The contribution of environmental pollutants to the obesity pandemic is still not yet fully recognized. Elucidating possible cellular and molecular mechanisms of their effects is of high importance. Our study aimed to evaluate the effect of chronic, 21-day-long, 2,2-bis (4-chlorophenyl)-1,1-dichlorethylenedichlorodiphenyldichloroethylene (p,p'-DDE) exposure of human adipose-derived mesenchymal stem cells committed to adipogenesis on mitochondrial oxygen consumption on days 4, 10, and 21. In addition, the mitochondrial membrane potential (MMP), the quality of the mitochondrial network, and lipid accumulation in maturing cells were evaluated. Compared to control differentiating adipocytes, exposure to p,p'-DDE at 1 μM concentration significantly increased basal (routine) mitochondrial respiration, ATP-linked oxygen consumption and MMP of intact cells on day 21 of adipogenesis. In contrast, higher pollutant concentration seemed to slow down the gradual increase in ATP-linked oxygen consumption typical for normal adipogenesis. Organochlorine p,p'-DDE did not alter citrate synthase activity. In conclusion, in vitro 1 μM p,p'-DDE corresponding to human exposure is able to increase the mitochondrial respiration per individual mitochondrion at the end of adipocyte maturation. Our data reveal that long-lasting exposure to p,p'-DDE could interfere with the metabolic programming of mature adipocytes.
- MeSH
- adipogeneze účinky léků MeSH
- buněčná diferenciace účinky léků MeSH
- dichlordifenyldichlorethylen toxicita MeSH
- kultivované buňky MeSH
- látky znečišťující životní prostředí toxicita MeSH
- lidé MeSH
- membránový potenciál mitochondrií MeSH
- mezenchymální kmenové buňky cytologie účinky léků MeSH
- mitochondrie účinky léků MeSH
- obezita metabolismus MeSH
- tukové buňky cytologie účinky léků MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Long-chain n-3 polyunsaturated fatty acids (Omega-3) and anti-diabetic drugs thiazolidinediones (TZDs) exhibit additive effects in counteraction of dietary obesity and associated metabolic dysfunctions in mice. The underlying mechanisms need to be clarified. Here, we aimed to learn whether the futile cycle based on the hydrolysis of triacylglycerol and re-esterification of fatty acids (TAG/FA cycling) in white adipose tissue (WAT) could be involved. We compared Omega-3 (30 mg/g diet) and two different TZDs-pioglitazone (50 mg/g diet) and a second-generation TZD, MSDC-0602K (330 mg/g diet)-regarding their effects in C57BL/6N mice fed an obesogenic high-fat (HF) diet for 8 weeks. The diet was supplemented or not by the tested compound alone or with the two TZDs combined individually with Omega-3. Activity of TAG/FA cycle in WAT was suppressed by the obesogenic HF diet. Additive effects in partial rescue of TAG/FA cycling in WAT were observed with both combined interventions, with a stronger effect of Omega-3 and MSDC-0602K. Our results (i) supported the role of TAG/FA cycling in WAT in the beneficial additive effects of Omega-3 and TZDs on metabolism of diet-induced obese mice, and (ii) showed differential modulation of WAT gene expression and metabolism by the two TZDs, depending also on Omega-3.
- MeSH
- bílá tuková tkáň metabolismus MeSH
- dieta s vysokým obsahem tuků MeSH
- hypoglykemika farmakologie MeSH
- kyseliny mastné omega-3 aplikace a dávkování farmakologie MeSH
- lipogeneze účinky léků MeSH
- mastné kyseliny metabolismus MeSH
- metabolismus lipidů účinky léků MeSH
- myši inbrední C57BL MeSH
- myši obézní MeSH
- myši MeSH
- obezita farmakoterapie metabolismus MeSH
- pioglitazon farmakologie MeSH
- thiazolidindiony aplikace a dávkování farmakologie MeSH
- triglyceridy metabolismus MeSH
- tukové buňky účinky léků MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
We found previously that white adipose tissue (WAT) hyperplasia in obese mice was limited by dietary omega-3 polyunsaturated fatty acids (omega-3 PUFA). Here we aimed to characterize the underlying mechanism. C57BL/6N mice were fed a high-fat diet supplemented or not with omega-3 PUFA for one week or eight weeks; mice fed a standard chow diet were also used. In epididymal WAT (eWAT), DNA content was quantified, immunohistochemical analysis was used to reveal the size of adipocytes and macrophage content, and lipidomic analysis and a gene expression screen were performed to assess inflammatory status. The stromal-vascular fraction of eWAT, which contained most of the eWAT cells, except for adipocytes, was characterized using flow cytometry. Omega-3 PUFA supplementation limited the high-fat diet-induced increase in eWAT weight, cell number (DNA content), inflammation, and adipocyte growth. eWAT hyperplasia was compromised due to the limited increase in the number of preadipocytes and a decrease in the number of endothelial cells. The number of leukocytes and macrophages was unaffected, but a shift in macrophage polarization towards a less inflammatory phenotype was observed. Our results document that the counteraction of eWAT hyperplasia by omega-3 PUFA in dietary-obese mice reflects an effect on the number of adipose lineage and endothelial cells.
- MeSH
- bílá tuková tkáň účinky léků MeSH
- dieta s vysokým obsahem tuků MeSH
- endoteliální buňky účinky léků MeSH
- kyseliny mastné omega-3 aplikace a dávkování MeSH
- makrofágy účinky léků patologie MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- proliferace buněk účinky léků MeSH
- tukové buňky cytologie účinky léků MeSH
- zánět patologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Global obesity rates are of epidemic proportion. With limited treatments available there is a large demand for therapeutic alternatives. Polyphenols derived from coloured rice varieties may serve as a potential functional food alternative in combating obesity and obesity-related diseases. The antioxidant and anti-inflammatory properties of polyphenols found in coloured rice varieties could have the ability to neutralize oxidative stress and modulate inflammatory responses in obese populations. This review discusses polyphenols derived from rice, the oxidative stress and inflammatory pathways involved in obesity pathogenesis, bioavailability of polyphenols and the therapeutic potential of polyphenols on transcriptional and molecular pathways related to obesity and obesity-related diseases.
- MeSH
- antioxidancia metabolismus MeSH
- LDL-cholesterol účinky léků MeSH
- lidé MeSH
- obezita farmakoterapie metabolismus patofyziologie MeSH
- oxidační stres účinky léků MeSH
- polyfenoly farmakologie terapeutické užití MeSH
- reaktivní formy kyslíku metabolismus MeSH
- rostlinné extrakty MeSH
- rýže (rod) chemie MeSH
- tukové buňky metabolismus účinky léků MeSH
- zánět metabolismus patofyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Obesity is characterized by accumulation of adipose tissue and is one the most important risk factors in the development of insulin resistance. Carbon monoxide-releasing (CO-releasing) molecules (CO-RMs) have been reported to improve the metabolic profile of obese mice, but the underlying mechanism remains poorly defined. Here, we show that oral administration of CORM-401 to obese mice fed a high-fat diet (HFD) resulted in a significant reduction in body weight gain, accompanied by a marked improvement in glucose homeostasis. We further unmasked an action we believe to be novel, by which CO accumulates in visceral adipose tissue and uncouples mitochondrial respiration in adipocytes, ultimately leading to a concomitant switch toward glycolysis. This was accompanied by enhanced systemic and adipose tissue insulin sensitivity, as indicated by a lower blood glucose and increased Akt phosphorylation. Our findings indicate that the transient uncoupling activity of CO elicited by repetitive administration of CORM-401 is associated with lower weight gain and increased insulin sensitivity during HFD. Thus, prototypic compounds that release CO could be investigated for developing promising insulin-sensitizing agents.
- MeSH
- adenosintrifosfát metabolismus MeSH
- buňky 3T3-L1 MeSH
- dieta s vysokým obsahem tuků MeSH
- hmotnostní přírůstek účinky léků MeSH
- inzulinová rezistence * MeSH
- myši inbrední C57BL MeSH
- myši obézní MeSH
- myši MeSH
- obezita metabolismus MeSH
- organokovové sloučeniny farmakologie MeSH
- oxid uhelnatý metabolismus MeSH
- tukové buňky účinky léků metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
This review provides evidence for the importance of white and brown adipose tissue (i.e. WAT and BAT) function for the maintenance of healthy metabolic phenotype and its preservation in response to omega-3 polyunsaturated fatty acids (omega-3 PUFA), namely in the context of diseased states linked to aberrant accumulation of body fat, systemic low-grade inflammation, dyslipidemia and insulin resistance. More specifically, the review deals with (i) the concept of immunometabolism, i.e. how adipose-resident immune cells and adipocytes affect each other and define the immune-metabolic interface; and (ii) the characteristic features of "healthy adipocytes" in WAT, which are relatively small fat cells endowed with a high capacity for mitochondrial oxidative phosphorylation, triacylglycerol/fatty acid (TAG/FA) cycling and de novo lipogenesis (DNL). The intrinsic metabolic features of WAT and their flexible regulations, reflecting the presence of "healthy adipocytes", provide beneficial local and systemic effects, including (i) protection against in situ endoplasmic reticulum stress and related inflammatory response during activation of adipocyte lipolysis; (ii) prevention of ectopic fat accumulation and dyslipidemia caused by increased hepatic VLDL synthesis, as well as prevention of lipotoxic damage of insulin signaling in extra-adipose tissues; and also (iii) increased synthesis of anti-inflammatory and insulin-sensitizing lipid mediators with pro-resolving properties, including the branched fatty acid esters of hydroxy fatty acids (FAHFAs), also depending on the activity of DNL in WAT. The "healthy adipocytes" phenotype can be induced in WAT of obese mice in response to various stimuli including dietary omega-3 PUFA, especially when combined with moderate calorie restriction, and possibly also with other life style (e.g. physical activity) or pharmacological (e.g. thiazolidinediones) interventions. While omega-3 PUFA could exert beneficial systemic effects by improving immunometabolism of WAT without a concomitant induction of BAT, it is currently not clear whether the metabolic effects of the combined intervention using omega-3 PUFA and calorie restriction or thiazolidinediones depend also on the activation of BAT function and/or the induction of brite/beige adipocytes in WAT. It remains to be established why omega-3 PUFA intervention in type 2 diabetic subjects does not improve insulin sensitivity and glucose homeostasis despite inducing various anti-inflammatory mediators in WAT, including the recently discovered docosahexaenoyl esters of hydroxy linoleic acid, the lipokines from the FAHFA family, as well as several endocannabinoid-related anti-inflammatory lipids. To answer the question whether and to which extent omega-3 PUFA supplementation could promote the formation of "healthy adipocytes" in WAT of human subjects, namely in the obese insulin-resistant patients, represents a challenging task that is of great importance for the treatment of some serious non-communicable diseases.
- MeSH
- bílá tuková tkáň účinky léků metabolismus MeSH
- inzulinová rezistence genetika MeSH
- kyseliny mastné omega-3 metabolismus terapeutické užití MeSH
- lidé MeSH
- lipolýza účinky léků MeSH
- metabolismus lipidů účinky léků genetika MeSH
- obezita dietoterapie genetika metabolismus MeSH
- tukové buňky účinky léků metabolismus MeSH
- zánět dietoterapie genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Zoledronic Acid (ZA) rapidly concentrates into the bone and reduces skeletal-related events and pain in bone metastatic prostate cancer (PCa), but exerts only a limited or absent impact as anti-cancer activity. Recently, we developed self-assembling nanoparticles (NPS) encapsulating zoledronic acid (NZ) that allowed a higher intratumor delivery of the drug compared with free zoledronic acid (ZA) in in vivo cancer models of PCa. Increasing evidence suggests that Bone Marrow (BM) Mesenchymal stromal cells (BM-MSCs) are recruited into the stroma of developing tumors where they contribute to progression by enhancing tumor growth and metastasis.We demonstrated that treatment with NZ decreased migration and differentiation into adipocytes and osteoblasts of MSCs and inhibited osteoclastogenesis. Treatment with NZ reduced the capability of MSCs to promote the migration and the clonogenic growth of the prostate cancer cell lines PC3 and DU145. The levels of Interleukin-6 and of the pro-angiogenic factors VEGF and FGF-2 were significantly reduced in MSC-CM derived from MSCs treated with NZ, and CCL5 secretion was almost totally abolished. Moreover, treatment of MSCs with supernatants from PC3 cells, leading to tumor-educated MSCs (TE-MSCs), increased the secretion of IL-6, CCL5, VEGF and FGF-2 by MSCs and increased their capability to increase PC3 cells clonogenic growth. Treatment with NZ decreased cytokine secretion and the pro-tumorigenic effects also of TE-MSCS. In conclusion, demonstrating that NZ is capable to inhibit the cross talk between MSCs and PCa, this study provides a novel insight to explain the powerful anticancer activity of NZ on PCa.
- MeSH
- bisfosfonáty aplikace a dávkování MeSH
- buněčná diferenciace účinky léků MeSH
- cytokiny metabolismus MeSH
- imidazoly aplikace a dávkování MeSH
- látky indukující angiogenezi metabolismus MeSH
- lidé MeSH
- mezenchymální kmenové buňky cytologie účinky léků metabolismus MeSH
- mezibuněčná komunikace účinky léků MeSH
- nádorové buněčné linie MeSH
- nádorové mikroprostředí účinky léků MeSH
- nádory prostaty metabolismus patologie MeSH
- nanočástice MeSH
- osteoblasty cytologie účinky léků metabolismus MeSH
- osteoklasty cytologie účinky léků metabolismus MeSH
- pohyb buněk účinky léků MeSH
- tukové buňky cytologie účinky léků metabolismus MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Emerging evidence indicates that polychlorinated biphenyls (PCBs) are involved in the development of diabetes mellitus in the obese. The purpose of this study was to determine mechanisms by which PCB 153 (2,2´,4,4´,5,5´-hexachloro-biphenyl) could influence diet-induced obesity and insulin resistance during adipogenesis. Lineage of h-ADMSCs was differentiated either as control (differentiation medium only), or with lipid vehicle modeling high fat nutrition (NuTRIflex) or lipid free vehicle (dimethylsulfoxide) for 28 days with or without PCB 153 daily co-exposure (in three concentrations 0.1, 1, and 10 microM). Gene expression analyses were performed using RT-qPCR at days 4, 10, 21, 24, 28; protein levels Akt and phosphorylated Akt (Phospho-Akt) by Western blot at days 4, and 21. PCB 153 treatment of h-ADMSCs only in lipid vehicle was associated with down regulation of key master genes of adipogenesis: PPARgamma, SREBP-1, PPARGC1B, and PLIN2 during the whole process of differentiation; and with increased Akt and decreased Phospho-Akt protein level at day 21. We have shown that PCB 153, in concentration 0.1 microM, has a potential in lipid rich environment to modulate differentiation of adipocytes. Because European and U.S. adults have been exposed to PCB 153, this particular nutrient-toxicant interaction potentially impacts human obesity and insulin sensitivity.
- MeSH
- buněčná diferenciace účinky léků fyziologie MeSH
- inzulinová rezistence fyziologie MeSH
- kultivované buňky MeSH
- lidé MeSH
- obezita chemicky indukované metabolismus MeSH
- polychlorované bifenyly toxicita MeSH
- tukové buňky účinky léků metabolismus MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Mutual interactions between adipocytes and immune cells in white adipose tissue (WAT) are involved in modulation of lipid metabolism in the tissue and also in response to omega-3 polyunsaturated fatty acids (PUFA), which counteract adverse effects of obesity. This complex interplay depends in part on in situ formed anti- as well as pro-inflammatory lipid mediators, but cell types engaged in the synthesis of the specific mediators need to be better characterized. We used tissue fractionation and metabolipidomic analysis to identify cells producing lipid mediators in epididymal WAT of mice fed for 5 weeks obesogenic high-fat diet (lipid content 35% wt/wt), which was supplemented or not by omega-3 PUFA (4.3 mg eicosapentaenoic acid and 14.7 mg docosahexaenoic acid per g of diet). Our results demonstrate selective increase in levels of anti-inflammatory lipid mediators in WAT in response to omega-3, reflecting either their association with adipocytes (endocannabinoid-related N-docosahexaenoylethanolamine) or with stromal vascular cells (pro-resolving lipid mediator protectin D1). In parallel, tissue levels of obesity-associated pro-inflammatory endocannabinoids were suppressed. Moreover, we show that adipose tissue macrophages (ATMs), which could be isolated using magnetic force from the stromal vascular fraction, are not the major producers of protectin D1 and that omega-3 PUFA lowered lipid load in ATMs while promoting their less-inflammatory phenotype. Taken together, these results further document specific roles of various cell types in WAT in control of WAT inflammation and metabolism and they suggest that also other cells but ATMs are engaged in production of pro-resolving lipid mediators in response to omega-3 PUFA.
- MeSH
- antiflogistika aplikace a dávkování MeSH
- aplikace orální MeSH
- bílá tuková tkáň cytologie účinky léků imunologie MeSH
- buňky stromatu účinky léků imunologie MeSH
- imunologické faktory imunologie MeSH
- kultivované buňky MeSH
- kyseliny mastné omega-3 aplikace a dávkování MeSH
- makrofágy cytologie účinky léků imunologie MeSH
- metabolismus lipidů účinky léků imunologie MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- potravní doplňky MeSH
- tukové buňky účinky léků enzymologie imunologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Obstructive sleep apnea (OSA) is associated with insulin resistance, glucose intolerance, and type 2 diabetes. Causal mechanisms mediating this association are not well defined; however, augmented lipolysis in adipose might be involved. Here, we investigated the effect of acipimox treatment (lipolysis inhibitor) on glucose tolerance and insulin sensitivity in mice exposed to intermittent hypoxia (IH). C57BL6/J mice were exposed for 14 days to IH or control conditions. IH was created by decreasing the fraction of inspired oxygen from 20.9 to 6.5%, 60 times/h. Control exposure was air (fraction of inspired oxygen, 20.9%) delivered at an identical flow rate. Acipimox was provided in drinking water (0.5 g/ml) during exposures. After exposures, intraperitoneal insulin (0.5 IU/kg) and glucose (1 g/kg) tolerance tests were performed, and primary adipocytes were isolated for lipolysis experiments. IH elevated fasting glucose by 51% and worsened glucose tolerance and insulin sensitivity by 33 and 102%, respectively. In parallel, IH increased spontaneous lipolysis by 264%, and reduced epididymal fat mass by 15% and adipocyte size by 8%. Acipimox treatment prevented IH-induced lipolysis and increased epididymal fat mass and adipocyte size by 19 and 10%, respectively. Acipimox fully prevented IH-induced impairments in fasting glycemia, glucose tolerance, and insulin sensitivity. For all reported results, P less than 0.05 was considered significant. Augmented lipolysis contributes to insulin resistance and glucose intolerance observed in mice exposed to IH. Acipimox treatment ameliorated the metabolic consequences of IH and might represent a novel treatment option for patients with obstructive sleep apnea.
- MeSH
- adipozita účinky léků MeSH
- experimentální diabetes mellitus krev komplikace genetika patologie MeSH
- fenotyp MeSH
- glukosa metabolismus MeSH
- hypoxie komplikace metabolismus MeSH
- inzulin metabolismus MeSH
- lipolýza * účinky léků MeSH
- mastné kyseliny krev MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední C57BL MeSH
- obstrukční spánková apnoe krev komplikace genetika patologie MeSH
- pyraziny farmakologie MeSH
- regulace genové exprese účinky léků MeSH
- signální transdukce účinky léků MeSH
- tukové buňky účinky léků patologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
