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RY Li, HD Song, WJ Shi, SM Hu, YS Yang, JF Tang, MD Chen, and JL Chen

In addition to serving as a fat depot, adipose tissue is also considered as an important endocrine organ that synthesizes and secretes a number of factors. Leptin is an adipocyte-derived hormone that plays a vital role in energy balance. Expression of leptin is regulated by dietary status and hormones. In the present study, we report that galanin, an orexigenic peptide, inhibits leptin expression and secretion in rat adipose tissue and in 3T3-L1 adipocytes. Treatment with galanin (25 micro g/animal) induced approximately 46% down-regulation of leptin secretion at 15 min, followed by 40, 37 and 47% decreases in leptin secretion at 1, 2 and 4 h respectively. Although Northern blot analysis of adipose tissue from the same animals showed that leptin mRNA expression in adipose tissue was unaffected by galanin treatment for 2 h, galanin treatment for 4 h led to decline of leptin mRNA expression in a dose-dependent manner. Meanwhile, treating the rats with galanin had no effect on leptin mRNA expression in the hypothalamus. The inhibitory action of the galanin on leptin mRNA and protein levels was also observed in vitro. When incubated with 10 nM galanin for 48 h, leptin mRNA expression and protein secretion also decreased in 3T3-L1 adipocytes. On the other hand, galanin was found not only to express in rat adipose tissue, but also to increase about 8-fold after fasting. Based on these data, we speculate that increased galanin expression in rat adipose tissue after fasting may be involved in reducing leptin expression and secretion in fasting rats.

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Jessica A Deis, Hong Guo, Yingjie Wu, Chengyu Liu, David A Bernlohr, and Xiaoli Chen

Lipocalin-2 (LCN2) has been previously characterized as an adipokine regulating thermogenic activation of brown adipose tissue and retinoic acid (RA)-induced thermogenesis in mice. The objective of this study was to explore the role and mechanism for LCN2 in the recruitment and retinoic acid-induced activation of brown-like or ‘beige’ adipocytes. We found LCN2 deficiency reduces key markers of thermogenesis including uncoupling protein-1 (UCP1) and peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) in inguinal white adipose tissue (iWAT) and inguinal adipocytes derived from Lcn2 −/− mice. Lcn2 −/− inguinal adipocytes have attenuated insulin-induced upregulation of thermogenic gene expression and p38 mitogen-activated protein kinase (p38MAPK) signaling pathway activation. This is accompanied by a lower basal and maximal oxidative capacity in Lcn2 −/− inguinal adipocytes, indicating mitochondrial dysfunction. Recombinant Lcn2 was able to restore insulin-induced p38MAPK phosphorylation in both WT and Lcn2 −/− inguinal adipocytes. Rosiglitazone treatment during differentiation of Lcn2 −/− adipocytes is able to recruit beige adipocytes at a normal level, however, further activation of beige adipocytes by insulin and RA is impaired in the absence of LCN2. Further, the synergistic effect of insulin and RA on UCP1 and PGC-1α expression is markedly reduced in Lcn2 −/− inguinal adipocytes. Most intriguingly, LCN2 and the retinoic acid receptor-alpha (RAR-α) are concurrently translocated to the plasma membrane of adipocytes in response to insulin, and this insulin-induced RAR-α translocation is absent in adipocytes deficient in LCN2. Our data suggest a novel LCN2-mediated pathway by which RA and insulin synergistically regulates activation of beige adipocytes via a non-genomic pathway of RA action.

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Diana Vargas, Noriaki Shimokawa, Ryosuke Kaneko, Wendy Rosales, Adriana Parra, Ángela Castellanos, Noriyuki Koibuchi, and Fernando Lizcano

Increasing thermogenesis in white adipose tissues can be used to treat individuals at high risk for obesity and cardiovascular disease. The objective of this study was to determine the function of EP300-interacting inhibitor of differentiation (EID1), an inhibitor of muscle differentiation, in the induction of beige adipocytes from adipose mesenchymal stem cells (ADMSCs). Subcutaneous adipose tissue was obtained from healthy women undergoing abdominoplasty. ADMSCs were isolated in vitro, grown, and transfected with EID1 or EID1 siRNA, and differentiation was induced after 48 h by administering rosiglitazone. The effects of EID1 expression under the control of the aP2 promoter (aP2-EID1) were also evaluated in mature adipocytes that were differentiated from ADMSCs. Transfection of EID1 into ADMSCs reduced triglyceride accumulation while increasing levels of thermogenic proteins, such as PGC1α, TFAM, and mitochondrial uncoupling protein 1 (UCP1), all of which are markers of energy expenditure and mitochondrial activity. Furthermore, increased expression of the beige phenotype markers CITED1 and CD137 was observed. Transfection of aP2-EID1 transfection induced the conversion of mature white adipocytes to beige adipocytes, as evidenced by increased expression of PGC1α, UCP1, TFAM, and CITED1. These results indicate that EID1 can modulate ADMSCs, inducing a brown/beige lineage. EID1 may also activate beiging in white adipocytes obtained from subcutaneous human adipose tissue.

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B Zietz, W Drobnik, H Herfarth, C Buechler, J Scholmerich, and A Schaffler

Plasminogen activator inhibitor-1 (PAI-1) levels were found to be associated with obesity indicating that adipocytes influence PAI-1 plasma levels. In addition, the 4 G/5 G promoter polymorphism of the PAI-1 gene may modulate PAI-1 transcription. We investigated the transcriptional regulation of the human PAI-1 gene in adipocytes and analyzed the genetic contribution of the 4 G/5 G polymorphism. The PAI-1 promoter was analyzed using electrophoretic mobility shift assays (EMSAs) and luciferase reporter gene assays. A putative binding site for the upstream stimulatory factor-1/2 (USF-1/2) at the polymorphic region of the PAI-1 promoter was identified. The binding of USF-1/2 was studied using nuclear extracts prepared from adipocytes and was similar in all the promoter variants as analyzed by EMSA. A 257 bp PAI-1 promoter fragment including the 4 G/5 G site was transcriptionally active in adipocytes and was not influenced by the polymorphism. The present data indicate for the first time that USF-1/2 is transcriptionally active in differentiated adipocytes. However, USF-1/2 binding activity and PAI-1 transcription are not influenced by the 4 G/5 G-allele. These data possibly explain the observation that PAI-1 secretion from adipose tissue is not influenced by the PAI-1 promoter polymorphism.

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Umberto Bernabucci, Loredana Basiricò, Patrizia Morera, Nicola Lacetera, Bruno Ronchi, and Alessandro Nardone

Studies have demonstrated that heat shock is associated with alteration in energy metabolism. In this study, we investigated the effect of heat shock on gene expression and secretion of adiponectin and leptin, and gene expression of Hspa2 and Pparγ in 3T3-L1 adipocytes. Compared with 37 °C, adiponectin mRNA was higher at 39 °C, and lower at 41 °C. Leptin mRNA was higher when adipocytes were exposed to 41 °C compared with 37 and 39 °C. Secretion of adiponectin increased at 39 °C, and when cells were exposed to 41 °C it was not detectable. Leptin secretion increased significantly at 41 °C, compared with 37  and 39 °C. Hspa2 mRNA was increased at 39 °C, and the highest level was reached at 41 °C. Pparγ mRNA exhibited a substantial increase in a temperature-dependent manner. The study provides the first evidence of a possible direct effect of heat shock on adiponectin and leptin gene expression and secretion, and demonstrates that the expression of the two adipokines is differentially regulated at the temperatures tested.

Free access

Ting Qi, Yanming Chen, Honggui Li, Ya Pei, Shih-Lung Woo, Xin Guo, Jiajia Zhao, Xiaoxian Qian, Joseph Awika, Yuqing Huo, and Chaodong Wu

Metformin improves obesity-associated metabolic dysregulation, but has controversial effects on adipose tissue inflammation. The objective of the study is to examine the direct effect of metformin on adipocyte inflammatory responses and elucidate the underlying mechanisms. Adipocytes were differentiated from 3T3-L1 cells and treated with metformin at various doses and for different time periods. The treated cells were examined for the proinflammatory responses, as well as the phosphorylation states of AMPK and the expression of PFKFB3/iPFK2. In addition, PFKFB3/iPFK2-knockdown adipocytes were treated with metformin and examined for changes in the proinflammatory responses. The following results were obtained from the study. Treatment of adipocytes with metformin decreased the effects of lipopolysaccharide on inducing the phosphorylation states of JNK p46 and on increasing the mRNA levels of IL-1β and TNFα. In addition, treatment with metformin increased the expression of PFKFB3/iPFK2, but failed to significantly alter the phosphorylation states of AMPK. In PFKFB3/iPFK2-knockdown adipocytes, treatment with metformin did not suppress the proinflammatory responses as did it in control adipocytes. In conclusion, metformin has a direct effect on suppressing adipocyte proinflammatory responses in an AMPK-independent manner. Also, metformin increases adipocyte expression of PFKFB3/iPFK2, which is involved in the anti-inflammatory effect of metformin.

Free access

Tingting Zhang, Jinhan He, Chong Xu, Luxia Zu, Hongfeng Jiang, Shenshen Pu, Xiaohui Guo, and Guoheng Xu

The mobilization of free fatty acids (FFA) from adipose tissue to the bloodstream primarily depends on triacylglycerol lipolysis in adipocytes. Catecholamines are major hormones that govern lipolysis through elevating cellular cAMP production and activating protein kinase, cAMP dependent, catalytic, alpha (PKA) and mitogen-activated protein kinase 1/2 (MAPK1/3). Obesity and type 2 diabetes are associated with elevated levels of systemic FFA, which restricts glucose utilization and induces insulin resistance. The biguanide metformin exerts its antihyperglycemic effect by enhancing insulin sensitivity, which is associated with decreased levels of circulating FFA. In this study, we examined the characteristics and basis of the inhibitory effect of metformin on adrenergic-stimulated lipolysis in primary rat adipocytes. We measured the release of FFA and glycerol as an index of lipolysis and examined the major signalings of the lipolytic cascade in primary rat adipocytes. Metformin at 250–500 μM efficiently attenuated FFA and glycerol release from the adipocytes stimulated with 1 μM isoproterenol. To elucidate the basis for this antilipolytic action, we showed that metformin decreased cellular cAMP production, reduced the activities of PKA and MAPK1/3, and attenuated the phosphorylation of perilipin during isoproterenol-stimulated lipolysis. Further, metformin suppressed isoproterenol-promoted lipase activity but did not affect the translocation of lipase, hormone-sensitive from the cytosol to lipid droplets in adipocytes. This study provides evidence that metformin acts on adipocytes to suppress the lipolysis response to catecholamine. This antilipolytic effect could be a cellular basis for metformin decreasing plasma FFA levels and improving insulin sensitivity.

Free access

Ilaria Cimmino, Francesco Oriente, Vittoria D’Esposito, Domenico Liguoro, Pasquale Liguoro, Maria Rosaria Ambrosio, Serena Cabaro, Francesco D’Andrea, Francesco Beguinot, Pietro Formisano, and Rossella Valentino

The dramatic rise in obesity and metabolic syndrome can be related, at least in part, to environmental chemical factors such as Bisphenol-A (BPA). In this study, we aimed to understand the effects of low-dose Bisphenol-A on the human mature adipocytes and stromal vascular fraction (SVF) cells, obtained from subcutaneous mammary adipose tissue of overweight female patients, undergoing surgical mammary reduction. 24 and/or 48-h exposure to BPA 0.1 nM elicited significant increase of the inflammatory molecules interleukin-6 (IL-6), interleukin-8 (IL-8), monocyte chemo-attractant protein 1α (MCP1α) and induced G protein-coupled estrogen receptor 30 (GPR30) levels more than two-fold both in mature adipocytes and SVF cells. These effects were similar to that obtained in the presence of GPR30-specific agonist G1 (100 nM) and were reverted by G15 (1 µM), a GPR30-selective antagonist. As a result of BPA-GPR30 signaling activation, fatty acid synthase (FAS) and leptin mRNA levels were significantly higher upon BPA exposure (P < 0.05) in mature adipocytes, with an opposite effect on adiponectin (ADIPOQ). In addition, an increase in SVF cell proliferation and ERK1/2 phosphorylation, was observed, compared to untreated cells. G15 reverted all of these effects. Interestingly, the action of BPA on SVF cell growth was mimicked by IL-8 treatment and was reverted by incubation with anti-IL8 antibodies. All these data suggest that BPA at 0.1 nM, a ten times lower concentration than environmental exposure, increases the expression of pro-inflammatory cytokines via GPR30 both in mature mammary adipocytes and in SVF cells with a possible involvement of IL-8.

Free access

Jacqueline M Wallace, John S Milne, Raymond P Aitken, and Clare L Adam

Intrauterine growth restriction (IUGR) is a risk factor for obesity, particularly when offspring are born into an unrestricted nutritional environment. In this study, we investigated the impact of IUGR and gender on circulating lipids and on expression of adipogenic, lipogenic and adipokine genes in perirenal adipose tissue. Singleton lambs born to overnourished adolescent dams were normal birth weight (N) or IUGR (32% lower birth weight due to placental insufficiency). IUGR lambs exhibited increased fractional growth rates but remained smaller than N lambs at necropsy (d77). At 48 days, fasting plasma triglycerides, non-esterified fatty acids and glycerol were elevated predominantly in IUGR males. Body fat content was independent of prenatal growth but higher in females than in males. In perirenal fat, relative to male lambs, females had larger adipocytes; higher lipoprotein lipase, fatty acid synthase and leptin and lower IGF1, IGF2, IGF1R, IGF2R and hormone-sensitive lipase mRNA expression levels, and all were independent of prenatal growth category; peroxisome proliferator-activated receptor gamma and glycerol-3-phosphate dehydrogenase (G3PDH) mRNA expression were not affected by IUGR or gender. Adiposity indices were inversely related to G3PDH mRNA expression, and for the population as a whole the expression of IGF system genes in perirenal fat was negatively correlated with plasma leptin, fat mass and adipocyte size, and positively correlated with circulating IGF1 levels. Higher plasma lipid levels in IUGR males may predict later adverse metabolic health and obesity, but in early postnatal life gender has the dominant influence on adipose tissue gene expression, reflecting the already established sexual dimorphism in body composition.

Free access

James E P Brown, David J Onyango, Manjunath Ramanjaneya, Alex C Conner, Snehal T Patel, Simon J Dunmore, and Harpal S Randeva

The role of the adipocyte-derived factor visfatin in metabolism remains controversial, although some pancreatic β-cell-specific effects have been reported. This study investigated the effects of visfatin upon insulin secretion, insulin receptor activation and mRNA expression of key diabetes-related genes in clonal mouse pancreatic β-cells. β-TC6 cells were cultured in RPMI 1640 and were subsequently treated with recombinant visfatin. One-hour static insulin secretion was measured by ELISA. Phospho-specific ELISA and western blotting were used to detect insulin receptor activation. Real-time SYBR Green PCR array technology was used to measure the expression of 84 diabetes-related genes in both treatment and control cells. Incubation with visfatin caused significant changes in the mRNA expression of several key diabetes-related genes, including marked up-regulation of insulin (9-fold increase), hepatocyte nuclear factor (HNF)1β (32-fold increase), HNF4α (16-fold increase) and nuclear factor κB (40-fold increase). Significant down-regulation was seen in angiotensin-converting enzyme (−3.73-fold) and UCP2 (−1.3-fold). Visfatin also caused a significant 46% increase in insulin secretion compared to control (P<0.003) at low glucose, and this increase was blocked by co-incubation with the specific nicotinamide phosphoribosyltransferase inhibitor FK866. Both visfatin and nicotinamide mononucleotide induced activation of both insulin receptor and extracellular signal-regulated kinase (ERK)1/2, with visfatin-induced insulin receptor/ERK1/2 activation being inhibited by FK866. We conclude that visfatin can significantly regulate insulin secretion, insulin receptor phosphorylation and intracellular signalling and the expression of a number of β-cell function-associated genes in mouse β-cells.