Subcutaneous Adipose Tissue Expression Research Articles

Effects of docosahexanoic acid supplementation on inflammatory and subcutaneous adipose tissue gene expression in HIV-infected patients on combination antiretroviral therapy (cART). A sub-study of a randomized, double-blind, placebo-controlled study

Omega-3 fatty acids have the potential to decrease inflammation and modify gene transcription. Whether docosahexanoic acid (DHA) supplementation can modify systemic inflammatory and subcutaneous adipose tissue (SAT) gene expression in HIV-infected patients is unknown. A randomized, double-blind, placebo-controlled trial that enrolled 84 antiretroviral-treated patients who had fasting TG levels from 2.26 to 5.65 mmol/l and received DHA or placebo for 48 weeks was performed (ClinicalTrials.gov, NCT02005900). Systemic inflammatory and SAT gene expression was assessed at baseline and at week 48 in 39 patients. Patients receiving DHA had a 43.9% median decline in fasting TG levels at week 4 (IQR: -31% to -56%), compared with -2.9% (-18.6% to 16.5%) in the placebo group (P < 0.0001). High sensitivity C reactive protein (hsCRP) and arachidonic acid levels significantly decreased in the DHA group. Adipogenesis-related and mitochondrial-related gene expression did not experience significant changes. Mitochondrial DNA (mtDNA) significantly decreased in the placebo group. SAT inflammation-related gene expression (Tumor necrosis factor alpha [TNF-α], and monocyte chemoattractant protein-1 [MCP-1]) significantly decreased in the DHA group. DHA supplementation down-regulated inflammatory gene expression in SAT. DHA impact on markers of systemic inflammation was restricted to hsCRP and arachidonic acid.

VEGF and GLUT1 are highly heritable, inversely correlated and affected by dietary fat intake: Consequences for cognitive function in humans

ObjectiveReduction of brain glucose transporter GLUT1 results in severe neurological dysfunction. VEGF is required to restore and maintain brain glucose uptake across the blood brain barrier via GLUT1, which was shown to be acutely diminished in response to a high fat diet (HFD) in mice. The genetic and HFD-related regulation and association of VEGF and GLUT1 (SLC2A1) in humans was investigated in the NUtriGenomic Analysis in Twins (NUGAT) study.Methods92 healthy and non-obese twins were standardized to a high-carbohydrate low-fat diet for 6 weeks before switched to a 6-week HFD under isocaloric conditions. Three clinical investigation days were conducted: after 6 weeks of low-fat diet and after 1 and 6 weeks of HFD. Serum VEGF and other cytokine levels were measured using ELISA. Gene expression in subcutaneous adipose tissue was assessed by quantitative Real-Time PCR. Genotyping was performed using microarray. The Auditory Verbal Learning Task was conducted to measure cognitive performance.ResultsIn this human study, we showed that the environmental regulation of SLC2A1 expression and serum VEGF by HFD was inversely correlated and both factors showed strong heritability (>90%). In response to the HFD containing 45% fat, serum VEGF levels increased (P = 0.002) while SLC2A1 mRNA expression in adipose tissue decreased (P = 0.001). Higher BMI was additionally associated with lower SLC2A1 expression. AA-genotypes of the rs9472159 polymorphism, which explained ∼39% of the variation in circulating VEGF concentrations, showed significantly reduced serum VEGF levels (P = 6.4 × 10−11) but higher SLC2A1 expression (P = 0.009) in adipose tissue compared to CC/CA-genotypes after 6 weeks of HFD. Memory performance in AA-genotypes declined in response to the HFD compared to CC- and CA-genotypes.ConclusionsThe results provide evidence to suggest the translatability of the dietary regulation of VEGF and GLUT1 from mouse models to humans. Our data demonstrate that HFD induces a genetically determined and correlated decrease of GLUT1 and increase of VEGF which may affect memory performance.Clinical Trial Registration NumberNCT01631123

Natriuretic peptides promote glucose uptake in a cGMP-dependent manner in human adipocytes

Robust associations between low plasma level of natriuretic peptides (NP) and increased risk of type 2 diabetes (T2D) have been recently reported in humans. Adipose tissue (AT) is a known target of NP. However it is unknown whether NP signalling in human AT relates to insulin sensitivity and modulates glucose metabolism. We here show in two European cohorts that the NP receptor guanylyl cyclase-A (GC-A) expression in subcutaneous AT was down-regulated as a function of obesity grade while adipose NP clearance receptor (NPRC) was up-regulated. Adipose GC-A mRNA level was down-regulated in prediabetes and T2D, and negatively correlated with HOMA-IR and fasting blood glucose. We show for the first time that NP promote glucose uptake in a dose-dependent manner. This effect is reduced in adipocytes of obese individuals. NP activate mammalian target of rapamycin complex 1/2 (mTORC1/2) and Akt signalling. These effects were totally abrogated by inhibition of cGMP-dependent protein kinase and mTORC1/2 by rapamycin. We further show that NP treatment favoured glucose oxidation and de novo lipogenesis independently of significant gene regulation. Collectively, our data support a role for NP in blood glucose control and insulin sensitivity by increasing glucose uptake in human adipocytes. This effect is partly blunted in obesity.

Circulating adipokines and mRNA expression in adipose tissue and the placenta in women with gestational diabetes mellitus

Maternal adipose tissue and the placenta secrete various molecules commonly called adipokines such as chemerin, omentin-1, visfatin, adiponectin, and leptin that are important players in the pathogenesis of insulin resistance. Gestational diabetes mellitus (GDM) is defined as a state of glucose intolerance characterized by β-cell dysfunction and insulin resistance. To examine whether circulating adipokines and their mRNA expression in the adipose tissue and the placenta are altered in GDM pregnancy, we compared 15 GDM women [obese (BMI > 30) and non-obese (BMI < 30)] to 23 NGT (normal glucose tolerance) women [obese and non-obese], at the time of the Cesarean section. Circulating chemerin and leptin were higher (p = 0.009 and p = 0.005, respectively) and circulating omentin-1, visfatin, as well as the adiponectin/leptin ratio were lower (p = 0.039, p = 0.007 and p = 0.011, respectively) in GDM-obese compared to NGT-non-obese women. Chemerin and leptin correlated positively with BMI and HOMA-IR and omentin-1 correlated negatively with BMI. Serum TNF-α was significantly elevated in all obese compared to non-obese pregnant women and correlated positively with BMI. Adiponectin levels were reduced -although not significantly- in GDM- and NGT-obese women compared to their non-obese counterparts. Resistin, RPB4 and IL-6 levels did not differ significantly between groups. Chemerin mRNA expression in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) was significantly higher compared to placenta in all women (6-to 24-times, p < 0.05). Chemerin-VAT mRNA expression in GDM-obese tended to be significantly higher compared to NGT-non-obese women (3-times, p = 0.005). Omentin-1 mRNA expression was significantly higher in VAT compared to SAT (50- to 100-times, p < 0.01) and its expression in placenta was negligible in all women. Although, leptin was expressed significantly higher in SAT compared to VAT and the placenta in all women (5- to 46-times, p < 0.05), only its mRNA expression in VAT of obese (GDM and NGT) differed significantly when compared to NGT-non-obese women (3-times higher, p < 0.02). Visfatin mRNA expression was comparable in all tissues. In conclusion, chemerin and leptin are elevated and omentin-1 and visfatin levels are decreased in GDM women complicated by obesity. This finding together with the positive association of chemerin and leptin with markers of insulin resistance, suggests that these adipokines and more especially chemerin and leptin accompanied by their adipose tissue expression could contribute to the increased insulin resistance and low grade inflammation that characterizes GDM-obese women.

Oral administration of Rehmannia glutinosa extract for obesity treatment via adiposity and fatty acid binding protein expression in obese rats

We investigated the anti-obesity effect of Rehmannia glutinosa aqueous extract (RGE) in high fat diet (HFD) induced obese rats on the blood lipid concentration and expression of adipocyte fatty acid binding protein (FABP). In additional experiments, C57BL6 mice were used to determine lipolysis and the oral lipid emulsion tolerance test. RGE administration significantly reduced the size of subcutaneous adipocytes and. Most importantly, RGE administration markedly attenuated the up-regulation of FABP mRNA and protein expression in subcutaneous adipose tissue induced by an HFD. Oral RGE administration prevented weight gain and hyperlipidemia induced by long-term HFD feeding, presumably via a mechanism that inhibits the intestinal absorption of dietary fat by RGE. Taken together, RGE can act as an anti-obesity agent by lowering FABP gene and protein expression in adipose tissue as well as blood lipid levels.

Transdisciplinary Research on Energetics and Cancer: From Adipose Tissue to the American Society of Clinical Oncology (ASCO) Summit Recommendations.

Transdisciplinary Research on Energetics and Cancer: From Adipose Tissue to the American Society of Clinical Oncology (ASCO) Summit Recommendations.

DNA methylation and gene expression of TXNIP in adult offspring of women with diabetes in pregnancy.

BackgroundFetal exposure to maternal diabetes increases the risk of type 2 diabetes (T2DM), possibly mediated by epigenetic mechanisms. Low blood TXNIP DNA methylation has been associated with elevated glucose levels and risk of T2DM, and increased skeletal muscle TXNIP gene expression was reported in subjects with impaired glucose metabolism or T2DM. Subcutaneous adipose tissue (SAT) and skeletal muscle play a key role in the control of whole body glucose metabolism and insulin action. The extent to which TXNIP DNA methylation levels are decreased and/or gene expression levels increased in SAT or skeletal muscle of a developmentally programmed at-risk population is unknown.Objective and methodsThe objective of this study was to investigate TXNIP DNA methylation and gene expression in SAT and skeletal muscle, and DNA methylation in blood, from adult offspring of women with gestational diabetes (O-GDM, n = 82) or type 1 diabetes (O-T1DM, n = 67) in pregnancy compared with offspring of women from the background population (O-BP, n = 57).ResultsSAT TXNIP DNA methylation was increased (p = 0.032) and gene expression decreased (p = 0.001) in O-GDM, but these differences were attenuated after adjustment for confounders. Neither blood/muscle TXNIP DNA methylation nor muscle gene expression differed between groups.ConclusionWe found no evidence of decreased TXNIP DNA methylation or increased gene expression in metabolic target tissues of offspring exposed to maternal diabetes. Further studies are needed to confirm and understand the paradoxical SAT TXNIP DNA methylation and gene expression changes in O-GDM subjects.

The effect of very-low-calorie diet on mitochondrial dysfunction in subcutaneous adipose tissue and peripheral monocytes of obese subjects with type 2 diabetes mellitus.

Mitochondrial dysfunction is a potentially important player in the development of insulin resistance and type 2 diabetes mellitus (T2DM). We investigated the changes of mRNA expression of genes encoding main enzymatic complexes of mitochondrial respiratory chain in subcutaneous adipose tissue (SCAT) and peripheral monocytes (PM) of 11 subjects with simple obesity (OB), 16 obese patients with T2DM and 17 healthy lean subjects (C) before and after very low-calorie diet (VLCD) using quantitative real time PCR. At baseline in SCAT, both T2DM and OB group had decreased mRNA expression of all investigated mitochondrial genes with the exception of 2 complex I (NDUFA 12) and complex IV (COX 4/1) enzymes in OB subjects. In contrast, in PM only the expression of complex I enzymes NDUFA 12 and MT-ND5 was reduced in both T2DM and OB subjects along with decreased expression of citrate synthase (CS) in T2DM group. Additionally, T2DM subjects showed reduced activity of pyruvate dehydrogenase and complex IV in peripheral blood elements. VLCD further decreased mRNA expression of CS and complex I (NT-ND5) and II (SDHA) enzymes in SCAT and complex IV (COX4/1) and ATP synthase in PM of T2DM group, while increasing the activity of complex IV in their peripheral blood elements. We conclude that impaired mitochondrial biogenesis and decreased activity of respiratory chain enzymatic complexes was present in SCAT and PM of obese and diabetic patients. VLCD improved metabolic parameters and ameliorated mitochondrial oxidative function in peripheral blood elements of T2DM subjects but had only minor and inconsistent effect on mitochondrial gene mRNA expression in SCAT and PM.

Effect of caloric restriction on gut permeability, inflammation markers, and fecal microbiota in obese women

Recent findings suggest an association between obesity, loss of gut barrier function and changes in microbiota profiles. Our primary objective was to examine the effect of caloric restriction and subsequent weight reduction on gut permeability in obese women. The impact on inflammatory markers and fecal microbiota was also investigated. The 4-week very-low calorie diet (VLCD, 800 kcal/day) induced a mean weight loss of 6.9 ± 1.9 kg accompanied by a reduction in HOMA-IR (Homeostasis model assessment-insulin resistance), fasting plasma glucose and insulin, plasma leptin, and leptin gene expression in subcutaneous adipose tissue. Plasma high-molecular weight adiponectin (HMW adiponectin) was significantly increased after VLCD. Plasma levels of high-sensitivity C-reactive protein (hsCRP) and lipopolysaccharide-binding protein (LBP) were significantly decreased after 28 days of VLCD. Using three different methods, gut paracellular permeability was decreased after VLCD. These changes in clinical parameters were not associated with major consistent changes in dominant bacterial communities in feces. In summary, a 4-week caloric restriction resulted in significant weight loss, improved gut barrier integrity and reduced systemic inflammation in obese women.

MicroRNA-221-3p Regulates Angiopoietin-Like 8 (ANGPTL8) Expression in Adipocytes.

Angiopoietin-like 8 (ANGPTL8) has been identified as a key regulator of lipid metabolism. We addressed the correlation between ANGPTL8 messenger RNA (mRNA) with hallmark insulin-regulated and lipogenic genes in human adipose tissue (AT). The regulation of ANGPTL8 expression in adipocytes was studied after inflammatory challenge, and the role of microRNA (miRNA)-221-3p therein was investigated. ANGPTL8 gene expression in subcutaneous AT (SAT) and visceral AT (VAT) was highly correlated with SLC2A4/GLUT4, ADIPOQ, fatty acyl synthase, and diacylglycerol O-acyltransferase 1. ANGPTL8 mRNA in human adipocytes was suppressed by the inflammatory impact of conditioned medium of lipopolysaccharide-stimulated macrophages, which markedly induced miR-221-3p. MiR-221-3p was shown to target the ANGPTL8 mRNA, and to reduce adipocyte ANGPTL8 protein expression. Analysis of SAT biopsies from 69 subjects ranging from lean to morbidly obese and of VAT of 19 female subjects biopsied during gynecologic surgery demonstrated a trend of negative correlation between ANGPTL8 and miR-221-3p. Significant negative correlation of ANGPTL8 and miR-221-3p was identified in presurgery SAT samples from 22 morbidly obese subjects undergoing bariatric surgery, but vanished after ∼2-year surgery-induced weight loss, which also resulted in a marked reduction of miR-221-3p. ANGPTL8 correlated negatively with the AT inflammatory gene phospholipase A2 G7, whereas miR-221-3p showed a significant positive correlation with this marker. Of note, no correlation was found between AT ANGPTL8 mRNA expression and plasma ANGPTL8. The inflammation-induced miR-221-3p regulates ANGPTL8 expression in adipocytes. This miRNA impact may become especially prominent under pathologic conditions such as morbid obesity, putatively contributing to the impaired AT lipid metabolism in metabolic disease.

C-reactive protein is highly expressed in visceral adipose tissue of obese but not lean subjects: A post mortem study

Aim: Obesity is an escalating problem in Malaysia and worldwide. Central obesity is associated with cardiovascular disease, and visceral fat has been reported to be more atherogenic compared to subcutaneous fat. This study aims to compare visceral and subcutaneous adipose tissue expression of C-reactive protein (CRP) and interleukin-6 (IL-6) in centrally obese and lean post mortem cases.

Survivin, a key player in cancer progression, increases in obesity and protects adipose tissue stem cells from apoptosis

Adipose tissue (AT) has a central role in obesity-related metabolic imbalance through the dysregulated production of cytokines and adipokines. In addition to its known risk for cardiovascular disease and diabetes, obesity is also a major risk for cancer. We investigated the impact of obesity for the expression of survivin, an antiapoptotic protein upregulated by adipokines and a diagnostic biomarker of tumor onset and recurrence. In a cross-sectional study of 111 subjects classified by body mass index, circulating levels of survivin and gene expression in subcutaneous AT were significantly higher in obese patients and positively correlated with leptin. Within AT, survivin was primarily detected in human adipocyte-derived stem cells (hASCs), the adipocyte precursors that determine AT expansion. Remarkably, survivin expression was significantly higher in hASCs isolated from obese patients that from lean controls and was increased by proinflammatory M1 macrophage soluble factors including IL-1β. Analysis of survivin expression in hASCs revealed a complex regulation including epigenetic modifications and protein stability. Surprisingly, obese hASCs showed survivin promoter hypermethylation that correlated with a significant decrease in its mRNA levels. Nonetheless, a lower level of mir-203, which inhibits survivin protein translation, and higher protein stability, was found in obese hASCs compared with their lean counterparts. We discovered that survivin levels determine the susceptibility of hASCs to apoptotic stimuli (including leptin and hypoxia). Accordingly, hASCs from an obese setting were protected from apoptosis. Collectively, these data shed new light on the molecular mechanisms governing AT expansion in obesity through promotion of hASCs that are resistant to apoptosis, and point to survivin as a potential new molecular player in the communication between AT and tumor cells. Thus, inhibition of apoptosis targeting survivin might represent an effective strategy for both obesity and cancer therapy.

CELL BIOLOGY SYMPOSIUM: Practical application of the basic aspects of GLUT4 membrane trafficking and insulin signaling on issues related to animal agriculture.

Because of the relatively short lifespans of beef cattle, membrane trafficking in relation to inflammation is not considered important unless it overtly affects productivity. However, glucose uptake and utilization is important for adipose tissue development in beef cattle, and increasing glucose utilization in intramuscular adipose tissue can increase carcass quality. Research from the 1980s demonstrated a lack of insulin sensitivity in isolated bovine adipocytes and adipose tissue explants incubated in vitro. Insulin did not stimulate glucose or acetate incorporation into fatty acids, nor did it increase concentrations of glycolytic intermediates in bovine adipose tissue incubated with exogenous glucose. Specific binding of [I] iodoinsulin and insulin degradation in bovine isolated adipocytes was low to non-detectable. These early studies indicated that insulin-dependent receptor-mediated signaling was less important in bovine adipose tissue than in adipose tissues of humans, swine, or laboratory species. More recent research demonstrated that glucose transporter protein 4 (GLUT4) expression in muscle and adipose tissue declines markedly after birth in calves, indicating the development of insulin resistance as cattle transition from suckling to functional ruminants. Insulin resistance is important in dairy cattle, causing ketosis and fatty liver. Consistent with this, subcutaneous adipose tissue expression decreases 50% following parturition in dairy cattle, although expression of genes associated with insulin responsiveness (, , and ) is up-regulated by 21 d postpartum. Understanding the underlying mechanisms of insulin resistance in beef and dairy cattle would increase animal health and thereby improve productivity.

36\xa0h fasting of young men influences adipose tissue DNA methylation of LEP and ADIPOQ in a birth weight-dependent manner

BackgroundSubjects born with low birth weight (LBW) display a more energy-conserving response to fasting compared with normal birth weight (NBW) subjects. However, the molecular mechanisms explaining these metabolic differences remain unknown. Environmental influences may dynamically affect epigenetic marks, also in postnatal life. Here, we aimed to study the effects of short-term fasting on leptin (LEP) and adiponectin (ADIPOQ) DNA methylation and gene expression in subcutaneous adipose tissue (SAT) from subjects with LBW and NBW.MethodsTwenty-one young LBW men and 18 matched NBW controls were studied during 36 h fasting. Eight subjects from each group completed a control study (overnight fast). We analyzed SAT LEP and ADIPOQ methylation (Epityper MassARRAY), gene expression (q-PCR), and adipokine plasma levels.ResultsAfter overnight fast (control study), LEP and ADIPOQ DNA methylation levels were higher in LBW compared to those in NBW subjects (p ≤ 0.03) and increased with 36 h fasting in NBW subjects only (p ≤ 0.06). Both LEP and ADIPOQ methylation levels were positively associated with total body fat percentage (p ≤ 0.05). Plasma leptin levels were higher in LBW versus NBW subjects after overnight fasting (p = 0.04) and decreased more than threefold in both groups after 36 h fasting (p ≤ 0.0001).ConclusionsThis is the first study to demonstrate that fasting induces changes in DNA methylation. This was shown in LEP and ADIPOQ promoters in SAT among NBW but not LBW subjects. The altered epigenetic flexibility in LBW subjects might contribute to their differential response to fasting, adipokine levels, and increased risk of metabolic disease.

Differential adipokine DNA methylation and gene expression in subcutaneous adipose tissue from adult offspring of women with diabetes in pregnancy

BackgroundOffspring of women with diabetes in pregnancy are at increased risk of type 2 diabetes mellitus (T2DM), potentially mediated by epigenetic mechanisms. The adipokines leptin, adiponectin, and resistin (genes: LEP, ADIPOQ, RETN) play key roles in the pathophysiology of T2DM. We hypothesized that offspring exposed to maternal diabetes exhibit alterations in epigenetic regulation of subcutaneous adipose tissue (SAT) adipokine transcription.We studied adipokine plasma levels, SAT gene expression, and DNA methylation of LEP, ADIPOQ, and RETN in adult offspring of women with gestational diabetes (O-GDM, N = 82) or type 1 diabetes (O-T1DM, N = 67) in pregnancy, compared to offspring of women from the background population (O-BP, N = 57).ResultsCompared to O-BP, we found elevated plasma leptin and resistin levels in O-T1DM, decreased gene expression of all adipokines in O-GDM, decreased RETN expression in O-T1DM, and increased LEP and ADIPOQ methylation in O-GDM. In multivariate regression analysis, O-GDM remained associated with increased ADIPOQ methylation and decreased ADIPOQ and RETN gene expression and O-T1DM remained associated with decreased RETN expression after adjustment for potential confounders and mediators.ConclusionsIn conclusion, offspring of women with diabetes in pregnancy exhibit increased ADIPOQ DNA methylation and decreased ADIPOQ and RETN gene expression in SAT. However, altered methylation and expression levels were not reflected in plasma protein levels, and the functional implications of these findings remain uncertain.

Serum levels of nesfatin-1 are increased in gestational diabetes mellitus

Objective: To analyze the concentrations of nesfatin-1 in maternal and cord serum, to evaluate the expression of nesfatin-1 in subcutaneous adipose tissue (SAT) from pregnant women with gestational diabetes mellitus (GDM) and those with normal glucose tolerance (NGT).Methods: We studied a total of 50 GDM and 50 NGT subjects. The clinical features, serum nesfatin-1, homeostasis model assessment of insulin resistance (HOMA-IR), lipid profiles were measured at the third trimester of pregnancy. The expression of nesfatin-1 in the SAT was determined by western blot.Results: Compared with the NGT group, the GDM group showed greater levels of serum nesfatin-1, adipocyte fatty acid binding protein (AFABP), and leptin; a greater level of cord blood nesfatin-1; and a higher level of expression in SAT (p < 0.05 or p < 0.01). Fasting insulin (FI) (b = 0.317, p= 0.022) and body mass index (BMI) before delivery (b = 0.367, p=0.008) were independently associated with serum nesfatin-1. Nesfatin-1 was the independent risk factor for GDM.Conclusions: The GDM group had higher levels of maternal serum and cord blood nesfatin-1, and greater nesfatin-1 expression in SAT. Nesfatin-1 is closely related to obesity and IR in pregnancy.

Examination of carnitine palmitoyltransferase 1 abundance in white adipose tissue: implications in obesity research.

Carnitine palmitoyltransferase 1 (CPT1) is essential for the transport of long-chain fatty acids into the mitochondria for oxidation. Recently, it was reported that decreased CPT1b mRNA in adipose tissue was a contributing factor for obesity in rats. We therefore closely examined the expression level of Cpt1 in adipose tissue from mice, rats, and humans. Cpt1a is the predominate isoform in adipose tissue from all three species. Rat white adipose tissue has a moderate amount of Cpt1b mRNA, but it is very minor compared with Cpt1b expression in muscle. Total CPT1 activity in adipose tissue is also minor relative to other tissues. Both Cpt1a and Cpt1b mRNA were increased in gonadal fat but not inguinal fat by diet-induced obesity in mice. We also measured CPT1a and CPT1b expression in subcutaneous adipose tissue from human subjects with a wide range of body mass indexes (BMIs). Interestingly, CPT1a expression positively correlated with BMI (R = 0.46), but there was no correlation with CPT1b (R = 0.04). Our findings indicate that white adipose tissue fatty acid oxidation capacity is minor compared with that of metabolically active tissues. Furthermore, given the already low abundance of Cpt1b in white adipose tissue, it is unlikely that decreases in its expression can quantitatively decrease whole body energy expenditure enough to contribute to an obese phenotype.

Angiopoietin-like protein 8/betatrophin as a new determinant of type 2 diabetes remission after bariatric surgery

This work aimed to explore the link between angiopoietin-like protein 8 (ANGPTL8) and weight loss after metabolic surgery. In the cross-sectional study (n=100), circulating ANGPTL8 concentrations were significantly lower in morbidly obese than in lean subjects, and strikingly lower in morbidly obese patients with type 2 diabetes mellitus (T2DM). Conversely, ANGPTL8 expression in subcutaneous adipose tissue (SAT) was higher in morbidly obese patients, particularly in those with T2DM, whereas its expression in visceral adipose tissue was unchanged. The main predictors for circulating levels of ANGPTL8 were BMI and T2DM, whereas ANGPTL8 expression in SAT was determined by the presence of T2DM. The prospective cohort studies before and 1 year after bariatric surgery in morbidly obese patients with (n=45) and without (n=30) T2DM, revealed a significant increase of circulating ANGPTL8 levels 1 year after the bariatric surgery. Intriguingly, this increment, which was predicted by basal ANGPTL8 concentrations, appeared as a determinant of T2DM remission. In conclusion, circulating ANGPTL8 levels have an inverse relationship with SAT expression. Low basal levels of ANGPTL8 rebound after bariatric surgery. The increment in ANGPTL8 concentrations at 1 month of follow-up after weight loss emerged as a significant predictor of the T2DM remission at 1 year of follow-up.

MiRNAs in human subcutaneous adipose tissue: Effects of weight loss induced by hypocaloric diet and exercise.

Obesity is central in the development of insulin resistance. However, the underlying mechanisms still need elucidation. Dysregulated microRNAs (miRNAs; post-transcriptional regulators) in adipose tissue may present an important link. The miRNA expression in subcutaneous adipose tissue from 19 individuals with severe obesity (10 women and 9 men) before and after a 15-week weight loss intervention was studied using genome-wide microarray analysis. The microarray results were validated with RT-qPCR, and pathway enrichment analysis of in silico predicted targets was performed to elucidate the biological consequences of the miRNA dysregulation. Lastly, the messenger RNA (mRNA) and/or protein expression of multiple predicted targets as well as several proteins involved in lipolysis were investigated. The intervention led to upregulation of miR-29a-3p and miR-29a-5p and downregulation of miR-20b-5p. The mRNA and protein expression of predicted targets was not significantly affected by the intervention. However, negative correlations between miR-20b-5p and the protein levels of its predicted target, acyl-CoA synthetase long-chain family member 1, were observed. Several other miRNA-target relationships correlated negatively, indicating possible miRNA regulation, including miR-29a-3p and lipoprotein lipase mRNA levels. Proteins involved in lipolysis were not affected by the intervention. Weight loss influenced several miRNAs, some of which were negatively correlated with predicted targets. These dysregulated miRNAs may affect adipocytokine signaling and forkhead box protein O signaling.

Upregulated TNF Expression 1\xa0Year After Bariatric Surgery Reflects a Cachexia-Like State in Subcutaneous Adipose Tissue

BackgroundAdipose tissue dysfunction contributes to obesity-associated chronic diseases. In the first year after bariatric surgery, obese patients significantly improve their metabolic status upon losing weight. We aimed to investigate whether changes in subcutaneous adipose tissue gene expression reflect a restoration of a healthy lean phenotype after bariatric surgery.MethodsThirty-one severely obese patients (BMI ≥ 40 kg/m2) were examined before and after surgery. subcutaneous adipose tissue (SAT) was collected during and 1 year after bariatric surgery. SAT from 20 matched lean and overweight patients (BMI < 30 kg/m2) was collected during elective abdominal surgery. Baseline characteristics and SAT gene expression relevant to glucose and lipid metabolism, inflammation, and apoptosis were analyzed.ResultsAfter surgery, mean BMI decreased from 46.1 ± 6.3 to 31.1 ± 5.7 kg/m2 and homeostasis model assessment of insulin resistance from 5.4 ± 5.3 to 0.8 ± 0.8. SAT expression of most analyzed inflammatory cytokines, growth factors, and metabolic and cell surface markers was greatly downregulated even compared to the lean cohort. In contrast, gene expression of TNF and CASP3 was significantly upregulated. Elastic net regression analysis showed that fasting glucose levels and CASP3 predicted increased TNF expression in the post-obese group.ConclusionsGene expression patterns in SAT 1 year after bariatric surgery point to a reduced inflammation. The unexpected high TNF expression in SAT of post-obese subjects is most likely not an indicator for inflammation, but rather an indicator for increased lipolysis and adipose tissue catabolism. Notably, after bariatric surgery SAT gene expression reflects a cachexia-like phenotype and differs from the lean state.