Adipose Tissue Of Obese Patients Research Articles

Obesity is associated with a decrease in expression but not with the hypermethylation of thermogenesis-related genes in adipose tissues.

BackgroundImpaired thermogenesis can promote obesity. Therefore, the aim of this study was to investigate whether the expression of thermogenesis-related genes is altered in adipose tissues of obese individuals and whether excessive methylation of their promoters is involved in this phenomenon.MethodsThe expression of genes encoding β adrenergic receptors (ADRBs), thyroid hormone receptors (THRs), 5’-iodothyronine deiodinases (DIOs), and uncoupling proteins (UCPs) was measured by real-time PCR in visceral and in subcutaneous adipose tissues of 58 obese (BMI >40 kg/m2) and 50 slim (BMI 20-24.9 kg/m2) individuals. The methylation status of these genes was studied by the methylation-sensitive digestion/real-time PCR method.ResultsThe expression of ADRB2, ADRB3, THRA, THRB, DIO2, UCP2 was significantly lower in the adipose tissues of obese patients than in tissues of normal-weight individuals (P < 0.00001). In the obese, the expression of ADRB2, ADRB3, DIO2 was lower in visceral adipose tissue than in subcutaneous adipose tissue (P = 0.008, P = 0.002, P = 0.001, respectively). However, the mean methylation of CpG islands of these genes was similar in tissues with their high and low expression, and there was no correlation between the level of expression and the level of methylation.ConclusionsDecreased expression of thermogenesis-related genes in adipose tissues of obese patients might result in the reduced reactivity to both hormonal and adrenergic stimuli and therefore in a lower potential to activate thermogenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0395-2) contains supplementary material, which is available to authorized users.

CTSK inhibitor exert its anti-obesity effects through regulating adipocyte differentiation in high-fat diet induced obese mice.

Obesity is associated with increased risk of developing numerous adverse health conditions. Cathepsin k (CTSK) is highly expressed in adipose tissues of obese patients and animal models. Although CTSK has been demonstrated to promote adipocyte differentiation in 3T3-L1 cells, the effects of CTSK selective inhibitor (CKSI) on weight gain and insulin resistance have not been well examined. High-fat diet (HFD) induced obese male C57BL/6 mice were fed a diet with or without CKSI for 8 weeks. The HFD induced increase in adipose tissue weight gain, increase in homeostasis model assessment (HOMA) index as well as accumulation of large adipocytes. After CKSI treatment, all these effects were blunted compared with the HFD control group. A study of the mechanism demonstrated a role for CKSI in significantly down-regulating the expression of two key transcription factors, peroxisome proliferators-activated receptor-γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), which are markers of adipogenic differentiation. These results indicated that the CKSI possesses an anti-obesity effect, possibly involving the inhibition of adipocyte differentiation. CTSK is likely to be a new target of therapeutic intervention for the treatment of obesity.

Increased dihydroceramide/ceramide ratio mediated by defective expression of degs1 impairs adipocyte differentiation and function.

Adipose tissue dysfunction is an important determinant of obesity-associated, lipid-induced metabolic complications. Ceramides are well-known mediators of lipid-induced insulin resistance in peripheral organs such as muscle. DEGS1 is the desaturase catalyzing the last step in the main ceramide biosynthetic pathway. Functional suppression of DEGS1 activity results in substantial changes in ceramide species likely to affect fundamental biological functions such as oxidative stress, cell survival, and proliferation. Here, we show that degs1 expression is specifically decreased in the adipose tissue of obese patients and murine models of genetic and nutritional obesity. Moreover, loss-of-function experiments using pharmacological or genetic ablation of DEGS1 in preadipocytes prevented adipogenesis and decreased lipid accumulation. This was associated with elevated oxidative stress, cellular death, and blockage of the cell cycle. These effects were coupled with increased dihydroceramide content. Finally, we validated in vivo that pharmacological inhibition of DEGS1 impairs adipocyte differentiation. These data identify DEGS1 as a new potential target to restore adipose tissue function and prevent obesity-associated metabolic disturbances.

Reduction of Specific Circulating Lymphocyte Populations with Metabolic Risk Factors in Patients at Risk to Develop Type 2 Diabetes

Low-grade inflammation, characterized by increased pro-inflammatory cytokine levels, is present in patients with obesity-linked insulin resistance, hyperglycemia and hyperlipidemia and considered to play a leading role to progression into type 2 diabetes (T2D). In adipose tissue in obese patients and in pancreatic islets in T2D patients cellular inflammation is present. However, the systemic leukocyte compartment and the circulating endothelial/precursor compartment in patients at risk to develop T2D has so far not been analyzed in detail. To address this, peripheral blood cells from a cohort of 20 subjects at risk to develop diabetes with normal to impaired glucose tolerance were analyzed by flow cytometry using a wide range of cellular markers and correlated to known metabolic risk factors for T2D i.e. fasting plasma glucose (FPG), 2 h plasma glucose (2 h PG), HbA1c, body mass index (BMI), homeostasis model assessment of β-cell function (HOMA-B), homeostasis model assessment of insulin sensitivity (HOMA-IS) and fasting insulin (FI). The four highest ranked cell markers for each risk factor were identified by random forest analysis. In the cohort, a significant negative correlation between the number of TLR4+ CD4 T cells and increased FPG was demonstrated. Similarly, with increased BMI the frequency of TLR4+ B cells was significantly decreased, as was the frequency of IL-21R+ CD4 T cells. Unlinked to metabolic risk factors, the frequency of regulatory T cells was reduced and TLR4+ CD4 T cells were increased with age. Taken together, in this small cohort of subjects at risk to develop T2D, a modulation of the circulating immune cell pool was demonstrated to correlate with risk factors like FPG and BMI. This may provide novel insights into the inflammatory mechanisms involved in the progression to diabetes in subjects at risk.

Discriminatory metabolic and inflammatory parameters in serum and omental adipose tissue of obese patients with different insulin sensitivity

ObjectiveMetabolically healthy obese phenotype is defined by high insulin sensitivity and lack of metabolic syndrome, parameters regulated by omental adipose tissue inflammation, ectopic fat deposition and adipose tissue dysfunction. Our study aimed to identify novel metabolic and inflammatory markers in serum and omental adipose tissue which characterize the “unhealthy” obese patients and distinguish them from obese patients with better metabolic profile. DesignCross-sectional study. PatientsSubjects included 75 obese patients undergoing bariatric surgery at the Tel-Aviv Medical Center (mean age 43.9 ± 13.9, mean BMI 41 ± 8.4). The HOMA median value was used as a cut-off to differentiate between patients with better or worse insulin resistance. MeasurementsDemographic data, fasting serum insulin, glucose, bile acids, serum metabolic and inflammatory markers were obtained. During the bariatric surgery, omental adipose tissue was harvested and analyzed for metabolic and inflammatory markers using qRT-PCR. Logistic regressions were used to calculate odds ratio and 95% confidence interval for the prediction of the metabolic profile. ResultsSerum markers that were significantly higher among the obese with HOMA >6 were total bile acids. In the omental adipose tissue the inflammatory markers TNFα and ADAM17 were significantly higher among obese patients with HOMA >6. In multivariate analysis, the strongest predictor for insulin resistance was ADAM17 (OR = 1.82, 1.06–3.14, P = 0.031). ConclusionsThe study highlighted the predictive value of serum bile acids in identifying obese patients at high risk. Secondly, omental adipose tissue ADAM17 was revealed as a novel and strongest independent predictor for higher insulin resistance in morbidly obese patients.

Decreased expression of genes encoding thermogenesis-related proteins in adipose tissues of obese patients is not associated with their methylation status

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Adaptive Expression of MicroRNA-125a in Adipose Tissue in Response to Obesity in Mice and Men

MicroRNAs are emerging as new mediators in the regulation of adipose tissue biology and the development of obesity. An important role of microRNA-125a has been suggested in the pathogenesis of insulin resistance (IR). Here, we characterized the function of microRNA-125a in adipose tissue in a context of experimentally-induced IR and obesity in mice and in obese patients. We showed time dependent overexpression of the microRNA in adipose tissue of BALB/c and C57BL/6J mice in response to high fat diet (HFD) feeding. MicroRNA-125a expression was downregulated in vitro in insulin resistant 3T3-L1 adipocytes and ex vivo in adipose tissue of obese patients. In vitro modulation of microRNA-125a expression in 3T3-L1 adipocytes did not affect glucose uptake. Gene set enrichment analysis (GSEA) identified significantly altered expression patterns of predicted microRNA-125a gene targets in transcriptomic datasets of adipose tissue from HFD-fed mice and obese patients. Among genes that contributed to global enrichment of altered expression of microRNA-125a targets, Thyrotroph embryonic factor (Tef), Mannan-binding lectin serine peptidase 1, Reticulon 2 and Ubiquitin-conjugating enzyme E2L3 were significantly differentially expressed in adipose tissue in these groups. We showed that Tef expression is reduced in adipose tissue of obese patients following gastric bypass surgery. Our findings indicate that microRNA-125a expression in adipose tissue adapts to IR and may play a role in the development of obesity in mice and obese subjects through uncoupled regulation of the expression of microRNA-125a and its targets.

STEAP4 and insulin resistance

Obesity is a multifactorial disease that caused by the interactions between genetic susceptibility genes and environmental cues. Obesity is considered as a major risk factor of insulin resistance. STEAP4 is a novel anti-obesity gene that is significantly down-regulated in adipose tissue of obese patients. Over-expression of STEAP4 can improve glucose uptake and mitochondrial function, and increase insulin sensitivity. STEAP4 expression is regulated by a variety of inflammatory cytokines, hormones, or adipokines. In this review, we discuss function of STEAP4 in regulating insulin resistance in adipose tissue in vivo, as well as in adipocytes in vitro.

Expression of Obesity Markers and Persistent Organic Pollutants Levels in Adipose Tissue of Obese Patients: Reinforcing the Obesogen Hypothesis?

IntroductionPersistent Organic Pollutants (POPs) accumulate in adipose tissue and some are described to possess endocrine disrupting capacities. Therefore, it is important to evaluate their effects on key endocrine pathways in adipose tissue (AT), to further evaluate their potential role in metabolic pathologies such as obesity.ObjectivesThe aim is twofold: (i) evaluate gene expression levels of obesity marker genes, i.e. the adipokines leptin (LEP), adiponectin (ADIPOQ) and Tumor Necrosis Factor α (TNFα) and the nuclear receptor, Peroxisome Proliferator Activated Receptor γ (PPARγ) in paired subcutaneous (SAT) and visceral (VAT) AT of obese subjects (n = 50) and to relate these values to serum concentrations of LEP and ADIPOQ (ii) evaluate the association of expression levels of marker genes in AT and serum with POP concentrations in AT.Results and ConclusionsLeptin and adiponectin levels in serum were positively correlated to respectively expression levels of leptin in SAT and adiponectin in VAT. Our study shows more significant correlations between gene expression of obesity marker genes and POP concentrations in VAT compared to SAT. Since VAT is more important than SAT in pathologies associated with obesity, this suggests that POPs are able to influence the association between obesity and the development of associated pathologies. Moreover, this finding reveals the importance of VAT when investigating the obesogen hypothesis. Concerning PPARγ expression in VAT, negative correlations with polychlorinated biphenyls (PCBs) concentrations were found in non T2D patients. LEP serum concentrations correlated with several PCBs in women whereas in men no correlations were found. This strengthens the potential importance of gender differences in obesity and within the obesogen hypothesis.

Stem cells isolated from adipose tissue of obese patients show changes in their transcriptomic profile that indicate loss in stemcellness and increased commitment to an adipocyte-like phenotype

BackgroundThe adipose tissue is an endocrine regulator and a risk factor for atherosclerosis and cardiovascular disease when by excessive accumulation induces obesity. Although the adipose tissue is also a reservoir for stem cells (ASC) their function and “stemcellness” has been questioned. Our aim was to investigate the mechanisms by which obesity affects subcutaneous white adipose tissue (WAT) stem cells.ResultsTranscriptomics, in silico analysis, real-time polymerase chain reaction (PCR) and western blots were performed on isolated stem cells from subcutaneous abdominal WAT of morbidly obese patients (ASCmo) and of non-obese individuals (ASCn). ASCmo and ASCn gene expression clustered separately from each other. ASCmo showed downregulation of “stemness” genes and upregulation of adipogenic and inflammatory genes with respect to ASCn. Moreover, the application of bioinformatics and Ingenuity Pathway Analysis (IPA) showed that the transcription factor Smad3 was tentatively affected in obese ASCmo. Validation of this target confirmed a significantly reduced Smad3 nuclear translocation in the isolated ASCmo.ConclusionsThe transcriptomic profile of the stem cells reservoir in obese subcutaneous WAT is highly modified with significant changes in genes regulating stemcellness, lineage commitment and inflammation. In addition to body mass index, cardiovascular risk factor clustering further affect the ASC transcriptomic profile inducing loss of multipotency and, hence, capacity for tissue repair. In summary, the stem cells in the subcutaneous WAT niche of obese patients are already committed to adipocyte differentiation and show an upregulated inflammatory gene expression associated to their loss of stemcellness.

Proteomic analysis of mature adipo cytes from obese patients in relation to aging

Obesity and aging are interrelated conditions that both cause changes in adipocyte metabolism and affect the distribution of fat in both subcutaneous and visceral depots. In addition, both weight gain and aging can lead to similar clinical outcomes such as insulin resistance, cardiovascular disease, type 2 diabetes mellitus, atherosclerosis and stroke. Our objective was to examine the changes in protein expression within the subcutaneous adipose tissue of obese patients, matched for BMI, in relation to age. Mature adipocytes were isolated from liposuction samples of abdominal subcutaneous adipose tissue collected from both young (26.2±4.3 (mean age±SD); n=7) and old (52.2±4.7 (mean age±SD); n=7) obese individuals. Total protein extracts were then compared by two-dimensional difference in gel electrophoresis (2D DIGE). Thirty differentially expressed protein spots (ANOVA test, p≤0.05; fold-change ≥1.8) were detected, of which, 15 were identified by MALDI-TOF mass spectrometry. These were comprised of a total of thirteen unique protein sequences. Nine proteins were more abundant in the adipocytes isolated from old vs. young individuals. These proteins included prohibitin 1, protein disulphide isomerase A3, beta actin, profilin, aldo-ketoreductase 1 C2, alpha crystallin B and the annexins A1, A5 and A6. Four other proteins were less abundant in the adipocytes from old, obese subjects and these included keratin type 2 cytoskeletal 1, keratin type 2 cytoskeletal 10 and hemoglobins A and B. The differentially abundant proteins were investigated by Ingenuity Pathway Analysis (IPA) to reveal their associations with known biological functions. This analysis identified signal transducer and activator of transcription 3 as the central molecule in the connectivity map and the apoptotic pathway as the pathway with the highest score. Differences in the abundances of several proteins were confirmed by immunoblotting: i.e., prohibitin 1, protein disulphide isomerase A3, beta actin, profilin and signal transducer and activator of transcription 3 proteins. In conclusion, proteomic analysis of subcutaneous adipose tissue reveals differences in the abundance of proteins in adipocytes isolated from young vs. old individuals. These differentially abundant proteins are involved in the regulation of apoptosis, cellular senescence and inflammatory response. All these are common pathologic events in both obesity and aging.

Modulation of Double‐Stranded RNA‐Activated Protein Kinase in Insulin Sensitive Tissues of Obese Humans

The double-stranded RNA-dependent protein kinase (PKR) was recently implicated in regulating molecular integration of nutrient- and pathogen-sensing pathways in obese mice. However, its modulation in human tissues in situations of insulin resistance has not been investigated. The present study was performed to first determine the tissue expression and phosphorylation levels of PKR in the liver, muscle, and adipose tissue in obese humans, and also the modulation of this protein in the adipose tissue of obese patients after bariatric surgery. Eleven obese subjects who were scheduled to undergo Roux-en-Y Gastric Bypass Procedure participated in this study. Nine apparently healthy lean subjects as a control group were also included. Our data show that PKR is activated in liver, muscle, and adipose tissue of obese humans and, after bariatric surgery, there is a clear reduction in PKR activation accompanied by a decrease in protein kinase-like endoplasmic reticulum kinase, c-Jun N-terminal kinase, inhibitor of kappa β kinase, and insulin receptor substrate-1 serine 312 phosphorylation in subcutaneous adipose tissue from these patients. Thus, it is proposed that PKR is an important mediator of obesity-induced insulin resistance and a potential target for the therapy.

Molecular signature of adipose tissue in patients with both Non-Alcoholic Fatty Liver Disease (NAFLD) and Polycystic Ovarian Syndrome (PCOS)

BackgroundPolycystic ovarian syndrome (PCOS) is one of the most common reproductive disorders with strong association with both insulin resistance and non-alcoholic fatty liver disease (NAFLD). To untangle the complex relationship between PCOS and NAFLD, we analyzed serum biomarkers of apoptosis, some adipokines and mRNA profiles in the visceral adipose tissue of obese patients with NAFLD who were also diagnosed with PCOS and compared to a group with NAFLD only.MethodsWe included patients with biopsy-proven NAFLD and PCOS (N = 12) and BMI-matched biopsy-proven NAFLD patients without PCOS (N = 12). Expression levels of individual mRNAs and soluble serum biomarkers were compared by non-parametric Mann–Whitney test. The analysis also included Spearman rank correlation tests and multiple regression analysis. For co-correlated genes, the factor analysis was performed.ResultsThe total serum levels of apoptotic biomarker M30 were significantly elevated in PCOS patients with liver steatosis as compared to non-PCOS NAFLD controls (P < 0.02), pointing that androgen-dependent proapoptotic PCOS environment that may directly contribute to NAFLD progression in these patients. Similarly, hyperandrogenism may explain the observed PCOS-specific decrease (P < 0.04) in adipose LDLR mRNA expression that may be connected to the proneness of PCOS patients to NAFLD. The levels of mRNA encoding angiogenesis-associated GSK-3B interacting protein ninein were also significantly increased in the adipose tissue of NAFLD patients with PCOS (P < 0.007). Furthermore, the levels of resistin positively correlated with expression levels of LDLR and prothrombin time (PT).ConclusionAn androgen-dependent proapoptotic PCOS environment may directly contribute to NAFLD progression in these patients. Hyperandrogenism may explain an observed decrease in adipose LDLR mRNA expression. An inflammation-associated increase in the release of resistin into circulation might contribute to the prothrombotic state observed under conditions associated with insulin resistance, including PCOS. The studies of larger cohorts of NAFLD with and without PCOS patients are needed to further assess these potential interactions.

DPP4 shedding from human adipocytes and smooth muscle cells is mediated by metalloproteinases but not altered by inflammatory stimuli

Introduction: DPP4 has recently been identified as a novel adipokine by comprehensive proteomic profiling of the adipocyte-secretome by our group. This protease is upregulated in visceral adipose tissue of obese patients and circulating DPP4 correlates with the metabolic syndrome. The release of DPP4 is increasing during the adipocyte differentiation in vitro. DPP4 enhances the proliferation of human smooth muscle cells (hSMC) and is therefore interesting in the context of atheriosclerosis. Our aim was to understand how DPP4 release is regulated and which factors are responsible for the shedding of DPP4 from the cell membrane.

Recent progress on the role of ChREBP in glucose and lipid metabolism [Review

Carbohydrate response element binding protein (ChREBP) is a transcription factor activated by glucose that is highly expressed in liver, pancreatic β-cells, brown and white adipose tissues, and muscle. We reported that hepatic suppression of the Chrebp gene improves hepatic steatosis, glucose intolerance, and obesity in genetically obese mice. Moreover, we have studied the role of ChREBP with special reference to feedforward and feedback looping in liver and pancreatic β-cells. Recently, several groups reported that (1) glucose activates ChREBP-α transactivity and in turn ChREBP-α induces ChREBP-β on both transcriptional and translational levels in adipose tissues, and (2) ChREBP regulates glucose transporter type 4 mRNA levels, which may affect glucose uptake in adipose tissues. Moreover, in adipose tissues of obese patients, Chrebpb mRNA levels were much lower than those in lean subjects, while the levels were much higher in liver of obese patients than those in lean subjects. These findings suggest that Chrebpb mRNA levels are different in various tissues and probably in the stages of diabetes mellitus. Herein, we review recent progress in the study of ChREBP with special references to (1) the mechanisms regulating ChREBP transactivity (posttranslational modifications, intramolecular glucose sensing module, feedforward mechanism, and the feedback loop between ChREBP and its target genes), and (2) the role of ChREBP in liver, pancreatic islets and adipose tissues. Understanding the role of ChREBP in each tissue will provide important insight into the pathogenesis of metabolic syndrome.

The Expression of &amp;lt;i&amp;gt;TIMP&amp;lt;/i&amp;gt;1, &amp;lt;i&amp;gt;TIMP&amp;lt;/i&amp;gt;2, &amp;lt;i&amp;gt;VCAN&amp;lt;/i&amp;gt;, &amp;lt;i&amp;gt;SPARC&amp;lt;/i&amp;gt;, &amp;lt;i&amp;gt;CLEC&amp;lt;/i&amp;gt;3&amp;lt;i&amp;gt;B&amp;lt;/i&amp;gt; and &amp;lt;i&amp;gt;E&amp;lt;/i&amp;gt;2&amp;lt;i&amp;gt;F&amp;lt;/i&amp;gt;1 in Subcutaneous Adipose Tissue of Obese Males and Glucose Intolerance

We investigated the expression of TIMP1, TIMP2, SPARC, VCAN, and CLEC3B genes, encoded matricellular proteins with pleiotropic functions, and glucose intolerance in obese male subjects with normal and impaired glucose tolerance. The purpose of this study was to examine the association between the gene expressions and glucose intolerance in obesity. The results indicate that obesity leads to significant increase of TIMP1, TIMP2, E2F1 and CLEC3B gene expressions in subcutaneous adipose tissue, especially TIMP2 gene. However, more significant increase of the expression of TIMP1 and TIMP2 was found in adipose tissue of obese patients with glucose intolerance. No significant changes were found in the expression of VCAN and SPARC genes in adipose tissue of obese subjects with normal glucose tolerance but increased in the group of obese subjects with glucose intolerance. At the same time, the E2F1 and CLEC3B gene expressions were decreased in adipose tissue of obese patients with glucose intolerance. Results of this study provide evidence that changes in the expression of genes encoded TIMP1, TIMP2, VCAN, SPARC, E2F1 and CLEC3B in subcutaneous adipose tissue of obese individuals associate with glucose intolerance.

Obesity‐Associated Dysregulation of Calpastatin and MMP‐15 in Adipose‐Derived Stromal Cells Results in their Enhanced Invasion

Adipose tissue maintains a subpopulation of cells, referred to as adipose-derived stromal/stem cells (ASCs), which have been associated with increased breast cancer tumorigenesis and metastasis. For ASCs to affect breast cancer cells, it is necessary to delineate how they mobilize and home to cancer cells, which requires mobilization and invasion through extracellular matrix barriers. In this study, ASCs were separated into four different categories based on the donor's obesity status and depot site of origin. ASCs isolated from the subcutaneous abdominal adipose tissue of obese patients (Ob(+)Ab(+)) demonstrated increased invasion through Matrigel as well as a chick chorioallantoic membrane, a type I collagen-rich extracellular matrix barrier. Detailed mRNA and protein analyses revealed that calpain-4, calpastatin, and MMP-15 were associated with increased invasion, and the silencing of each protease or protease inhibitor confirmed their role in ASC invasion. Thus, the data indicate that both the donor's obesity status and depot site of origin distinguishes the properties of subcutaneous-derived ASCs with respect to enhanced invasion and this is associated with the dysregulation of calpain-4, calpastatin, and MMP-15.

The increase of serum chemerin concentration is mainly associated with the increase of body mass index in obese, non-diabetic subjects.

Chemerin is a newly discovered adipokine, whose circulating concentration is increased in obesity. To elucidate whether the increased circulating chemerin concentrations in obese subjects are associated with the increase of fat mass, the increase in chemerin gene expression in adipose tissue or both. Serum chemerin concentrations in 20 non-obese healthy volunteers and 21 non-diabetic obese subjects were measured using ELISA. Chemerin mRNA and chemerin protein levels in visceral and subcutaneous adipose tissues of obese subjects were analyzed by Real-Time PCR and Western blot respectively. We found that the serum chemerin concentrations were significantly higher in obese subjects than in controls and positively correlated with BMI, fat mass and body mass. Moreover serum chemerin concentrations were correlated positively with serum CRP concentrations independently of BMI. No correlation was found between the chemerin mRNA and chemerin protein levels in visceral and subcutaneous adipose tissues and BMI, fat mass, or body weight. Likewise, there was no correlation between the serum chemerin concentrations and the levels of chemerin mRNA and protein in adipose tissue of obese patients. Multiple regression analysis suggests that BMI was the main predictor of serum chemerin concentration. In contrast to chemerin, both serum leptin concentrations and adipose tissue leptin mRNA levels positively correlated with BMI. The results presented here indicate that serum chemerin concentrations correlated with BMI, whereas chemerin mRNA levels in adipose tissue did not. Thus the elevated circulating chemerin concentration in obese, non-diabetic patients was mainly associated with the increased BMI.

Functional relevance of genes implicated by obesity genome-wide association study signals for human adipocyte biology

Genome-wide association studies (GWAS) have identified numerous single-nucleotide polymorphisms associated with obesity, consequently implying a role in adipocyte biology for many closely residing genes. We investigated the functional relevance of such genes in human adipocytes. We selected eight genes (BDNF, MAF, MTCH2, NEGR1, NPC1, PTER, SH2B1 and TMEM18) from obesity GWAS and analysed their effect in human adipogenesis using small interfering (si)RNA-mediated knockdown, their regulation by metabolic agents in adipocytes and pre-adipocytes, and gene expression in paired samples of human fat biopsies (68 non-obese, 165 obese) by quantitative real-time PCR. We show a two- to threefold upregulation of MAF, MTCH2 and NEGR1 and a two- to fourfold downregulation of BDNF and PTER during adipogenesis. Knockdown of BDNF (mean ± SEM; 83.8 ± 4.7% of control; p = 0.0002), MTCH2 (72.7 ± 9.5%; p = 0.0006), NEGR1 (70.2 ± 5.7%; p < 0.0001) and TMEM18 (70.8 ± 6.1%; p < 0.0001) significantly inhibited adipocyte maturation, while knockdown of the other proteins had no effect. Insulin slightly induced MAF (1.65-fold; p = 0.0009) and MTCH2 (1.72-fold; p < 0.0001), while it suppressed BDNF (59.6%; p = 0.0009), NEGR1 (58.0%; p = 0.0085) and TMEM18 (69.3%; p = 0.0377) in adipocytes. The synthetic glucocorticoid dexamethasone suppressed MAF (45.7%; p = 0.0022), BDNF (66.6%; p = 0.0012) and TMEM18 (63.5%; p = 0.0181), but induced NEGR1 (3.2-fold; p = 0.0117) expression. Furthermore, MTCH2, NEGR1 and TMEM18 were differentially expressed in subcutaneous and visceral adipose tissue. TMEM18 expression was decreased in the adipose tissue of obese patients, and negatively correlated with anthropometric variables and adipocyte size. Our results imply a regulatory role for TMEM18, BDNF, MTCH2 and NEGR1 in adipocyte differentiation and biology. In addition, we show a variation of MAF expression during adipogenesis, while NPC1, PTER and SH2B1 were not regulated.

The relationship between obesity and prostate cancer: from genetics to disease treatment and prevention

Recent studies demonstrated that obesity is associated with prostate cancer aggressiveness and prognosis. However, the mechanisms underlying this relationship are poorly understood. Tumor microenvironment has been increasingly considered as an important determinant of cancer growth and progression. In the light of this growing evidence, Ribeiro et al., in a BMC Medicine research article, investigated the gene expression profiles of periprostatic adipose tissue of obese patients with and without prostate cancer and compared them to those of lean patients. Their findings provide the first evidence of a differential gene expression in the periprostatic adipose tissue of obese individuals. Differences were also observed when comparing the periprostatic adipose tissue of patients with and without prostate cancer. Differentially expressed genes are related to cell proliferation and immunological responses. Besides suggesting the genetic bases for the observed relationship between obesity and prostate cancer aggressiveness, these findings provide new insights on the important link between local microenvironment and cancer progression.