Subcutaneous Adipose Tissue Expression Research Articles

Association of lipid-modifying therapy with risk of obstructive sleep apnea: A drug-target mendelian randomization study

BackgroundObstructive sleep apnea (OSA) is considered to be an important contributor of dyslipidemia. However, there lacks observational studies focusing on the potential effect of lipid management on OSA risk. Thus, we aimed to investigate the genetic association of lipid-modifying therapy with risk of OSA. MethodsA drug-target mendelian randomization (MR) study using both cis-variants and cis-expression quantitative trait loci (eQTLs) of lipid-modifying drug targets was performed. The MR analyses used summary-level data of genome wide association studies (GWAS). Primary MR analysis was conducted using inverse-variance-weighted (IVW) method. Sensitivity analysis was performed using weighted median (WM) and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods. ResultsGenetically proxied low-density lipoprotein cholesterol (LDL-C)-lowering effect of cholesteryl ester transfer protein (CETP) was associated with reduced risk of OSA (odds ratio [OR] =0.75, 95% confidence interval [CI]: 0.60–0.94, false discovery rate [FDR] q value = 0.046). A significant MR association with risk of OSA was observed for CETP expression in subcutaneous adipose tissue (OR = 0.94, 95%CI: 0.89–1.00, FDR q value = 0.049), lung (OR = 0.94, 95%CI: 0.89–1.00, FDR q value = 0.049) and small intestine (OR = 0.96, 95%CI: 0.93–1.00, FDR q value = 0.049). No significant effects of high-density lipoprotein cholesterol (HDL-C)-raising effect of CETP inhibition, LDL-C-lowering and triglycerides-lowering effect of other drug targets on OSA risk were observed. ConclusionsThe present study presented genetic evidence supporting the association of LDL-C-lowering therapy by CETP inhibition with reduced risk of OSA. These findings provided novel insights into the role of lipid management in patients with OSA and encouraged further clinical validations and mechanistic investigations.

Subcutaneous adipose tissue expression of genes associated with glucocorticoid action: relationship with insulin sensitivity, obesity, and weight loss.

Subcutaneous adipose tissue expression of genes associated with glucocorticoid action: relationship with insulin sensitivity, obesity, and weight loss.

Subcutaneous adipose tissue dopamine D2 receptor is increased in prediabetes and T2D

PurposeTo evaluate the dopaminergic signaling in human adipose tissue in the context of obesity and type 2 diabetes (T2D) and potential direct implications in adipose tissue metabolism.MethodsmRNA and protein expression of dopamine receptors D1 and D2 (DRD1 and DRD2) were determined in subcutaneous adipose tissue from subjects without or with T2D and with different body weight, and correlated with markers of obesity, hyperglycemia, and insulin resistance. Glucose uptake and lipolysis were measured in adipocytes ex vivo following short-term exposure to dopamine, DRD1 receptor agonist (SKF81297), or DRD2 receptor agonist (bromocriptine).ResultsDRD1 and DRD2 gene expression in subcutaneous adipose tissue correlated positively with clinical markers of insulin resistance (e.g. HOMA-IR, insulin, and triglycerides) and central obesity in subjects without T2D. Protein expression of DRD2 in subcutaneous adipose tissue, but not DRD1, is higher in subjects with impaired fasting glucose and T2D and correlated positively with hyperglycemia, HbA1c, and glucose AUC, independent of obesity status. DRD1 and DRD2 proteins were mainly expressed in adipocytes, compared to stromal vascular cells. Dopamine and dopaminergic agonists did not affect adipocyte glucose uptake ex vivo, but DRD1 and DRD2 agonist treatment inhibited isoproterenol-stimulated lipolysis.ConclusionThe results suggest that protein expression of DRD2 in subcutaneous adipose tissue is up-regulated with hyperglycemia and T2D. Whether DRD2 protein levels contribute to T2D development or occur as a secondary compensatory mechanism needs further investigation. Additionally, dopamine receptor agonists inhibit adipocyte beta-adrenergic stimulation of lipolysis, which might contribute to the beneficial effects in lipid metabolism as observed in patients taking bromocriptine.

CABLES1 expression is reduced in human subcutaneous adipose tissue in obesity and type 2 diabetes but may not directly impact adipocyte glucose and lipid metabolism

ABSTRACT Cdk5 and Abl enzyme substrate 1 (CABLES1) is a cell cycle regulator that has previously been identified as a candidate gene for obesity-related phenotypes, but little is known about its role in adipose tissue metabolism. In this study, we explore the role of CABLES1 in obesity and type 2 diabetes (T2D) in human subcutaneous adipose tissue (SAT). We performed gene expression analysis of SAT obtained from subjects with and without T2D, and from a second validation cohort consisting of subjects without T2D. We used CRISPR/Cas9 genome editing to perform CABLES1 loss-of-function studies in human primary preadipocytes and assessed them functionally after differentiation. CABLES1 gene expression in SAT was decreased in T2D by almost 25%, and inversely associated with insulin resistance markers and hyperglycaemia. mRNA levels were reduced with increasing BMI and negatively correlated with obesity markers. We found that adipocytes are likely the main CABLES1-expressing cell type in SAT, but CABLES1 depletion in adipocytes caused no phenotypical changes in regards to differentiation, glucose uptake, or expression of key genes of adipocyte function. These findings suggest that CABLES1 gene expression in SAT might be altered in obesity and T2D as a consequence of metabolic dysregulation rather than being a causal factor.

Genetic association of lipids and lipid-lowering drug target genes with non-alcoholic fatty liver disease.

Some observational studies found that dyslipidaemia is a risk factor for non-alcoholic fatty liver disease (NAFLD), and lipid-lowering drugs may lower NAFLD risk. However, it remains unclear whether dyslipidaemia is causative for NAFLD. This Mendelian randomisation (MR) study aimed to explore the causal role of lipid traits in NAFLD and evaluate the potential effect of lipid-lowering drug targets on NAFLD. Genetic variants associated with lipid traits and variants of genes encoding lipid-lowering drug targets were extracted from the Global Lipids Genetics Consortium genome-wide association study (GWAS). Summary statistics for NAFLD were obtained from two independent GWAS datasets. Lipid-lowering drug targets that reached significance were further tested using expression quantitative trait loci data in relevant tissues. Colocalisation and mediation analyses were performed to validate the robustness of the results and explore potential mediators. No significant effect of lipid traits and eight lipid-lowering drug targets on NAFLD risk was found. Genetic mimicry of lipoprotein lipase (LPL) enhancement was associated with lower NAFLD risks in two independent datasets (OR1=0.60 [95% CI 0.50-0.72], p1=2.07×10-8; OR2=0.57 [95% CI 0.39-0.82], p2=3.00×10-3). A significant MR association (OR=0.71 [95% CI, 0.58-0.87], p=1.20×10-3) and strong colocalisation association (PP.H4=0.85) with NAFLD were observed for LPL expression in subcutaneous adipose tissue. Fasting insulin and type 2 diabetes mediated 7.40% and 9.15%, respectively, of the total effect of LPL on NAFLD risk. Our findings do not support dyslipidaemia as a causal factor for NAFLD. Among nine lipid-lowering drug targets, LPL is a promising candidate drug target in NAFLD. The mechanism of action of LPL in NAFLD may be independent of its lipid-lowering effects. Capital's Funds for Health Improvement and Research (2022-4-4037). CAMS Innovation Fund for Medical Sciences (CIFMS, grant number: 2021-I2M-C&T-A-010).

Elevated adipose differentiation-related protein level in ovariectomized mice correlates with tissue-specific regulation of estrogen.

Redistribution of adipose tissue in the abdomen during the menopausal transition is attributable mostly to estrogen drop with aging. Adipose differentiation-related protein (ADRP), a major component of lipid droplets, is closely related to the onset of lipid accumulation. We hypothesized that estrogen exerted its tissue-specific effect in reducing abdominal fat accumulation by regulation of ADRP. Twenty-four female C57/BL6 mice aged 8 weeks were randomly divided into 3 groups: sham operation (Sham), bilateral ovariectomy (OVX), and OVX plus 17β-estradiol (OVX + E2). After being fed 8 weeks of a high-fat diet, plasma lipid profiles including total cholesterol (TC), total triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels, body weight gain, visceral, and subcutaneous adipose tissue, adipocyte size, and ADRP expression were measured. In comparison to sham-operated mice, OVX mice presented a weight gain with higher plasma TC, TG, LDL-C levels, and lower HDL-C levels. E2 supplement ameliorated the increase in weight and lipid profiles. Elevated ADRP expression was observed in visceral adipose tissue of OVX mice, whereas treatment of estrogen suppressed the ADPR expression and reversed the fat accumulation in the abdomen. However, no significant difference of ADRP expression in subcutaneous adipose tissue was detected between sham, OVX, and OVX + E2 mice. Our findings suggested that enhanced ADRP expression in ovariectomized mice correlates with the tissue-specific regulation of estrogen, which may provide useful clues for further exploring the regulatory mechanism and corresponding anti-abdominal obesity treatment in postmenopausal women.

FABP4 Expression in Subcutaneous Adipose Tissue Is Independently Associated with Circulating Triglycerides in Obesity.

Hypertriglyceridemia (HTG) has been associated with an increased risk of pancreatitis and cardiovascular disease. Adipose tissue plays a major role in lipid metabolism, mobilization and distribution. We have compared the histological and transcriptomic profiles of the subcutaneous (SAT) and visceral (VAT) adipose tissues from subjects with severe obesity undergoing bariatric surgery with (Ob-HTG, n = 37) and without HTG (Ob-NTG, n = 67). Mean age and BMI were 51.87 ± 11.21 years, 45.78 ± 6.96 kg/m2 and 50.03 ± 10.17 years, 44.04 ± 4.69 kg/m2, respectively. The Ob-HTG group showed higher levels of glycosylated hemoglobin, fasting plasma glucose, high-sensitivity C-reactive protein and prevalence of hypertension. The degree of fibrosis was increased by 14% in SAT from the Ob-HTG group (p = 0.028), while adipocyte size distribution was comparable. Twenty genes were found differentially expressed in SAT and VAT between study groups. Among them, only SAT expression of FABP4 resulted significantly associated with circulating triglyceride levels after adjusting for other covariates and independently explained 5% of the variance in triglyceride levels in the combined model. This relationship was not found in the cohort of lean or overweight patients with normotriglyceridemia (non-Ob, n = 21). These results emphasize the contribution of SAT to triglyceride concentrations in obesity and indicate that FABP4 may be a potential drug target for the treatment of HTG.

Interleukin-33 inhibits glucose uptake in human adipocytes and its expression in adipose tissue is elevated in insulin resistance and type 2 diabetes.

Interleukin-33 (IL-33) is associated with obesity-related inflammation. We aim to investigate IL-33 expression in subcutaneous adipose tissue (SAT) in type 2 diabetes (T2D) subjects and its effects on human adipocyte glucose uptake. Expression of IL-33 was analysed in SAT from cohort studies including subjects with and without obesity and T2D and correlated with insulin resistance and obesity markers. Magnetic resonance imaging (MRI) of tissue fat volumes was performed. We investigated the effects of IL-33 treatment on ex vivo adipocyte glucose uptake. T2D subjects had higher IL-33 gene and protein expression in SAT than the control subjects. IL-33 mRNA expression was positively correlated with markers of dysglycemia (e.g. HbA1c), insulin resistance (e.g. HOMA-IR) and adiposity (BMI, visceral adipose tissue volume, liver and pancreas fat %). In multiple linear regression analyses, insulin resistance and T2D status were the strongest predictors of IL-33, independent of BMI. IL-33 mRNA expression was negatively correlated with expression of genes regulating adipocyte glucose uptake, lipid storage, and adipogenesis (e.g.glucose transporter 1 and 4 (GLUT1/4), fatty acid binding protein 4 (FABP4), and PPARG). Additionally, incubation of SAT with IL-33 reduced adipocyte glucose uptake and GLUT4 gene and protein expression. Our findings suggest that T2D subjects have higher IL-33 gene and protein expressionin SATthan control subjects, which is associated with insulin resistance and reduced gene expression of lipid storage and adipogenesis markers. IL-33 may reduce adipocyte glucose uptake. This opens up a potential pharmacological route for reversing insulin resistance in T2D and prediabetes.

Analysis of different adipose depot gene expression in cachectic patients with gastric cancer

PurposeThis study aimed to identify the differentially expressed genes (DEGs) that contributed to the different amount of fat loss between subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) among cachectic patients.MethodsRNA sequencing was performed and bioinformatic tools were utilized to analyze the biological functions and construct regulation networks of DEGs. We presumed that iroquois homeobox 1 (IRX1) to be a hub gene and analyzed its clinical significance. Mouse model of cancer cachexia was established and differences between SAT and VAT were compared. The function of IRX1 on lipid metabolism was clarified by Oil Red O staining, qRT-PCR, and Western blotting in adipocytes.ResultsA total of 455 DEGs were screened between SAT and VAT in cachectic patients. Several hub genes were selected and IRX1 was presumed to contribute to the pathological difference between SAT and VAT in cancer cachexia. Patients with higher expression of IRX1 in SAT than VAT revealed significantly higher weight loss, IL-6 and TNF-α, as well as lower BMI, SAT, and VAT area. IRX1 expression in SAT was negatively correlated with SAT area. In cachectic mice, the expression of IRX1 in SAT was significantly higher than that in VAT. The inhibition effect on adipogenesis exerted by IRX1 was also proved in vitro.ConclusionThese data supported that DEGs contribute to the different degrees of fat loss among adipose depots in cachectic patients. IRX1 in SAT promoted fat loss by inhibiting adipocyte differentiation and adipogenesis.

Dectin-1 as a Potential Inflammatory Biomarker for Metabolic Inflammation in Adipose Tissue of Individuals with Obesity.

In obesity, macrophage activation and infiltration in adipose tissue (AT) underlie chronic low-grade inflammation-induced insulin resistance. Although dectin-1 is primarily a pathogen recognition receptor and innate immune response modulator, its role in metabolic syndromes remains to be clarified. This study aimed to investigate the dectin-1 gene expression in subcutaneous AT in the context of obesity and associated inflammatory markers. Subcutaneous AT biopsies were collected from 59 nondiabetic (lean/overweight/obese) individuals. AT gene expression levels of dectin-1 and inflammatory markers were determined via real-time reverse transcriptase-quantitative polymerase chain reaction. Dectin-1 protein expression was assessed using immunohistochemistry. Plasma lipid profiles were measured by ELISA. AT dectin-1 transcripts and proteins were significantly elevated in obese as compared to lean individuals. AT dectin-1 transcripts correlated positively with body mass index and fat percentage (r ≥ 0.340, p ≤ 0.017). AT dectin-1 RNA levels correlated positively with clinical parameters, including plasma C-reactive protein and CCL5/RANTES, but negatively with that of adiponectin. The expression of dectin-1 transcripts was associated with that of various proinflammatory cytokines, chemokines, and their cognate receptors (r ≥ 0.300, p ≤ 0.05), but not with anti-inflammatory markers. Dectin-1 and members of the TLR signaling cascade were found to be significantly associated, suggesting an interplay between the two pathways. Dectin-1 expression was correlated with monocyte/macrophage markers, including CD16, CD68, CD86, and CD163, suggesting its monocytes/macrophage association in an adipose inflammatory microenvironment. Dectin-1 expression was independently predicted by CCR5, CCL20, TLR2, and MyD88. In conclusion, dectin-1 may be regarded as an AT biomarker of metabolic inflammation in obesity.

ASC Regulates Subcutaneous Adipose Tissue Lipogenesis and Lipolysis via p53/AMPKα Axis.

Obesity has become an extensive threat to human health due to associated chronic inflammation and metabolic diseases. Apoptosis-associated speck-like protein (ASC) is a critical link between inflammasome and apoptosis-inducing proteins. In this study, we aimed to clarify the role of ASC in lipid metabolism. With high-fat diet (HFD) and knockout leptin gene mice (ob/ob), we found that ASC expression in subcutaneous adipose tissue (SAT) correlated with obesity. It could also positively regulate the reprogramming of cellular energy metabolism. Stromal vascular fractions (SVF) cells derived from the SAT of Asc−/− mice or SVF from wild-type (WT) mice transfected with ASC siRNA were used to further investigate the underlying molecular mechanisms. We found ASC deficiency could lead to lipogenesis and inhibit lipolysis in SAT, aggravating lipid accumulation and impairing metabolic balance. In addition, our results showed that p53 and AMPKα expression were inhibited in SAT when ASC level was low. p53 and AMP-activated protein kinase α (AMPKα) were then assessed to elucidate whether they were downstream of ASC in regulating lipid metabolism. Our results revealed that ASC deficiency could promote lipid accumulation by increasing lipogenesis and decreasing lipolysis through p53/AMPKα axis. Regulation of ASC on lipid metabolism might be a novel therapeutic target for obesity.

ESR2 expression in subcutaneous adipose tissue is related to body fat distribution in women, and knockdown impairs preadipocyte differentiation

ABSTRACT Oestrogen receptor 2 (ESR2) expression has been shown to be higher in subcutaneous adipose tissue (SAT) from postmenopausal compared to premenopausal women. The functional significance of altered ESR2 expression is not fully known. This study investigates the role of ESR2 for adipose tissue lipid and glucose metabolism. SAT biopsies were obtained from 44 female subjects with or without T2D. Gene expression of ESR2 and markers of adipose function and metabolism was assessed. ESR2 knockdown was performed using CRISPR/Cas9 in preadipocytes isolated from SAT of females, and differentiation rate, lipid storage, and glucose uptake were measured. ESR2 expression was inversely correlated with measures of central obesity and expression of some fatty acid oxidation markers, and positively correlated with lipid storage and glucose transport markers. Differentiation was reduced in ESR2 knockdown preadipocytes. This corresponded to reduced expression of markers of differentiation and lipogenesis. Glucose uptake was reduced in knockdown adipocytes. Our results indicate that ESR2 deficiency in women is associated with visceral adiposity and impaired subcutaneous adipocyte differentiation as well as glucose and lipid utilization. High ESR2 expression, as seen after menopause, could be a contributing factor to SAT expansion. This may support a possible target to promote a healthy obesity phenotype.

Identification of novel genes whose expression in adipose tissue affects body fat mass and distribution: an RNA-Seq and Mendelian Randomization study.

Many studies have shown that abdominal adiposity is more strongly related to health risks than peripheral adiposity. However, the underlying pathways are still poorly understood. In this cross-sectional study using data from RNA-sequencing experiments and whole-body MRI scans of 200 participants in the EPIC-Potsdam cohort, our aim was to identify novel genes whose gene expression in subcutaneous adipose tissue has an effect on body fat mass (BFM) and body fat distribution (BFD). The analysis identified 625 genes associated with adiposity, of which 531 encode a known protein and 487 are novel candidate genes for obesity. Enrichment analyses indicated that BFM-associated genes were characterized by their higher than expected involvement in cellular, regulatory and immune system processes, and BFD-associated genes by their involvement in cellular, metabolic, and regulatory processes. Mendelian Randomization analyses suggested that the gene expression of 69 genes was causally related to BFM and BFD. Six genes were replicated in UK Biobank. In this study, we identified novel genes for BFM and BFD that are BFM- and BFD-specific, involved in different molecular processes, and whose up-/downregulated gene expression may causally contribute to obesity.

Adapting Random Forests to Predict Obesity-Associated Gene Expression.

Random forests (RFs) are effective at predicting gene expression from genotype data. However, a comparison of RF regressors and classifiers, including feature selection and encoding, has been under-explored in the context of gene expression prediction. Specifically, we examine the role of ordinal or one-hot encoding and of data balancing via oversam-pling in the prediction of obesity-associated gene expression. Our work shows that RFs compete with PrediXcan in the prediction of obesity-associated gene expression in subcutaneous adipose tissue, a highly relevant tissue to obesity. Additionally, RFs generate predictions for obesity-associated genes where PrediXcan fails to do so.

P-658 NLRP3 Inflammasome and polycystic ovarian syndrome – a possible novel association

Abstract Study question Is NLRP3 inflammasome expression in subcutaneous adipose tissue (SAT) and peripheral blood monocytes upregulated in women with polycystic ovarian syndrome (PCOS) compared to healthy controls? Summary answer NLRP3 expression was upregulated in subcutaneous adipose tissue but not in peripheral blood mononuclear cells (PBMCs) of women with PCOS compared to controls. What is known already Emerging evidence strongly suggests that PCOS is a chronic inflammatory condition. Inflammasomes are multiprotein complexes, which act as intracellular regulators of inflammation. It is now well established that NLRP3 inflammasome plays a central role in obesity-induced inflammation and insulin resistance. Given the close link between obesity and PCOS, it is plausible to hypothesize that the NLRP3 inflammasome may play a role in PCOS-related chronic inflammation and insulin resistance. This hypothesis has never been investigated before. Study design, size, duration This lab-based study involved reproductive age women (age 18–45years; BMI≤40kg/m2) who were diagnosed with PCOS (n = 24) according to the Rotterdam criteria. A healthy control group of non-PCOS women (n = 13) of similar age and BMI was included. Ethics approval was obtained, and all participants signed a written, informed consent. SAT biopsies were obtained during routine gynaecological surgery through the abdominal skin incision. Blood samples were obtained during surgery or during clinic visits. Participants/materials, setting, methods Blood samples were processed to separate plasma and to isolate peripheral blood mononuclear cells (PBMCs). SAT and PBMCs were analysed using qPCR and Western Blot (WB) to measure the relative gene and protein expression levels of NLRP3, CYP17, Caspase-1, IL-1β and IL-18 in both groups. ELISA was used to measure concentrations of Caspase-1, IL-1β and IL-18 in the plasma. Main results and the role of chance NLRP3 gene expression in SAT was significantly (p = 0.038) higher in PCOS women (2.08±3.5 (n = 12)) compared to controls (0.77±2.9 (n = 8)). Both groups were matched for age (PCOS, 29.4±3.7 vs controls, 30.3±4.0) and BMI (PCOS, 25.4±3.2 vs controls, 26.9±4.3). CYP17 expression was significantly (p = 0.001) higher in PCOS women (4.8±0.1) versus controls (1.5±1.6). There was a moderate positive correlation (r²=0.576, P < 0.05) between SAT NLRP3 and CYP17 expressions. NLRP3 gene expression in PBMCs were not significantly (p < 0.05) different between non-obese PCOS (-2.64±1.55 (n = 4)), obese PCOS (-2.847±1.85 (n = 8)) and non-PCOS women (0.000±2.67 (n = 5)). Using WB in PBMCs, NLRP3 band had a mean molecular weight of 72.59±5.43kDa with no significant difference between groups, with a trend towards higher levels in PCOS. Using ELISA in PBMCs, NLRP3 levels were not significantly (p = 0.3) different between PCOS (1.53±1.32pg/ml (n = 12)) vs controls (1.03±0.583 (n = 5)). Gene expression levels of Caspase-1, IL-1b and IL-18 in PBMCs were not significantly (P > 0.05) different between groups. Plasma IL-1β levels were significantly (p < 0.05) higher in PCOS (51.64±91.00ng/ml) vs. controls (0.47±0.93ng/ml). Plasma IL-18 concentrations were not significantly different between PCOS (3.79±0.53μg/ml) vs. controls (4.08±0.21μg/ml). Limitations, reasons for caution One limitation of this study is the lack of data on the protein expression of NLRP3 in the adipose tissue. There was also no data on other inflammasome components in the SAT analysis e.g. Caspase-1. However, all these data were available for the PBMCs. Wider implications of the findings The novel and interesting finding of an increase in NLRP3 in adipose tissue of PCOS women suggests that this inflammasome may play a central role in this common condition. Our study may therefore pave the way to further research to help understand the role of inflammation in PCOS Trial registration number N/A

A Signature of Exaggerated Adipose Tissue Dysfunction in Type 2 Diabetes Is Linked to Low Plasma Adiponectin and Increased Transcriptional Activation of Proteasomal Degradation in Muscle.

Insulin resistance in skeletal muscle in type 2 diabetes (T2D) is characterized by more pronounced metabolic and molecular defects than in obesity per se. There is increasing evidence that adipose tissue dysfunction contributes to obesity-induced insulin resistance in skeletal muscle. Here, we used an unbiased approach to examine if adipose tissue dysfunction is exaggerated in T2D and linked to diabetes-related mechanisms of insulin resistance in skeletal muscle. Transcriptional profiling and biological pathways analysis were performed in subcutaneous adipose tissue (SAT) and skeletal muscle biopsies from 17 patients with T2D and 19 glucose-tolerant, age and weight-matched obese controls. Findings were validated by qRT-PCR and western blotting of selected genes and proteins. Patients with T2D were more insulin resistant and had lower plasma adiponectin than obese controls. Transcriptional profiling showed downregulation of genes involved in mitochondrial oxidative phosphorylation and the tricarboxylic-acid cycle and increased expression of extracellular matrix (ECM) genes in SAT in T2D, whereas genes involved in proteasomal degradation were upregulated in the skeletal muscle in T2D. qRT-PCR confirmed most of these findings and showed lower expression of adiponectin in SAT and higher expression of myostatin in muscle in T2D. Interestingly, muscle expression of proteasomal genes correlated positively with SAT expression of ECM genes but inversely with the expression of ADIPOQ in SAT and plasma adiponectin. Protein content of proteasomal subunits and major ubiquitin ligases were unaltered in the skeletal muscle of patients with T2D. A transcriptional signature of exaggerated adipose tissue dysfunction in T2D, compared with obesity alone, is linked to low plasma adiponectin and increased transcriptional activation of proteasomal degradation in skeletal muscle.

Effect of genetic merit for backfat thickness and paternal breed on performance, carcass traits, and gene expression in subcutaneous adipose tissue of feedlot-finished steers

• Backfat thickness trait can be selected through genetic merit in Nellore and crossbred steers (½ Aberdeen Angus + ½ Nellore). • Animal performance is not affected by genetic merit for backfat thickness. • The expression of ACACA, ADIPOQ, FASN, PLIN 1, PPARG and SREBF1 genes in subcutaneous adipose tissue is not affected by genetic merit for backfat thickness. This study evaluated selection for backfat thickness based on genetic merit (GMB) in Nellore (N) and crossbred (½ Aberdeen Angus + ½ Nellore, AN) steers, as well as the effects of this selection on animal performance, carcass traits, and gene expression in subcutaneous adipose tissue (SAT). The animals were obtained by mating Nellore cows with Nellore or Aberdeen Angus bulls. Both paternal genetic groups were selected to have positive (+, high GMB) or negative (-, low GMB) expected progeny differences for backfat thickness. Seventy-six animals (14 N+, 20 N-, 20 AN+, and 22 AN-) were reared on pasture and finished in the feedlot. The animals were slaughtered, and SAT samples were collected to investigate the relative expression of the acetyl-CoA carboxylase alpha ( ACACA ), adiponectin, C1Q and collagen domain containing ( ADIPOQ ), fatty acid synthase ( FASN ), perilipin 1 ( PLIN1 ), peroxisome proliferator activated receptor gamma ( PPARG ), and sterol regulatory element binding protein ( SREBF1 ) genes. Carcass weight and yield, conformation, finishing score, fat distribution score, and measurements of backfat thickness and rib eye area were evaluated. There was no effect of GMB on performance or on the relative expression of the genes studied. High GMB steers had greater backfat thickness and higher finishing, conformation and fat distribution scores in the carcass than low GMB animals. The use of high GMB animals provides better carcass finishing without affecting performance. The greater fat deposition in carcasses of high GMB animals is not associated with the relative expression of the genes studied.

The armadillo-repeat containing X-linked protein 3, ARMCX3, is a negative regulator of the browning of adipose tissue associated with obesity.

To determine the role of armadillo repeat-containing X-linked protein 3 (ARMCX3) in the thermogenic plasticity of adipose tissue. Adipose tissues were characterized in Armcx3-KO male mice. Armcx3 gene expression was analyzed in adipose tissue from mice exposed to thermogenic inducers (cold, β3-adenergic stimulus) and in differentiating brown and beige cells in culture. Analyses encompassed circulating metabolite and hormonal profiling, tissue characterization, histology, gene expression patterns, and immunoblot assays. Armcx3 gene expression was assessed in subcutaneous adipose tissue from lean individuals and individuals with obesity and was correlated with expression of marker genes of adipose browning. The effects of adenoviral-mediated overexpression of ARMCX3 on differentiating brown adipocyte gene expression and respiratory activity were determined. Male mice lacking ARMCX3 showed significant induction of white adipose tissue browning. In humans, ARMCX3 expression in subcutaneous adipose tissue was inversely correlated with the expression of marker genes of thermogenic activity, including CIDEA, mitochondrial transcripts, and creatine kinase-B. Armcx3 expression in adipose tissues was repressed by thermogenic activation (cold or β3-adrenergic stimulation) and was upregulated by obesity in mice and humans. Experimentally-induced increases in Armcx3 caused down-regulation of thermogenesis-related genes and reduced mitochondrial oxidative activity of adipocytes in culture, whereas siRNA-mediated Armcx3 knocking-down enhanced expression of thermogenesis-related genes. ARMCX3 is a novel player in the control of thermogenic adipose tissue plasticity that acts to repress acquisition of the browning phenotype and shows a direct association with indicators of obesity in mice and humans.

Detection of SARS-CoV-2 in subcutaneous fat but not visceral fat, and the disruption of fat lymphocyte homeostasis in both fat tissues in the macaque

The well documented association between obesity and the severity of SARS-CoV-2 infection raises the question of whether adipose tissue (AT) is impacted during this infection. Using a model of SARS-CoV-2 infection in cynomolgus macaques, we detected the virus within subcutaneous AT (SCAT) but not in visceral AT (VAT) or epicardial AT on day 7 post-infection. We sought to determine the mechanisms responsible for this selective detection and observed higher levels of angiotensin-converting-enzyme-2 mRNA expression in SCAT than in VAT. Lastly, we evaluated the immunological consequences of SARS-CoV-2 infection on AT: both SCAT and VAT T cells showed a drastic reduction in CD69 expression, a standard marker of resident memory T cell in tissue, that is also involved in the migratory and metabolic properties of T cells. Our results demonstrate that in a model of mild infection, SCAT is selectively infected by SARS-CoV-2 although changes in the immune properties of AT are observed in both SCAT and VAT.

Over Expression of FOXO1 in Subcutaneous Fatty Tissue and its Response to Resistance Training in High Fat Diet and Type 2 Diabetic Rat

Objective: Forkhead box proteins and Forkhead box transcription factor O1 (FOXO1) in particular, mediate insulin signaling pathways and glucose homeostasis. This study aimed to compare FOXO1 expression in subcutaneous adipose (SA) tissue between obese rats with and without type 2 diabetes (T2D) and its response to resistance training in T2D.
 Materials and Methods: 21 male wistar rats (220±20 g) were obese by 6 weeks high fat diet (HFD) and randomly assigned to either non-diabetes (n=7) or two T2D groups (control and exercise groups, n=7 in each case). Fasting glucose, insulin, insulin resistance and FOXO1 expression were compared between non-diabetes and diabetes groups. All variables were also assigned after resistance training in the form of climbing a ladder (6 weeks/5 times weekly) in exercise compare with control groups. Data were compared by ANOVA, independent and paired t-test methods (P<0.05).
 Results: Induction of diabetes resulted in significant increase in insulin resistance, glucose, and FOXO expression in SA tissue and a decrease in insulin compared to obese health rats (P< 0.0001). A significant decrease in fasting insulin (P< 0.0001), insulin resistance (P< 0.0001) and FOXO1 expression in SA tissue (P< 0.0001) and increase in insulin (P: 0.002) were observed by resistance training compared to control diabetes rats.
 Conclusion: Based on our results, improving insulin resistance and glucose in response to resistance training in obese diabetic rats may be rooted in decreased insulin expression following these exercises.