White Adipose Tissue Hypertrophy Research Articles

Synergistic Role Among Adipose Tissue Hypertrophy, Dyslipidemia, and Systemic Inflammation in the Development of Atherosclerosis

Recent experimental and clinical evidence has suggested a synergistic causal role among adipose tissue hypertrophy, dyslipidemia, and systemic inflammation in the development and instability of the atherosclerotic plaque. Here, we summarize some of the most recent findings regarding the role of whi te adipose tissue hypertrophy in the development of dyslipidemia and chronic low-grade systemic inflammation. We also review the contribution of dyslipidemia in releasing free-fatty acids, cholesterol, and oxidized low-density lipoproteins as metabolic ligands able to trigger inflammatory signal pathways in macrophages via pattern recognition receptor (PRR) activation. Finally, we discuss the possible mechanisms through which dyslipidemia-related metabolic ligands and chronic low-grade systemic inflammation are capable of inducing macrophage activation, which in turn is involved in mediating instability and rupture of the atherosclerotic plaque. A better understanding of the inflammatory mechanisms contributing to atherosclerosis may help to identify potential molecular targets to decrease the cardiovascular risk in patients by using anti-inflammatory therapies and PRR blockers.

Raspberry Supplementation Improves Insulin Signaling and Promotes Brown-Like Adipocyte Development in White Adipose Tissue of Obese Mice.

Excessive lipid accumulation in white adipose tissue (WAT) leads to chronic inflammation and metabolic dysfunction. Raspberry (RB) contains high amount of polyphenols and dietary fibers. The objective of the study is to evaluate the effects of RB supplementation on WAT morphology, inflammation, and insulin signaling in high fat diet (HFD)-induced obese mice, and further explore the underlying mechanisms. C57BL/6J mice are fed with a control diet or a HFD supplemented with 0 or 5% freeze dried RB for 12 weeks. RB supplementation decreases WAT hypertrophy induced by HFD and suppresses pro-inflammatory cytokines expression and macrophage infiltration in WAT. Meanwhile, RB addition improves insulin sensitivity of HFD-mice. Additionally, RB supplementation drives the browning of WAT (beige adipogenesis), which is associated with elevated PGC-1α and FNDC5/irisin contents. Consistently, the content of beige adipocyte markers including UCP1, PRDM16, Cytochrome C, Cidea, and Elvol3 is enhanced in HFD-mice, which are correlated with increased AMPK phosphorylation and Sirt1 protein contents. Dietary RB attenuated adipocyte hypertrophy and inflammation of WAT in HFD-mice and improves insulin sensitivity and beige adipogenesis, which is associated with increased FNDC5/irisin content and activation of AMPK/Sirt1 pathway. RB supplementation provides a promising strategy to prevent diet-induced obesity.

MicroRNAs-361-5p and miR-574-5p associate with human adipose morphology and regulate EBF1 expression in white adipose tissue.

Reduced adipose expression of the transcription factor Early B cell factor 1 (EBF1) is linked to white adipose tissue (WAT) hypertrophy. We aimed to identify microRNAs (miRNAs) associated with WAT hypertrophy and EBF1 regulation. We mapped WAT miRNA expression from 26 non-obese women discordant in WAT morphology and determined EBF1 activity in the non-obese and 30 obese women. Expression of 15 miRNAs was higher in hypertrophy and 10 were predicted to target EBF1. Binding of miR-365-5p/miR-574-5p were validated with 3'-UTR assay. Overexpression of miR-365-5p or miR-574-5p reduced EBF1 while inhibition of miR-574 increased EBF1 expression in human adipocytes invitro. Additive effects on EBF1 were observed when concomitantly overexpressing both miRNAs. EBF1 targets were affected by over expression/inhibition of either miRNAs. Finally, miR-365-5p/miR-574-5p expression in 56 individuals correlated significantly with EBF1 activity. Our results suggest that miR-365-5p and miR-574-5p may be linked to WAT hypertrophy via effects on EBF1 expression.

Inactivation of SPAK kinase reduces body weight gain in mice fed a high-fat diet by improving energy expenditure and insulin sensitivity.

The STE20/SPS1-related proline-alanine-rich protein kinase (SPAK) controls the activity of the electroneutral cation-chloride cotransporters (SLC12 family) and thus physiological processes such as modulation of cell volume, intracellular chloride concentration [Cl-]i, and transepithelial salt transport. Modulation of SPAK kinase activity may have an impact on hypertension and obesity, as STK39, the gene encoding SPAK, has been suggested as a hypertension and obesity susceptibility gene. In fact, the absence of SPAK activity in mice in which the activating threonine in the T loop was substituted by alanine (SPAK-KI mice) is associated with decreased blood pressure; however its consequences in metabolism have not been explored. Here, we fed wild-type and homozygous SPAK-KI mice a high-fat diet for 17 wk to evaluate weight gain, circulating substrates and hormones, energy expenditure, glucose tolerance, and insulin sensitivity. SPAK-KI mice exhibit resistance to HFD-induced obesity and hepatic steatosis associated with increased energy expenditure, higher thermogenic activity in brown adipose tissue, increased mitochondrial activity in skeletal muscle, and reduced white adipose tissue hypertrophy mediated by augmented whole body insulin sensitivity and glucose tolerance. Our data reveal a previously unrecognized role for the SPAK kinase in the regulation of energy balance, thermogenesis, and insulin sensitivity, suggesting that this kinase could be a new drug target for the treatment of obesity and the metabolic syndrome.

Dietary emulsifiers from milk and soybean differently impact adiposity and inflammation in association with modulation of colonic goblet cells in high-fat fed mice.

Enhanced adiposity and metabolic inflammation are major features of obesity that could be impacted by dietary emulsifiers. We investigated in high-fat fed mice the effects of using a new polar lipid (PL) emulsifier from milk (MPL) instead of soybean lecithin (soybean PL [SPL]) on adipose tissue and intestinal mucosa function. Four groups of C57BL6 mice received for 8 wks a low-fat (LF) diet or a high-fat diet devoid of PLs or an high-fat diet including MPL (high-fat-MPL) or SPL (high-fat-SPL). Compared with high-fat diet, high-fat-SPL diet increased white adipose tissue (WAT) mass (p < 0.05), with larger adipocytes (p < 0.05) and increased expression of tumor necrosis factor alpha, monochemoattractant protein-1, LPS-binding protein, and leptin (p < 0.05). This was not observed with high-fat-MPL diet despite similar dietary intakes and increased expression of fatty acid transport protein 4 and microsomal TG transfer protein, involved in lipid absorption, in upper intestine (p < 0.05). High-fat-MPL mice had a lower expression in WAT of cluster of differentiation 68, marker of macrophage infiltration, versus high-fat and high-fat-SPL mice (p < 0.05), and more goblet cells in the colon (p < 0.05). Unlike SPL, MPL in the high-fat diet did not induce WAT hypertrophy and inflammation but increased colonic goblet cells. This supports further clinical exploration of different sources of dietary emulsifiers in the frame of obesity outbreak.

2,4,6-Trihydroxybenzaldehyde, a potential anti-obesity treatment, suppressed adipocyte differentiation in 3T3-L1 cells and fat accumulation induced by high-fat diet in C57BL/6 mice

In the present study, 2,4,6-trihydroxybenzaldehyde (THB) was evaluated for inhibitory effects on adipocyte differentiation in 3T3-L1 cells and anti-obesity effects in mice with high-fat diet (HFD)-induced obesity. Lipid accumulation measurement indicated that THB markedly inhibited adipogenesis, and this involved down-regulation of the expression of the adipogenesis-related proteins, CCAAT/enhancer-binding protein α (C/EBPα), peroxisome proliferator-activated receptor γ (PPARγ), fatty acid synthase (FAS) and sterol regulatory element-binding protein-1c (SREBP-1c), in 3T3-L1 pre-adipocyte cells. In a mouse model of HFD-induced obesity, oral administration of THB (5 and 25mg/kg for 13 weeks) reduced the HFD-induced increase in weight gain. THB administration also reduced serum levels of glucose, triglycerides, and total cholesterol. A reduction in the hypertrophy of white adipose tissue was also observed. Furthermore, THB administration inhibited HFD-induced hepatic steatosis. These results provided evidence that administration of THB alleviated HFD-induced obesity in C57BL/6 mice and revealed the potential of THB as a nutraceutical to help prevent or treat obesity and the associated metabolic disorders.

Adipose tissue morphology predicts improved insulin sensitivity following moderate or pronounced weight loss.

Cross-sectional studies show that white adipose tissue hypertrophy (few, large adipocytes), in contrast to hyperplasia (many, small adipocytes), associates with insulin resistance and increased risk of developing type 2 diabetes. We investigated if baseline adipose cellularity could predict improvements in insulin sensitivity following weight loss. Plasma samples and subcutaneous abdominal adipose biopsies were examined in 100 overweight or obese individuals before and 10 weeks after a hypocaloric diet (7±3% weight loss) and in 61 obese subjects before and 2 years after gastric by-pass surgery (33±9% weight loss). The degree of adipose tissue hypertrophy or hyperplasia (termed the morphology value) in each individual was calculated on the basis of the relationship between fat cell volume and total fat mass. Insulin sensitivity was determined by homeostasis model assessment-estimated insulin resistance (HOMAIR). In both cohorts at baseline, subjects with hypertrophy displayed significantly higher fasting plasma insulin and HOMAIR values than subjects with hyperplasia (P<0.0001), despite similar total fat mass. Plasma insulin and HOMAIR were normalized in both cohorts following weight loss. The improvement (delta insulin or delta HOMAIR) was more pronounced in individuals with hypertrophy, irrespective of whether adipose morphology was used as a continuous (P=0.0002-0.027) or nominal variable (P=0.002-0.047). Absolute adipocyte size associated (although weaker than morphology) with HOMAIR improvement only in the surgery cohort. Anthropometric measures at baseline (fat mass, body mass index, waist-to-hip ratio or waist circumference) showed no significant association with delta insulin or delta HOMAIR. In contrast to anthropometric variables or fat cell size, subcutaneous adipose morphology predicts improvement in insulin sensitivity following both moderate and pronounced weight loss in overweight/obese subjects.

Early B Cell Factor 1 Regulates Adipocyte Morphology and Lipolysis in White Adipose Tissue

White adipose tissue (WAT) morphology characterized by hypertrophy (i.e., fewer but larger adipocytes) associates with increased adipose inflammation, lipolysis, insulin resistance, and risk of diabetes. However, the causal relationships and the mechanisms controlling WAT morphology are unclear. Herein, we identified EBF1 as an adipocyte-expressed transcription factor with decreased expression/activity in WAT hypertrophy. In human adipocytes, the regulatory targets of EBF1 were enriched for genes controlling lipolysis and adipocyte morphology/differentiation, and in both humans and murine models, reduced EBF1 levels associated with increased lipolysis and adipose hypertrophy. Although EBF1 did not affect adipose inflammation, TNFα reduced EBF1 gene expression. High-fat diet intervention in Ebf1(+/-) mice resulted in more pronounced WAT hypertrophy and attenuated insulin sensitivity compared with wild-type littermate controls. We conclude that EBF1 is an important regulator of adipose morphology and fat cell lipolysis and may constitute a link between WAT inflammation, altered lipid metabolism, adipose hypertrophy, and insulin resistance.

Coordinated and Interactive Expression of Genes of Lipid Metabolism and Inflammation in Adipose Tissue and Liver during Metabolic Overload

BackgroundChronic metabolic overload results in lipid accumulation and subsequent inflammation in white adipose tissue (WAT), often accompanied by non-alcoholic fatty liver disease (NAFLD). In response to metabolic overload, the expression of genes involved in lipid metabolism and inflammatory processes is adapted. However, it still remains unknown how these adaptations in gene expression in expanding WAT and liver are orchestrated and whether they are interrelated.Methodology/Principal FindingsApoE*3Leiden mice were fed HFD or chow for different periods up to 12 weeks. Gene expression in WAT and liver over time was evaluated by micro-array analysis. WAT hypertrophy and inflammation were analyzed histologically. Bayesian hierarchical cluster analysis of dynamic WAT gene expression identified groups of genes (‘clusters’) with comparable expression patterns over time. HFD evoked an immediate response of five clusters of ‘lipid metabolism’ genes in WAT, which did not further change thereafter. At a later time point (>6 weeks), inflammatory clusters were induced. Promoter analysis of clustered genes resulted in specific key regulators which may orchestrate the metabolic and inflammatory responses in WAT. Some master regulators played a dual role in control of metabolism and inflammation. When WAT inflammation developed (>6 weeks), genes of lipid metabolism and inflammation were also affected in corresponding livers. These hepatic gene expression changes and the underlying transcriptional responses in particular, were remarkably similar to those detected in WAT.ConclusionIn WAT, metabolic overload induced an immediate, stable response on clusters of lipid metabolism genes and induced inflammatory genes later in time. Both processes may be controlled and interlinked by specific transcriptional regulators. When WAT inflammation began, the hepatic response to HFD resembled that in WAT. In all, WAT and liver respond to metabolic overload by adaptations in expression of gene clusters that control lipid metabolism and inflammatory processes in an orchestrated and interrelated manner.

Semaphorin 3C is a novel adipokine linked to extracellular matrix composition

Alterations in white adipose tissue (WAT) function, including changes in protein (adipokine) secretion and extracellular matrix (ECM) composition, promote an insulin-resistant state. We set out to identify novel adipokines regulated by body fat mass in human subcutaneous WAT with potential roles in adipose function. Adipose transcriptome data and secretome profiles from conditions with increased/decreased WAT mass were combined. WAT donors were predominantly women. In vitro effects were assessed using recombinant protein. Results were confirmed by quantitative PCR/ELISA, metabolic assays and immunochemistry in human WAT and adipocytes. We identified a hitherto uncharacterised adipokine, semaphorin 3C (SEMA3C), the expression of which correlated significantly with body weight, insulin resistance (HOMA of insulin resistance [HOMAIR], and the rate constant for the insulin tolerance test [KITT]) and adipose tissue morphology (hypertrophy vs hyperplasia). SEMA3C was primarily found in mature adipocytes and had no direct effect on human adipocyte differentiation, lipolysis, glucose transport or the expression of β-oxidation genes. This could in part be explained by the significant downregulation of its cognate receptors during adipogenesis. In contrast, in pre-adipocytes, SEMA3C increased the production/secretion of several ECM components (fibronectin, elastin and collagen I) and matricellular factors (connective tissue growth factor, IL6 and transforming growth factor-β1). Furthermore, the expression of SEMA3C in human WAT correlated positively with the degree of fibrosis in WAT. SEMA3C is a novel adipokine regulated by weight changes. The correlation with WAT hypertrophy and fibrosis in vivo, as well as its effects on ECM production in human pre-adipocytes in vitro, together suggest that SEMA3C constitutes an adipocyte-derived paracrine signal that influences ECM composition and may play a pathophysiological role in human WAT.

Anti-obesity effects of glabridin-rich supercritical carbon dioxide extract of licorice in high-fat-fed obese mice

Licorice (Glycyrrhiza glabra Linne) is a well-known medicinal plant and glabridin is an isoflavan isolated from licorice. In this study, we investigated the anti-obesity effect of glabridin and glabridin-rich supercritical fluid extract of licorice (LSC). Glabridin effectively inhibited adipogenesis in 3T3-L1 cells. Moreover, LSC showed inhibitory effect on adipogenesis in a dose-dependent manner. The inhibitory effect of LSC resulted from inhibiting the induction of the transcriptional factors CCAAT enhancer binding protein alpha and peroxisome proliferator-activated receptor gamma. Then we fed mice with high-fat diet containing none, 0.1% and 0.25% LSC for 8weeks to explore the anti-obesity effect of LSC in vivo. LSC significantly reduced weight gain by high-fat diet in a dose-dependent manner. The reductions of the hypertrophy of white adipose tissue and of fat cell size were also observed. In the liver, LSC supplementation effectively inhibited high-fat diet-induced hepatic steatosis through downregulation of gluconeogenesis related phosphoenolpyruvate carboxykinase and glucose 6-phosphatase and upregulation of the β-oxidation related carnitine palmitoyltransferase 1. Taken together, our results suggest that glabridin and glabridin-rich licorice extract would be effective anti-obesity agents.

Methotrexate is effective in reactivated colitis and reduces inflammatory alterations in mesenteric adipose tissue during intestinal inflammation

Mesenteric white adipose tissue hypertrophy and modifications in adipocytokine production are described features of Crohn's disease. Experimentally, mesenteric white adipose tissue alterations, associated with intestinal inflammation, can be induced in a model of reactivated colitis by repeated administration of intrarectal trinitrobenzenosulfonic acid (TNBS) in ethanol solution. Crohn's disease patients refractory to corticosteroid treatment are frequently treated with methotrexate; however, there is no information regarding the drug's effect on adipose tissue alterations and in a reactivated colitis experimental model. Thus, we evaluated the effect of methotrexate upon mesenteric WAT alterations and inflammatory features in experimental colitis in rats. Colitis status was evaluated by macroscopic score, histopathological analysis, myeloperoxidase activity, TNF-α and IL-10 expression, as well as iNOS and TLR-4 expression in colon samples. The adipose tissue alterations were assessed by TNF-α, IL-10, leptin and adiponectin production, as well as by macrophage infiltration evaluation. Methotrexate exerts an anti-inflammatory activity in experimental reactivated colitis by regulating the shift from Th1 to Th2 cytokines, reducing TNF-α and improving IL-10 production. Additionally, methotrexate reduces other inflammatory parameters in the colon, such as iNOS and TLR-4 expression. In mesenteric white adipose tissue, methotrexate treatment reduces the production of pro- and anti-inflammatory adipocytokines as well as macrophage infiltration, suggesting that immunosuppressant drugs diminish adipose tissue inflammatory alterations associated with intestinal inflammation.

Resistin: another rising biomarker in inflammatory bowel disease?

The researchers' view regarding the role of white adipose tissue (WAT) in inflammation has been greatly transformed over the last 10 years. WAT is now considered as an active organ producing many crucial molecules called adipokines. Resistin is a recently discovered cysteine-rich adipokine that has emerged during this decade as a promising inflammatory marker in various diseases. It is synthesized either from adipocytes or from immune cells, and exerts a pro-inflammatory profile in a variety of different experimental settings. Inflammatory bowel disease (IBD) is characterized by anorexia, malnutrition, altered body composition and the development of mesenteric WAT hypertrophy. The study by Konrad-Zerna et al. in this issue of the journal demonstrates an increased serum resistin in IBD patients, this being in agreement with previous IBD studies in mesenteric WAT and serum. Interesting aspects like the true validity of resistin as a marker of disease activity, the role of its different molecular isoforms, the cells that predominantly produce this molecule, and the possible use of resistin as a guide for therapeutic interventions, arise.