Dexamethasone decreases the autotaxin‐lysophosphatidate‐inflammatory axis in adipose tissue: implications for the metabolic syndrome and breast cancer

e22009 Background: Worldwide, the prevalence of obesity is rapidly increasing, correlating with a direct increase in cancer rates1. Adipose tissue is considered an important endocrine organ producing several important hormones and cytokines including leptin and adiponectin. Mechanisms for the role of obesity in cancer states includes the excess or unregulated secretion of adipocytokines from adipose tissue, and potentially the metabolic syndrome (a cluster of co-morbidities linked to metabolic dysregulation). Mammary adipose tissue is proposed to play a vital role in the microenvironment of normal and tumour states within the breast2. Breast adipose tissue is a good candidate to investigate effects of obesity and metabolic disturbances on cancer states. Methods: Peritumoural (PT) adipose tissue adjacent to the tumour and distal adipose tissue (D) within the breast was sampled in 10 patients. The tissue was processed and cultured for 72hrs in serum free minimal cytokine media. A-MB-231 and MCF-7 breast cancer cell lines were then cultured with this adipocyte conditioned media (ACM) and cell proliferation response was then measured using BrDU assays. The adipocytokine profile at the mRNA and protein level was measured in ACM and adipose tissue for comparative differences using RT-PCR, ELISA and Cytokine Profiler technology. Results: ACM from both sites promoted tumour cell survival. There was however, a differential cell proliferation response noted between the peritumoural (PT) ACM and that from the distant (D) ACM. Pro-inflammatory mediators (VEGF, TNF-α, EGF) were also demonstrated a trend to be differentially expressed between the 2 sites. Conclusions: Proliferation of breast cancer cell lines occurs in response to ACM, with differential effects seen between peritumoural ACM and distant ACM. This may be mediated through increased pro-inflammatory or pro- mitogenic adipocytokine production in adipose tissue surrounding tumour. Further analysis will determine what role obesity and the metabolic syndrome plays in the results noted. No significant financial relationships to disclose.

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Abstract 3672: Loss of Perivascular Adipocyte Paracrine Function Leads to Increased Vascular Tone and Glucose Intolerance in Hypertension

Circulation ◽

10.1161/circ.118.suppl_18.s_463-b ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Kaivan Khavandi ◽

Adam Greenstein ◽

Sarah Withers ◽

Kazuhiko Sonoyama ◽

Sarah Lewis ◽

...

Keyword(s):

Oxidative Stress ◽

Metabolic Syndrome ◽

Adipose Tissue ◽

Vascular Tone ◽

Tnf Alpha ◽

Perivascular Adipose Tissue ◽

The Metabolic Syndrome ◽

Adipocyte Cell ◽

Therapeutic Opportunity

In order to investigate the contribution of perivascular adipose tissue (PVAT) to arterial function, a total of 55 small arteries harvested from 35 skin biopsies of patients with Metabolic Syndrome and matched controls were mounted as ring preparations in a wire myograph. Contractility to cumulative doses of Norepinephrine in the presence or absence of PVAT showed an anticontractile effect in arteries from healthy volunteers (p=0.009), which was lost in patients with Metabolic Syndrome. Bioassay studies confirmed that PVAT releases a hydrophilic anticontractile factor in health, which is absent in obesity. Using a soluble fragment of the human Type 1 receptor, we identified that the anticontractile factor was adiponectin, which is the sole mediator of vasodilation, acting by increasing endothelial bioavailability of nitric oxide. Significant endothelial dysfunction was observed in patients with Metabolic Syndrome (p<0.001). Quantitative image analysis of adipose tissue revealed significantly increased adipocyte cell size in patients with Metabolic Syndrome, compared with healthy controls (p<0.006). There was immunohistochemical evidence of inflammation with upregulation of TNF-alpha receptor 1 in these patients (p<0.001). Application of exogenous TNF-alpha abolished the anticontractile effect of PVAT by reducing adiponectin bioavailability. Oxidative stress also induced by cytokines TNF-alpha and IL-6 but not IL-1, reduced adiponectin production from PVAT and increased basal tone. When the obese microenvironment was replicated in vitro by inflicting hypoxia on PVAT, adiponectin activity was lost but then rescued by incubation with cytokine antagonists. Further application of the adiponectin receptor fragment abolished PVAT relaxation. We conclude that in healthy arteries, PVAT releases adiponectin which reduces vascular tone. In obesity, this is lost by a cascade of adipocyte hypertrophy, hypoxia, inflammation and oxidative stress. The resulting vasoconstriction contributes to hypertension, hypertriglyceridaemia and insulin resistance. Direct targeting of adiponectin release from PVAT therefore provides a novel therapeutic opportunity in the Metabolic Syndrome.

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Mouse breast cancer model-dependent changes in metabolic syndrome-associated phenotypes caused by maternal dioxin exposure and dietary fat

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90368.2008 ◽

2009 ◽

Vol 296 (1) ◽

pp. E203-E210 ◽

Cited By ~ 13

Author(s):

Michele La Merrill ◽

David S. Baston ◽

Michael S. Denison ◽

Linda S. Birnbaum ◽

Daniel Pomp ◽

...

Keyword(s):

Breast Cancer ◽

Metabolic Syndrome ◽

Adipose Tissue ◽

Blood Glucose ◽

Estrogenic Activity ◽

Fasting Blood Glucose ◽

Growth Spurt ◽

Cancer Model ◽

Serum Triglycerides ◽

Cancer Models

Diets high in fat are associated with increased susceptibility to obesity and metabolic syndrome. Increased adipose tissue that is caused by high-fat diets (HFD) results in altered storage of lipophilic toxicants like 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD), which may further increase susceptibility to metabolic syndrome. Because both TCDD and HFD are associated with increased breast cancer risk, we examined their effects on metabolic syndrome-associated phenotypes in three mouse models of breast cancer: 7,12-dimethylbenz[a]anthracene (DMBA), Tg(MMTV-Neu)202Mul/J (HER2), and TgN(MMTV-PyMT)634Mul/J (PyMT), all on an FVB/N genetic background. Pregnant mice dosed with 1 μg/kg of TCDD or vehicle on gestational day 12.5 were placed on a HFD or low-fat diet (LFD) at parturition. Body weights, percent body fat, and fasting blood glucose were measured longitudinally, and triglycerides were measured at study termination. On HFD, all cancer models reached the pubertal growth spurt ahead of FVB controls. Among mice fed HFD, the HER2 model had a greater increase in body weight and adipose tissue from puberty through adulthood compared with the PyMT and DMBA models. However, the DMBA model consistently had higher fasting blood glucose levels than the PyMT and HER2 models. TCDD only impacted serum triglycerides in the PyMT model maintained on HFD. Because the estrogenic activity of the HFD was three times lower than that of the LFD, differential dietary estrogenic activities did not drive the observed phenotypic differences. Rather, the HFD-dependent changes were cancer model dependent. These results show that cancer models can have differential effects on metabolic syndrome-associated phenotypes even before cancers arise.

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Use of Blood as a Surrogate Model for the Assessment of Visceral Adipose Tissue Methylation Profiles Associated with the Metabolic Syndrome in Men

Journal of Molecular and Genetic Medicine ◽

10.4172/1747-0862.1000198 ◽

2016 ◽

Vol 10 (01) ◽

Cited By ~ 8

Author(s):

Frédéric Guénard ◽

Yves Deshaies

Keyword(s):

Metabolic Syndrome ◽

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Surrogate Model ◽

The Metabolic Syndrome ◽

Visceral Adipose

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Prevalence of Metabolic Syndrome among Breast Cancer Survivors in East Coast of Peninsular Malaysia

10.21203/rs.3.rs-22221/v5 ◽

2021 ◽

Author(s):

Mohd Razif Shahril ◽

Syed Amirfaiz ◽

Pei Lin Lua ◽

Ali Nurnazahiah ◽

Nor Syamimi Zakarai ◽

...

Keyword(s):

Breast Cancer ◽

Metabolic Syndrome ◽

Blood Glucose ◽

Cancer Survivors ◽

Breast Cancer Survivors ◽

East Coast ◽

Fasting Blood Glucose ◽

Peninsular Malaysia ◽

The Metabolic Syndrome ◽

Metabolic Syndrome Components

Abstract Background: To date, limited data are available on metabolic syndrome prevalence among breast cancer survivors in Malaysia. Therefore, this study was conducted to determine the prevalence of metabolic syndrome and abnormal metabolic syndrome components among breast cancer survivors in East Coast of Peninsular Malaysia. Methods: This cross-sectional study included 95 breast cancer survivors (age 53.7±7.6 years) who have completed main cancer treatments for ≥6 months. Cancer survivors were recruited from two main government hospitals in Kelantan and Terengganu using a purposive sampling method. Results: According to the Harmonized criteria, the metabolic syndrome prevalence was 50.5%. Among those with metabolic syndrome, the most prevalent abnormal metabolic components were triglycerides (91.2%), fasting blood glucose (79.6%) and HDL-c level (78.4%). Except for total cholesterol and LDL-c, all other metabolic syndrome components were significantly different (p<0.05) between those with and without metabolic syndrome. Significant differences between metabolic syndrome and non-metabolic syndrome groups were found for weight, BMI, waist circumference, body fat percentage and cancer stages (p<0.05). However, no significant relationship was reported between sociodemographic, clinical parameters and metabolic syndrome among breast cancer survivors in this study. Conclusions: Metabolic syndrome was highly prevalent among breast cancer survivors. It is recommended for health care professionals to closely monitor and improve the triglycerides, blood glucose and HDL-c level of the breast cancer survivors under their care to control the detrimental effect of metabolic syndrome.

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Visceral adipose tissue specific persistence of Mycobacterium tuberculosis may be reason for the metabolic syndrome

Medical Hypotheses ◽

10.1016/j.mehy.2008.03.028 ◽

2008 ◽

Vol 71 (2) ◽

pp. 222-228 ◽

Cited By ~ 10

Author(s):

Adnan Erol

Keyword(s):

Metabolic Syndrome ◽

Mycobacterium Tuberculosis ◽

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Tissue Specific ◽

The Metabolic Syndrome ◽

Visceral Adipose

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The metabolic syndrome alters the miRNA signature of porcine adipose tissue-derived mesenchymal stem cells

Cytometry Part A ◽

10.1002/cyto.a.23165 ◽

2017 ◽

Vol 93 (1) ◽

pp. 93-103 ◽

Cited By ~ 23

Author(s):

Yu Meng ◽

Alfonso Eirin ◽

Xiang-Yang Zhu ◽

Hui Tang ◽

Pritha Chanana ◽

...

Keyword(s):

Metabolic Syndrome ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Adipose Tissue ◽

Mirna Signature ◽

The Metabolic Syndrome

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Micro-RNAS Regulate Metabolic Syndrome-induced Senescence in Porcine Adipose Tissue-derived Mesenchymal Stem Cells through the P16/MAPK Pathway

Cell Transplantation ◽

10.1177/0963689718795692 ◽

2018 ◽

Vol 27 (10) ◽

pp. 1495-1503 ◽

Cited By ~ 13

Author(s):

Y. Meng ◽

A. Eirin ◽

X.-Y. Zhu ◽

H. Tang ◽

L.J. Hickson ◽

...

Keyword(s):

Metabolic Syndrome ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Adipose Tissue ◽

Mapk Pathway ◽

Mapk Signaling ◽

Repair System ◽

The Metabolic Syndrome ◽

Micro Rnas ◽

Mirna Sequencing

Mesenchymal stem cells (MSCs) constitute an important repair system, but may be impaired by exposure to cardiovascular risk factors. Consequently, adipose tissue-derived MSCs from pigs with the metabolic syndrome (MetS) show decreased vitality. A growing number of microRNAs (miRNAs) are recognized as key modulators of senescence, but their role in regulating senescence in MSC in MetS is unclear. We tested the hypothesis that MetS upregulates in MSC expression of miRNAs that can serve as post-transcriptional regulators of senescence-associated (SA) genes. MSCs were collected from swine abdominal adipose tissue after 16 weeks of Lean or Obese diet ( n = 6 each). Next-generation miRNA sequencing (miRNA-seq) was performed to identify miRNAs up-or down-regulated in MetS-MSCs compared with Lean-MSCs. Functional pathways of SA genes targeted by miRNAs were analyzed using gene ontology. MSC senescence was evaluated by p16 and p21 immunoreactivity, H2AX protein expression, and SA-β-Galactosidase activity. In addition, gene expression of p16, p21, MAPK3 (ERK1) and MAPK14, and MSC migration were studied after inhibition of SA-miR-27b. Senescence biomarkers were significantly elevated in MetS-MSCs. We found seven upregulated miRNAs, including miR-27b, and three downregulated miRNAs in MetS-MSCs, which regulate 35 SA genes, particularly MAPK signaling. Inhibition of miR-27b in cultured MSCs downregulated p16 and MARP3 genes, and increased MSC migration. MetS modulates MSC expression of SA-miRNAs that may regulate their senescence, and the p16 pathway seems to play an important role in MetS-induced MSC senescence.

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Abstract 1125: Mulberry Leaf Ameliorates The Production Of Adipocytokines By Inhibiting Oxidative Stress In White Adipose Tissue In db/db Mice

Circulation ◽

10.1161/circ.116.suppl_16.ii_226-c ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Masayuki Sugimoto ◽

Hidenori Arai ◽

Yukinori Tamura ◽

Toshinori Murayama ◽

Koh Ono ◽

...

Keyword(s):

Oxidative Stress ◽

Metabolic Syndrome ◽

Adipose Tissue ◽

White Adipose Tissue ◽

Metabolic Disorders ◽

The Body ◽

Mulberry Leaf ◽

The Metabolic Syndrome ◽

Pparγ Agonist ◽

Tnf Α

Mulberry leaf (ML) is commonly used to feed silkworms. Previous study showed that ML ameliorates atherosclerosis. However, its mechanism is not completely understood. Because dysregulated production of adipocytokines is involved in the development of the metabolic syndrome and cardiovascular disease, we examined the effect of ML on the production of adipocytokines and metabolic disorders related to the metabolic syndrome, and compared its effect with that of a PPARγ agonist, pioglitazone (Pio). By treating obese diabetic db/db mice with ML, Pio, and their combination, we investigated the mechanism by which they improve metabolic disorders. In this study, db/+m (lean control) and db/db mice were fed a standard diet with or without 3% (w/w) ML and/or 0.01% (w/w) Pio for 12 weeks from 9 weeks of age. At the end of the experiment we found that ML decreased plasma glucose and triglyceride by 32% and 30%, respectively. Interestingly, administration of ML in addition to Pio showed additive effects; further 40% and 30% reduction in glucose and triglyceride compared with Pio treatment, respectively. Moreover, administration of ML in addition to Pio suppressed the body weight increase by Pio treatment and reduced visceral/subcutaneous fat ratio by 20% compared with control db/db mice. Importantly, ML treatment increased expression of adiponectin in white adipose tissue (WAT) by 40%, which was only found in db/db mice, not in control db/+m mice. Combination of ML and Pio increased plasma adiponectin concentrations by 25% and its expression in WAT by 17% compared with Pio alone. In contrast, ML decreased expression of TNF-α and MCP-1 by 25% and 20%, respectively, and the addition of Pio resulted in a further decrease of these cytokines by about 45%. To study the mechanism, we examined the role of oxidative stress. ML decreased the amount of lipid peroxides by 43% and the expression of NADPH oxidase subunits in WAT, which was consistent with the results of TNF-α and MCP-1. Thus our results indicate that ML ameliorates adipocytokine dysregulation by inhibiting oxidative stress in WAT of obese mice, and that ML may have a potential for the treatment of the metabolic syndrome as well as reducing adverse effects of Pio.

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