-resistant NAFLD/NASH mouse models as well as in obese patients with NASH. Moreover, TSP1 deletion in adipocytes did not protect mice from diet-induced NAFLD/NASH. However, myeloid/macrophage-specific TSP1 deletion protected mice against obesity-associated liver injury, accompanied by reduced liver inflammation and fibrosis. Importantly, this protection was independent of the levels of obesity and hepatic steatosis. Mechanistically, through an autocrine effect, macrophage-derived TSP1 suppressed Smpdl3b expression in liver, which amplified liver proinflammatory signalling (Toll-like receptor 4 signal pathway) and promoted NAFLD progression.ConclusionsMacrophage-derived TSP1 is a significant contributor to obesity-associated NAFLD/NASH development and progression and could serve as a therapeutic target for this disease.Lay summaryObesity-associated non-alcoholic fatty liver disease is a most common chronic liver disease in the Western world and can progress to liver cirrhosis and cancer. No treatment is currently available for this disease. The present study reveals an important factor (macrophage-derived TSP1) that drives macrophage activation and non-alcoholic fatty liver disease development and progression and that could serve as a therapeutic target for non-alcoholic fatty liver disease/steatohepatitis.

Influence of plasma circulating exosomes obtained from obese women on tumorigenesis and tamoxifen resistance in MCF-7 cells.

Obesity is associated with breast cancer aggressiveness and drug resistance. Although the underlying mechanisms are unknown, recent studies indicated that exosomes have a principal contributory role in obesity-associated metabolic complications. Hence, we investigated whether obesity can mediate breast cancer progression and resistance to tamoxifen by plasma-derived-exosomes from obese women or not. Plasma exosomes isolated from five normal-weight (N-Exo) and five obese women (O-Exo) were characterized for size, zeta potential, and CD63 expression. After the treatment of MCF-7 cells with N-Exo and O-Exo, cell proliferation, migration, invasion as well as levels of MMP-9 and MMP-2 were evaluated by the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, wound healing, transwell, and zymography methods, respectively. For evaluating resistance to tamoxifen, the cell viability, apoptosis, and the p53 protein were evaluated using the MTT assay, flow cytometry, and western blot methods, respectively. Cell proliferation, migration, and invasion were significantly increased in the cells treated with O-Exo than untreated cells (p = .001, p = .018, p = .034, respectively). Levels of MMP-2 and MMP-9 were remarkably increased in the cells treated with O-Exo in comparison with ones treated with N-Exo (p = .040, p = .043, respectively). As for resistance to tamoxifen, O-Exo had significantly the greater anti-apoptotic effects in comparison with the N-Exo group (p = .013). Besides, p53 levels were significantly decreased in the cells treated with O-Exo than ones treated with N-Exo (p = .045). The cell viability was significantly more in cells treated with O-Exo in comparison with the cells only treated with tamoxifen (p = .040). Our findings demonstrated that circulating exosomes derived from obese women could lead to tumorigenesis and tamoxifen resistance in breast cancer cells. However, more studies are needed to establish this notion.

Supplementation with Sea Vegetables Palmaria mollis and Undaria pinnatifida Exerts Metabolic Benefits in Diet-Induced Obesity in Mice.

ABSTRACTBackgroundSea vegetables are rich sources of nutrients as well as bioactive components that are linked to metabolic health improvement. Algal polysaccharides improve satiety and modulate gut microbiota while proteins, peptides, and phenolic fractions exert anti-inflammatory, antioxidant, and antidiabetic effects.ObjectiveWe tested the hypothesis that dietary supplementation with either Pacific dulse (Palmaria mollis, red algae) or wakame (Undaria pinnatifida, brown algae) could remediate metabolic complications in high-fat diet-induced obesity.MethodsIndividually caged C57BL/6J mice (n = 8) were fed ad libitum with either a low-fat diet (LFD), 10% kcal fat; high-fat diet (HFD), 60% kcal fat; HFD + 5% (wt:wt) dulse (HFD + D); or HFD + 5% (wt:wt) wakame (HFD + W) for 8 weeks. Food intake and weight gain were monitored weekly. Glucose tolerance, hepatic lipids, fecal lipids, and plasma markers were evaluated, and the gut microbiome composition was assessed.ResultsDespite the tendency of higher food and caloric intake than the HFD (P = 0.04) group, the HFD + D group mice did not exhibit higher body weight, indicating lower food and caloric efficiency (P < 0.001). Sea vegetable supplementation reduced plasma monocyte chemotactic protein (MCP-1) (P < 0.001) and increased fecal lipid excretion (P < 0.001). Gut microbiome analysis showed that the HFD + D group had higher alpha-diversity than the HFD or LFD group, whereas beta-diversity analyses indicated that sea vegetable–supplemented HFD-fed mice (HFD + D and HFD + W groups) developed microbiome compositions more similar to those of the LFD-fed mice than those of the HFD-fed mice.ConclusionSea vegetable supplementation showed protective effects against obesity-associated metabolic complications in C57BL/6J male mice by increasing lipid excretion, reducing systemic inflammatory marker, and mitigating gut microbiome alteration. While the obese phenotype development was not prevented, metabolic issues related to lipid absorption, inflammation, and gut microbial balance were improved, showing therapeutic promise and warranting eventual mechanistic elucidations.

Towards a novel marker of insulin resistance in obesity: S100A4 in girls along the puberty. The longitudinal study “PUBMEP”

AbstractIntroduction:Insulin resistance (IR) is the major driver for the development of obesity-associated metabolic and cardiovascular complications. It is well known that IR increase physiologically during puberty; hence, pubertal maturation might favour this metabolic risk in obese children. Recently, a study carried out in adult women with obesity has identified a new adipokine, known as S100A4, strongly associated with IR and inflammation in adipose tissue. On the contrary, little is known about the implication of S100A4 in the development of such metabolic disturbances during the onset and course of pubertal development.Materials and methods:A longitudinal study was conducted on 53 Spanish girls distributed in six experimental conditions according to their obesity and IR status (before (T0) and after (T1) the onset of puberty). Anthropometric and biochemical parameters were evaluated in all samples and time points. Classification of pubertal stage was made according to the Tanner scale. S100A4 protein levels were quantified by ELISA CSB-EL02032HU in plasma samples (Cusabio Biotech, Wuhan, China). The statistical analysis of the results was carried out with the “nlme” package in R v3.4.4, using a mixed-effects linear model with random intercept and slope.Results:At a significance level of alpha = 0.05, a linear mixed-effects model reported a significant association (P = 0.03) between the interaction term “time*experimental group” and S100A4 levels. Post-hoc pairwise comparisons between experimental groups revealed a strong association between a worsening/improvement of the IR status and the increase/decrease of S100A4 levels (yielding significant results for 5 of the 15 comparisons (P = 0.008, P = 0.04, P = 0.02, P = 0.04 and P = 0.02)). Furthermore, a multiple linear regression model reported a positive correlation between the increase in S100A4 levels and the increase in HOMA values during the course of puberty (B = 6.03, SE = 2.66 and P = 0.028).Discussion:The S100A4 protein is strongly associated with the development of IR in girls with childhood obesity and this association is accentuated during pubertal development. Increase in S100A4 levels could be one of the molecular mechanisms by which pubertal maturation favour an increased metabolic risk in children with obesity.