Fat Cell Function Research Articles

Effect of DHCR7 on adipocyte differentiation in goats

Cholesterol is regarded as a signaling molecule in regulating the metabolism and function of fat cells, in which 7-Dehydrocholesterol reductase (DHCR7) is a key enzyme that catalyzes the conversion of 7-dehydrocholesterol to cholesterol, however, the exact function of DHCR7 in goat adipocytes remains unknown. Here, the effect of DHCR7 on the formation of subcutaneous and intramuscular fat in goats was investigated in vitro, and the result indicated that the mRNA level of DHCR7 showed a gradual downward trend in subcutaneous adipogenesis, but an opposite trend in intramuscular adipogenesis. In the process of subcutaneous preadipocytes differentiation, overexpression of DHCR7 inhibited the expression of adipocytes differentiation marker genes (CEBP/α, CEBP/β, SREBP1 and AP2), lipid metabolism-related genes (AGPAT6, FASN, SCD1 and LPL), and the lipid accumulation. However, in intramuscular preadipocyte differentiation, DHCR7 overexpression showed a promoting effect on adipocyte differentiation marker genes (CEBP/α, CEBP/β, PPARγ and SREBP1) and lipid metabolism-related genes (GPAM, AGPAT6, DGAT1 and SCD1) expression, and on lipid accumulation. In summary, our work demonstrated that DHCR7 played an important role in regulating adipogenic differentiation and lipid metabolism in preadipocytes in goats, which is of great significance for uncovering the underlying molecular mechanism of adipocyte differentiation and improving goat meat quality.

Long-term improvement of adipocyte insulin action during body weight relapse after bariatric surgery: a longitudinal cohort study.

There are few long-term mechanistic studies in adipose tissue that investigate the metabolic effects of bariatric surgery. Changes in lipogenesis may be involved in long-term weight development. To investigate the long-term effect of bariatric surgery on lipogenesis in abdominal fat cells and whether surgical treatment could induce an epigenetic memory that would maintain improved lipogenesis in spite of body weight relapse. Karolinska University Hospital in Stockholm County, Sweden. A total of 22 women with obesity living in the Stockholm area were examined before, 2, 5, and 10 years after bariatric surgery. Abdominal adipose tissue biopsies were obtained. Fat cells were isolated and spontaneous and insulin stimulated glucose incorporation into lipids were assayed. CpG-methylation profiling was performed on adipocytes using the Infinium EPIC BeadChips. Bariatric surgery was associated with improvement in adipocyte spontaneous and insulin stimulated lipogenesis, which was maintained despite some later weight regain (29 % of initial weight loss). There was also an increase in fat cell size between 2- and 10-year follow-up, albeit not to presurgery levels. There were 7729 differentially methylated CpG sites (DMS) at 2 years that showed no sign of return to baseline at either 5 or 10 years. Merging results with expression profiles identified 1259 genes with DMS which showed early response or continual change in expression in one direction after surgery. Upregulated genes with DMS were enriched in gene sets linked to cellular response to insulin stimulus (e.g., IRS1, IRS2, PDE3B, and AKT2) and regulation of lipid metabolic processes. Bariatric surgery leads to long-term improvement of lipogenesis and insulin responsiveness in subcutaneous adipocytes in women in spite of some partial body weight regain postoperatively. This may to some extent be explained by epigenetic modifications of fat cell function.

Transcriptome and fatty-acid signatures of adipocyte hypertrophy and its non-invasive MR-based characterization in human adipose tissue.

SummaryBackgroundThe adipocyte-hypertrophy associated remodeling of fat cell function is considered causal for the development of metabolic disorders. A better understanding of transcriptome and fatty acid (FA) related alterations with adipocyte hypertrophy combined with less-invasive strategies for the detection of the latter can help to increase the prognostic and diagnostic value of adipocyte size and FA composition as markers for metabolic disease.MethodsTo clarify adipocyte-hypertrophy associated transcriptomic alterations, fat cell size was related to RNA-Seq data from white adipose tissue and size-separated adipocytes. The relationship between adipocyte size and adipose tissue FA composition as measured by GC-MS was investigated. MR spectroscopy (MRS) methods for clinical scanning were developed to characterize adipocyte size and FA composition in a fast and non-invasive manner.FindingsWith enlarged adipocyte size, substantial transcriptomic alterations of genes involved in mitochondrial function and FA metabolism were observed. Investigations of these two mechanisms revealed a reciprocal relationship between adipocyte size and estimated thermogenic adipocyte content as well as depot-specific correlations of adipocyte size and FA composition. MRS on a clinical scanner was suitable for the in-parallel assessment of adipose morphology and FA composition.InterpretationThe current study provides a comprehensive overview of the adipocyte-hypertrophy associated transcriptomic and FA landscape in both subcutaneous and visceral adipose tissue. MRS represents a promising technique to translate the observed mechanistic, structural and functional changes in WAT with adipocyte hypertrophy into a clinical context for an improved phenotyping of WAT in the context of metabolic diseases.FundingCompetence network for obesity (FKZ 42201GI1128), ERC (No 677661, ProFatMRI; No 875488, FatVirtualBiopsy), Else Kröner-Fresenius-Foundation.

Quercetin May Improve Fat Graft Survival by Promoting Fat Browning Peripherally.

Adipose browning occurs after white fat transfer. But its location and effects on fat graft survival remains controversial. This study was performed to locate the browning of fat grafts, and to explore the effects of quercetin on fat graft browning and fat graft survival. Human fat granules were injected into the subcutaneous layer of 12 nude mice. Control group was injected with fat granules and 10% of normal saline, while quercetin group was injected with fat granules and 10% of quercetin. The graft samples (n = 6 for each group) were obtained in weeks 2, 4, 8 and 12. Weight retention rate of the grafts was calculated. Gene and protein expression of mitochondrial markers (silent information regulator 1, SIRT1; heat shock protein 60, HSP60), browning marker (uncoupling protein 1, UCP1), peroxisome proliferator-activated receptor-γ (PPAR-γ), vascular endothelial growth factor A (VEGF-A) were evaluated. Hematoxylin and eosin staining and anti-UCP1 staining were performed. Clusters of small multilocular beige adipocytes were observed in the periphery of fat grafts. Compared with control group, quercetin group had a higher weight retention rate, a higher gene/protein expression of SIRT1, HSP60, UCP1, PPAR-γ and VEGF-A, and a higher occurrence of peripheral adipose browning. Peripherally located adipose browning occurred after white fat transfer. It can be enhanced by the addition of quercetin through promoting mitochondrial function of fat cells, and may be one of the mechanisms that quercetin improves fat graft survival. This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

The Impact of Oxidative Stress on Adipose Tissue Energy Balance.

Overnutrition and sedentary activity reinforce the growing trend of worldwide obesity, insulin resistance, and type 2 diabetes. However, we have limited insight into how food intake generates sophisticated metabolic perturbations associated with obesity. Accumulation of mitochondrial oxidative stress contributes to the metabolic changes in obesity, but the mechanisms and significance are unclear. In white adipose tissue (WAT), mitochondrial oxidative stress, and the generation of reactive oxygen species (ROS) impact the endocrine and metabolic function of fat cells. The central role of mitochondria in nutrient handling suggests pharmacological targeting of pathological oxidative stress likely improves the metabolic profile of obesity. This review will summarize the critical pathogenic mechanisms of obesity-driven oxidative stress in WAT.

Faktori rizika i komorbiditeti koji predisponiraju fibrilaciju atrija

Objective. Atrial fibrillation (AF) is the most common arrhythmia in clinical practice affecting 1-2% of the world population. It is characterized by high-frequency atrial excitation, consequent asynchronous contraction, and irregular ventricular excitation. Risk factors and comorbidities predispose to AF by altering the extracellular matrix, altering the function of fibroblasts and fat cells, ion channels, myocytes, the autonomic nervous system, endothelial and vascular changes. The study aimed to identify risk factors and comorbidities that were statistically significantly associated with the onset of AF. Methods. The study was a cross-sectional study conducted at the Krupa Health Center at Uni in the period from 1 November 2017 to 1 January 2019. Data were collected through medical history, physical examination, electrocardiograms, laboratory diagnostics, ultrasound examination and available medical records. Data processing was performed using standard statistical methods. Results. The study included 145 randomly selected patients, 96 (66.2%) women and 49 (33.8%) men., average age 63 ± 9.8 years. AF was more common in women older than 60 years and people consuming alcohol (p<0.05). Comorbidities associated with FA are: left ventricular hypertrophy, mitral regurgitation, hypertension, diabetes, chronic obstructive pulmonary disease, and obesity (p<0.05). Conclusion. Early detection, timely and adequate management of comorbidity and risk factors of FA prevents or slows the progression of AF, raises the quality of life of patients, reduces the costs of health care and work absenteeism.

Rosiglitazone-induced changes in the oxidative stress metabolism and fatty acid composition in relation with trace element status in the primary adipocytes.

BackgroundMetabolic syndrome, obesity and type 2 diabetes are metabolic disorders characterized by the insulin resistance and the impairment in the insulin secretion. Since impairment in the oxidative stress and adipocyte metabolism contribute to the formation of obesity and diabetes, targeting adipose tissue can be considered as an effective approach to fight against them. Rosiglitazone is used for treatment for patients with type 2 diabetes via inducing lipogenesis and transdifferentiation of white adipose tissue into brown adipose tissue. Since the development of such therapeutics is required to control the formation and function of brown fat cells, we aimed to reveal possible molecular mechanisms behind rosiglitazone induced biochemical changes in the adipose tissue.MethodsCells were expanded in the adipocyte culture medium supplemented with 5 µg/mL insulin following 2 days' induction. After those cells were treated with rosiglitazone 0, 0.13 mol/L and 10 µmol/L rosiglitazone for 48 hours and at 8th day, cells were collected and stored at -80 °C. Then the cells were used to evaluate antioxidant enzyme activities, mineral and trace element levels and fatty acid composition.ResultsGlucose-6-phosphate dehydrogenase and glutathione reductase significantly reduced in rosiglitazone-treated groups compared to the control. Na, Mg, K, Ca, Cr, Fe, Ni, Cu, Zn, Rb, Sr, Cs, Ba and Pb were determined in the cell lysates via ICP-MS. Also, relative FAME content decreased in the rosiglitazone-treated groups compared to the control.ConclusionsRosiglitazone treatment at low doses showed promising results which may promote brown adipose tissue formation.

Metabolic adaptation and maladaptation in adipose tissue.

Adipose tissue possesses the remarkable capacity to control its size and function in response to a variety of internal and external cues, such as nutritional status and temperature. The regulatory circuits of fuel storage and oxidation in white adipocytes and thermogenic adipocytes (brown and beige adipocytes) play a central role in systemic energy homeostasis, whereas dysregulation of the pathways is closely associated with metabolic disorders and adipose tissue malfunction, including obesity, insulin resistance, chronic inflammation, mitochondrial dysfunction, and fibrosis. Recent studies have uncovered new regulatory elements that control the above parameters and provide new mechanistic opportunities to reprogram fat cell fate and function. In this Review, we provide an overview of the current understanding of adipocyte metabolism in physiology and disease and also discuss possible strategies to alter fuel utilization in fat cells to improve metabolic health.

Obesity-Associated miR-199a/214 Cluster Inhibits Adipose Browning via PRDM16-PGC-1α Transcriptional Network.

miRNAs are important regulators of differentiation, development, and function of brown and beige fat cells. In this study, we identify the role of the miR-199a/214 cluster in the regulation of brown and beige adipocyte development and thermogenesis in vitro and in vivo. We show that expression of the miR-199a/214 cluster is dramatically decreased during brown and beige adipocyte differentiation and in response to cold exposure or β-adrenergic receptor activation. The cluster levels are significantly upregulated in the adipose tissues of obese mice and human subjects. Overexpression of the miR-199a/214 cluster suppresses brown adipocyte differentiation and inhibits thermogenic gene expression and mitochondrial respiration, whereas knockdown of the cluster increases thermogenic gene expression and mitochondrial function in beige adipocytes. In addition, inhibition of the miR-199a/214 cluster promotes beiging effects in vivo. We further show that miR-199a/214 suppresses brown adipocyte differentiation and beige fat development by directly targeting PRDM16 and peroxisome PGC-1α, two key transcriptional regulators of adipose browning. Together, these observations reveal that the miR-199a/214 cluster is a key negative regulator of brown and beige fat development and thermogenesis.

Exercise training decreases pancreatic fat content and improves beta cell function regardless of baseline glucose tolerance: a randomised controlled trial

Aims/hypothesisPancreatic fat accumulation may contribute to the development of beta cell dysfunction. Exercise training improves whole-body insulin sensitivity, but its effects on pancreatic fat content and beta cell dysfunction are unclear. The aim of this parallel-group randomised controlled trial was to evaluate the effects of exercise training on pancreatic fat and beta cell function in healthy and prediabetic or type 2 diabetic participants and to test whether the responses were similar regardless of baseline glucose tolerance.MethodsUsing newspaper announcements, a total of 97 sedentary 40–55-year-old individuals were assessed for eligibility. Prediabetes (impaired fasting glucose and/or impaired glucose tolerance) and type 2 diabetes were defined by ADA criteria. Of the screened candidates, 28 healthy men and 26 prediabetic or type 2 diabetic men and women met the inclusion criteria and were randomised into 2-week-long sprint interval or moderate-intensity continuous training programmes in a 1:1 allocation ratio using random permuted blocks. The primary outcome was pancreatic fat, which was measured by magnetic resonance spectroscopy. As secondary outcomes, beta cell function was studied using variables derived from OGTT, and whole-body insulin sensitivity and pancreatic fatty acid and glucose uptake were measured using positron emission tomography. The measurements were carried out at the Turku PET Centre, Finland. The analyses were based on an intention-to-treat principle. Given the nature of the intervention, blinding was not applicable.ResultsAt baseline, the group of prediabetic or type 2 diabetic men had a higher pancreatic fat content and impaired beta cell function compared with the healthy men, while glucose and fatty acid uptake into the pancreas was similar. Exercise training decreased pancreatic fat similarly in healthy (from 4.4% [3.0%, 6.1%] to 3.6% [2.4%, 5.2%] [mean, 95% CI]) and prediabetic or type 2 diabetic men (from 8.7% [6.0%, 11.9%] to 6.7% [4.4%, 9.6%]; p = 0.036 for time effect) without any changes in pancreatic substrate uptake (p ≥ 0.31 for time effect in both insulin-stimulated glucose and fasting state fatty acid uptake). In prediabetic or type 2 diabetic men and women, both exercise modes similarly improved variables describing beta cell function.Conclusions/interpretationTwo weeks of exercise training improves beta cell function in prediabetic or type 2 diabetic individuals and decreases pancreatic fat regardless of baseline glucose tolerance. This study shows that short-term training efficiently reduces ectopic fat within the pancreas, and exercise training may therefore reduce the risk of type 2 diabetes.Trial registrationClinicalTrials.gov NCT01344928FundingThis study was funded by the Emil Aaltonen Foundation, the European Foundation for the Study of Diabetes, the Finnish Diabetes Foundation, the Orion Research Foundation, the Academy of Finland (grants 251399, 256470, 281440, and 283319), the Ministry of Education of the State of Finland, the Paavo Nurmi Foundation, the Novo Nordisk Foundation, the Finnish Cultural Foundation, the Hospital District of Southwest Finland, the Turku University Foundation, and the Finnish Medical Foundation.

In vivo Effects of Adipose‐Specific Deletion of Jagged 1 in Mice Administered a High Fat Diet

Adipose tissue is a major site of lipid metabolism that works synergistically with other organs to regulate whole body energy homeostasis. Adipose tissue also modulates metabolism by secretion of adipokines such as leptin and adiponectin. Abnormalities in the differentiation and function of mature fat cells (adipocytes) are linked to metabolic disease. The evolutionarily‐conserved Notch signaling pathway is necessary for the differentiation of all cell types including adipocytes. Both inhibition and activation of Notch 1 interfere with adipose remodeling in response to nutritional stress. Although activation of the canonical Notch pathway requires binding to one of its transmembrane ligands such as Jagged‐1, the importance of the ligand itself in regulating adipose development and function has been poorly studied. Furthermore, the ability of the Jagged1 ligand to regulate adipocyte cell fate decisions directly through translocation of its intracellular domain (ICD) into the nucleus is unknown. To address these questions regarding the role of Jagged1 in maintaining metabolically healthy adipose, we generated a novel Cre‐mediated conditional knockout murine strain (ap2‐Jag1tm2Grid) to study the impact that jagged1 gene dosage has on visceral adipose depots under conditions of dietary stress. The ap2‐Jag1tm2Grid line produces progeny with three possible Jagged‐1 genotypes that result in either wild type, haploinsufficient or complete loss of Jagged1 expression in mature adipocytes. Physiological and biochemical measurements conducted on young mice representing all three genotypes after administration of either a high fat (“Western”) or standard diet for 5 weeks support our hypothesis that complete or partial loss of Jagged1 in adipocytes is detrimental to the ability of adipose to remodel and function normally in response to the intake of dietary lipids. Differences among the cohorts regarding weight gain, % visceral fat mass, fasting blood glucose, serum lipids and expression of adipokines leptin and adiponectin support a role for Jagged‐1 in maintaining proper adipose growth and metabolism. Data from this study may lead to a better understanding of how the expression level of Jagged1 influences an individual's susceptibility to obesity and metabolic disease.Support or Funding InformationDeena J. Small, University of New England Department of Chemistry & PhysicsWoon Yuen Koh, University of New England Department of Mathematical SciencesThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The impact of quality and quantity of visceral fat on survival outcome of early-stage breast cancer patients with prior chemotherapy.

584 Background: Obesity not only increases morbidity, but also chemo-resistance of breast cancer (BC). Several studies focusing on body mass index (BMI) of BC patients have been performed; however, a recent report suggested that the quality of visceral adipose tissue (VAT) plays a crucial role in fat cell function. We set out to clarify the effect of quality and quantity of VAT on survival outcome of BC patients who underwent chemotherapy. Methods: From 2,230 patients who underwent treatment for BC at our institution from January 2004 to December 2015, we included 271 patients who received chemotherapy in neo-adjuvant (NAC) or adjuvant setting. Quantification was performed using computed tomography (CT) 3-dimensional volumetric software and quality of VAT was assessed based on the CT Hounsfield Unit of VAT (VAT-HU) using electrically stocked CT images. The correlation between BMI, amount of VAT (aVAT), and VAT-HU were analyzed using Pearson’s correlation test. The effect of these factors on pathologic complete response (pCR) was evaluated using Logistic regression model with the following covariates: menopausal status, size, nodal status, and subtype. Furthermore, survival analysis for distant disease-free survival (DDFS) was performed using Kaplan Meier method and Cox proportional hazard model. Results: aVAT and VAT-HU were significantly correlated with patient BMI (p<0.05). Forty-six patients achieved pCR (24%). Logistic regression model for pCR showed that aVAT and VAT-HU did not affect pCR (p=0.60 and 0.36). After a median follow-up of 112 months, tertile stratification revealed that the third tertile of aVAT had significantly shorter DDFS in the NAC setting (p<0.05). When adjusted by covariates in the Cox proportional regression model, aVAT and VAT-HU demonstrated significant contribution to worse DDFS ([p<0.05, hazard ratio {HR} 1.39; 95% confidence interval {CI} 1.11 to 1.75] and [p<0.05, HR 1.20, 95% CI 1.01 to 1.43], respectively). Conclusions: The quantity and quality of VAT was significantly related to the survival outcome especially in the NAC setting. This new insight would enable prediction of recurrence risk in obese BC patients with prior chemotherapy.

Abstract 72: Subselected Adipocyte Progenitor Niche Cells Show Superior Incorporation and Function in a Mouse Model

PURPOSE: Previous work from our group has reported that human fat elaborates vascular sprouts when placed in angiogenic media. These vascular sprouts constitute a unique niche for specific cells (Adipocyte Progenitor Niche Cells =APNC) which, when then subjected to adipogenic media, differentiate into adipocytes. This study shows that these subselected adipocytes have superior fat cell function when grafted into a mouse host, as assessed by functional and biochemical parameters that report degree of differentiation and vascularization (levels of human adiponectin in mouse serum and human and mouse PLIN1 and CDH5 mRNA levels in graft). METHODS: Fat excised from a human panniculectomy specimen, was embedded to obtain vascular sprouts. APNCs were extracted, plated and at confluence exposed to control vehicle (APNC_control) or adipogenic cocktail (insulin, dexamethosome and IBMX) for three days (APNC_differentated). After 10 days cells were injected subcutaneously into the flanks of NOD mice. The following groups were compared: 1) APNC_differentated, 2) lipoaspirate from the same specimen, 3) APNC_control and 4) ADSCs prepared from the stromovascular fraction. Grafts were assayed for volume by micro-CT, and functional integration by human serum adiponectin. In addition, immunohistochemistry and RT-PCR for both human and mouse cadherin5 (CDH5, endothelium) and perilipin 1 (PLIN1, adipose) were performed on grafts, and compared to human and mouse adipose tissue samples. RESULTS: Grafts formed from APNC_differentiated produced higher levels of adiponectin per unit volume compared to grafts formed from liposuctioned tissue. Grafts formed from APNC_differentiated were vascularized by host vessels to the same extent as endogenous mouse fat, and contained the same levels of perilipin as human fat. APNC_control, but not ADSCs were able to differentiate in-vivo to a lesser degree, as assessed by detection of human adiponectin in mouse serum. CONCLUSIONS: APNCs may represent more elegant way to retrieve the balanced niche of cells needed for adipocyte tissue engineering. In this pilot work, we show that APNCs produce a superior graft in terms of host incorporation and adipocyte function. Although processing time is an issue, if these cells prove to be more effective than other cells extracted from fat tissue, then they could be used to improve fat graft survival and/or deliver tissue regenerative stimuli in altered wound states. Further work will look to compare APNC_differentiated and APNC_control to the function of SVF and ADSC isolates (important control groups which are already used to ‘supercharge fat grafts) after they have been differentiated through the same media exchanges as APNC_differentiated.

Cold Water Swimming Beneficially Modulates Insulin Sensitivity in Middle-Aged Individuals.

We determined whether cold water swimming for six consecutive months results in adaptive changes in body composition and insulin sensitivity. Thirty healthy subjects aged 50.2 ± 9.4 years were exposed to cold water at least twice a week. Body composition was determined and serum glucose and insulin served to calculate beta-cell function, insulin sensitivity, and resistance using HOMA2. Compared with control subjects, swimmers were overweight, and had greater percent body fat and beta cell function. Women had lower values of BMI, fat free mass, muscle mass, visceral adipose tissue level, and greater percent body fat than men. Increased insulin sensitivity and decreased insulin secretion and resistance from beginning to middle of swim season was observed in females and in lean subjects. Findings suggest that men and women differ in regard to body composition and response to repeated cold exposure. Cold water swimming may beneficially modulate insulin sensitivity in cold acclimated lean swimmers.

The epigenetic signature of subcutaneous fat cells is linked to altered expression of genes implicated in lipid metabolism in obese women.

BackgroundObesity is associated with changes in fat cell gene expression and metabolism. What drives these changes is not well understood. We aimed to explore fat cell epigenetics, i.e., DNA methylation, as one mediator of gene regulation, in obese women. The global DNA methylome for abdominal subcutaneous fat cells was compared between 15 obese case (BMI 41.4 ± 4.4 kg/m2, mean ± SD) and 14 never-obese control women (BMI 25.2 ± 2.5 kg/m2). Global array-based transcriptome analysis was analyzed for subcutaneous white adipose tissue (WAT) from 11 obese and 9 never-obese women. Limma was used for statistical analysis.ResultsWe identified 5529 differentially methylated DNA sites (DMS) for 2223 differentially expressed genes between obese cases and never-obese controls (false discovery rate <5 %). The 5529 DMS displayed a median difference in beta value of 0.09 (range 0.01 to 0.40) between groups. DMS were under-represented in CpG islands and in promoter regions, and over-represented in open sea-regions and gene bodies. The 2223 differentially expressed genes with DMS were over-represented in key fat cell pathways: 31 of 130 (25 %) genes linked to “adipogenesis” (adjusted P = 1.66 × 10−11), 31 of 163 (19 %) genes linked to “insulin signaling” (adjusted P = 1.91 × 10−9), and 18 of 67 (27 %) of genes linked to “lipolysis” (P = 6.1 × 10−5). In most cases, gene expression and DMS displayed reciprocal changes in obese women. Furthermore, among 99 candidate genes in genetic loci associated with body fat distribution in genome-wide association studies (GWAS); 22 genes displayed differential expression accompanied by DMS in obese versus never-obese women (P = 0.0002), supporting the notion that a significant proportion of gene loci linked to fat distribution are epigenetically regulated.ConclusionsSubcutaneous WAT from obese women is characterized by congruent changes in DNA methylation and expression of genes linked to generation, distribution, and metabolic function of fat cells. These alterations may contribute to obesity-associated metabolic disturbances such as insulin resistance in women.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0126-9) contains supplementary material, which is available to authorized users.

The current development of heme oxygenase-1 and its correlation with macrophage infiltration in adipose tissue of obese individuals

Obesity is mostly recognized as a chronic inflammatory condition in which the balance of normal state is destroyed and it is a risk of cardiovascular disease and many other chronic metabolic disease.Heme oxygenase-1(HO-1), a major cytoprotective enzyme, exerts significant antioxidant and anti-inflammatory effects.It also can improve the function of fat cells and enhanced insulin sensitivity in obese individuals.The researches of HO-1 for the anti-inflammatory effects and its intervention have great significance in improving the inflammatory state and its related diseases in obesity.This paper elaborates the change of HO-1 and its effect for macrophage infiltration in obesity. Key words: Obesity; Heme oxygenase-1; Inflammation; Macrophage infiltration

Tangeritin inhibits adipogenesis by down-regulating C/EBPα, C/EBPβ, and PPARγ expression in 3T3-L1 fat cells.

The treatment of obese patients is a topic investigated by an increasing number of researchers. This study aimed to elucidate the possible inhibitory effect of tangeritin on the development and function of fat cells. 3T3-L1 fat cells were grown to confluence and subjected to different concentrations of tangeritin. The most effective tangeritin inhibition concentration was determined by the MTT assay. The treated cells were subjected to real-time reverse transcriptase PCR and western blot analysis, to detect changes in the CCAAT/enhancer binding protein (C/EBP)α, C/EBPβ, and peroxisome proliferator activated receptor (PPAR)γ expression levels. The MTT assay revealed that the fat cell growth was inhibited at a 20 ng/mL concentration of tangeritin. The results of real-time PCR revealed a significant decrease in the expression of C/EBPα, C/EBPβ, and PPARγ mRNA, following the treatment with tangeritin. Western blot analysis also presented similar results at a protein level. Therefore, we concluded that tangeritin inhibits adipogenesis via the down-regulation of C/EBPα, C/EBPβ, and PPARγ mRNA and protein expression in 3T3-L1 cells.

Caveolin-1 expression and cavin stability regulate caveolae dynamics in adipocyte lipid store fluctuation.

Adipocytes specialized in the storage of energy as fat are among the most caveolae-enriched cell types. Loss of caveolae produces lipodystrophic diabetes in humans, which cannot be reversed by endothelial rescue of caveolin expression in mice, indicating major importance of adipocyte caveolae. However, how caveolae participate in fat cell functions is poorly understood. We investigated dynamic conditions of lipid store fluctuations and demonstrate reciprocal regulation of caveolae density and fat cell lipid droplet storage. We identified caveolin-1 expression as a crucial step in adipose cell lines and in mice to raise the density of caveolae, to increase adipocyte ability to accommodate larger lipid droplets, and to promote cell expansion by increased glucose utilization. In human subjects enrolled in a trial of 8 weeks of overfeeding to promote fattening, adipocyte expansion response correlated with initial caveolin-1 expression. Conversely, lipid mobilization in cultured adipocytes to induce lipid droplet shrinkage led to biphasic response of cavin-1 with ultimate loss of expression of cavin-1 and -3 and EHD2 by protein degradation, coincident with caveolae disassembly. We have identified the key steps in cavin/caveolin interplay regulating adipocyte caveolae dynamics. Our data establish that caveolae participate in a unique cell response connected to lipid store fluctuation, suggesting lipid-induced mechanotension in adipocytes.

Artemisia scoparia enhances adipocyte development and endocrine function in vitro and enhances insulin action in vivo.

BackgroundFailure of adipocytes to expand during periods of energy excess can result in undesirable metabolic consequences such as ectopic fat accumulation and insulin resistance. Blinded screening studies have indicated that Artemisia scoparia (SCO) extracts can enhance adipocyte differentiation and lipid accumulation in cultured adipocytes. The present study tested the hypothesis that SCO treatment modulates fat cell development and function in vitro and insulin sensitivity in adipose tissue in vivo.Methods In vitro experiments utilized a Gal4-PPARγ ligand binding domain (LBD) fusion protein-luciferase reporter assay to examine PPARγ activation. To investigate the ability of SCO to modulate adipogenesis and mature fat cell function in 3T3-L1 cells, neutral lipid accumulation, gene expression, and protein secretion were measured by Oil Red O staining, qRT-PCR, and immunoblotting, respectively. For the in vivo experiments, diet-induced obese (DIO) C57BL/6J mice were fed a high-fat diet (HFD) or HFD containing 1% w/w SCO for four weeks. Body weight and composition, food intake, and fasting glucose and insulin levels were measured. Phospho-activation and expression of insulin-sensitizing proteins in epididymal adipose tissue (eWAT) were measured by immunoblotting.ResultsEthanolic extracts of A. scoparia significantly activated the PPARγ LBD and enhanced lipid accumulation in differentiating 3T3-L1 cells. SCO increased the transcription of several PPARγ target genes in differentiating 3T3-L1 cells and rescued the negative effects of tumor necrosis factor α on production and secretion of adiponectin and monocyte chemoattractant protein-1 in fully differentiated fat cells. DIO mice treated with SCO had elevated adiponectin levels and increased phosphorylation of AMPKα in eWAT when compared to control mice. In SCO-treated mice, these changes were also associated with decreased fasting insulin and glucose levels.ConclusionSCO has metabolically beneficial effects on adipocytes in vitro and adipose tissue in vivo, highlighting its potential as a metabolically favorable botanical supplement.

Artemisia scoparia enhances adipocyte development and endocrine function in vitro and enhances insulin action in vivo (LB771)

Background: Failure of adipocytes to expand during periods of energy excess can result in undesirable metabolic consequences. Blinded screening studies have indicated that Artemisia scoparia (SCO) extracts can enhance adipocyte differentiation and lipid accumulation in cultured adipocytes. The present study tested the hypothesis that SCO treatment modulates fat cell development and function in vitro and insulin sensitivity in adipose tissue in vivo.Methods: In vitro experiments utilized a Gal4‐PPAR[[Unsupported Character ‐ Symbol Font □]] ligand binding domain (LBD) fusion protein‐luciferase reporter assay to examine PPAR[[Unsupported Character ‐ Symbol Font □]] activation. Neutral lipid accumulation, gene expression, and protein secretion were measured by Oil Red O staining, qRT‐PCR, and immunoblotting, respectively. For the in vivo experiments, diet‐induced obese (DIO) C57BL/6J mice were fed a high‐fat diet (HFD) or HFD containing 1% w/w SCO for four weeks. Body weight and composition, food intake, and fasting glucose and insulin levels were measured. Phospho‐activation and expression of insulin‐sensitizing proteins in epididymal adipose tissue (eWAT) were measured by immunoblotting.Results: Ethanolic extracts of A. scoparia significantly activated the PPAR[[Unsupported Character ‐ Symbol Font □]] LBD and enhanced lipid accumulation in differentiating 3T3‐L1 cells. SCO increased the transcription of several PPAR[[Unsupported Character ‐ Symbol Font □]] target genes in differentiating 3T3‐L1 cells and rescued the negative effects of tumor necrosis factor [[Unsupported Character ‐ Symbol Font □]] on production and secretion of adiponectin and monocyte chemoattractant protein‐1 in fully differentiated fat cells. DIO mice treated with SCO had elevated adiponectin levels and increased phosphorylation of AMPK[[Unsupported Character ‐ Symbol Font □]] in eWAT when compared to control mice. In SCO‐treated mice, these changes were also associated with decreased fasting insulin and glucose levels.Conclusion: SCO has metabolically beneficial effects on adipocytes in vitro and adipose tissue in vivo, highlighting its potential as a metabolically favorable botanical supplement.Grant Funding Source: Supported by NIH 2P30DK072476