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Remodeling on adipocytic physiology of organophosphorus esters in mature adipocytes
2022
Liu, Ying | Le, Yifei | Xu, Mengting | Wang, Wanyue | Chen, Hang | Zhang, Quan | Wang, Cui
The emerging endocrine disruption chemicals organophosphate esters (OPEs) pose high risk of metabolic disruption. However, limited information is available on physiological disturbance of OPEs on adipose, a major endocrine and metabolic organ. In this study, physiological change was investigated after exposing 3T3-L1fully differentiated adipocytes to six OPEs at non-cytotoxic concentrations. We found two chlorinated-OPEs (tris-(2-chloro-1-(chloromethyl) ethyl) phosphate (TDCPP) and tris(2-chloroisopropyl) phosphate (TCPP)) and two alkyl-OPEs (tributyl phosphate (TBP) and tris (2-butoxyethyl) phosphate (TBEP)) induced inflammation-like adipokines (chemoattractant protein 1 and interleukin-6), respectively. Increment of insulin-resistance-related hormones (resistin and leptin) were observed under TDCPP, TCPP, and TBP exposure. Functional and mechanistic investigation revealed that all of the compounds inhibited lipolysis at basal level through dephosphorylated HSLˢᵉʳ⁵⁶³, the rate limiting enzyme of lipolysis. Triphenyl phosphate (TPhP), tricresyl phosphate (TCP), TDCPP, TBP and TBEP enhanced glucose uptake at both basal and insulin-stimulated status. We evidenced that impact was independent of the classical pIRSˢᵉʳ⁶³⁹/pAKTˢᵉʳ⁴⁷³ nor the insulin-independent AMPK pathway. The elevated mRNA of slc2a4 and its transcriptional factor LXRα may, at least partially, explain for the increase of glucose uptake. Given the focus within the endocrine disruption on glands, it would be prudent not to ignore endocrinal impact on adipocytes.
Afficher plus [+] Moins [-]Obesogenic effect of erythromycin on Caenorhabditis elegans through over-eating and lipid metabolism disturbances
2022
Luo, Zhili | Yu, Zhenyang | Yin, Daqiang
Environmental obesogens contributed significantly to the obesity prevalence. Recently, antibiotics joined the list of environmental obesogens, while the underlying mechanisms remained to be explored. In the present study, effects of erythromycin (ERY), one widely used macrolide antibiotic, were measured on C. elegans to investigate the obesogenic mechanism. Results showed that ERY at 0.1 μg/L significantly increased the fat content by 17.4% more than the control and also stimulated triacylglycerol (TAG) levels by 25.7% more than the control. Regarding the obesogenic mechanisms, ERY provoked over-eating by stimulation on the pharyngeal pumping and reduction on the satiety quiescence percentage and duration. Such effects were resulted from stimulation on the neurotransmitters including serotonin (5-HT), dopamine (DA) and acetylcholine (ACh). The nervous responses involved the up-regulation of Gsα (e.g., ser-7, gsa-1, acy-1 and kin-2) signaling pathway and the down-regulation of TGFβ (daf-7) but not via cGMP-dependent regulations (e.g., egl-4). Moreover, ERY stimulated the activities of fatty acid synthase (FAS) and glycerol-3-phosphateacyl transferases (GPAT) that catalyze lipogenesis, while ERY inhibited those of acyl-CoA synthetase (ACS), carnitine palmitoyl transferase (CPT) and acyl-CoA oxidase (ACO) that catalyze lipolysis. The unbalance between lipogenesis and lipolysis resulted in the fat accumulation which was consistent with up-regulation on mgl-1 and mgl-3 which are the down-steam of TGFβ regulation. Such consistence supported the close connection between nervous regulation and lipid metabolism. In addition, ERY also disturbed insulin which connects lipid with glucose in metabolism.
Afficher plus [+] Moins [-]Early-life exposure to bisphenol A induces dysregulation of lipid homeostasis by the upregulation of SCD1 in male mice
2022
Fang, Ruyue | Yang, Shaohua | Gu, Xiaozhen | Li, Changqing | Bi, Nanxi | Wang, Hui-Li
Exposure of Bisphenol A (BPA) is closely associated with an increased prevalence of obesity-related metabolic syndrome. However, the potential mechanism of BPA-induced adipogenesis remains to be fully elucidated. Herein, potential mechanisms of BPA-induced adipogenesis in 3T3-L1 preadipocytes were evaluated using RNA-Seq. Then, using an early-life BPA exposure model, we further evaluated the effects of BPA exposure on lipid and glucose homeostasis. The results showed that lipid content in 3T3-L1 adipocytes was significantly increased after BPA exposure (p < 0.01) and male C57BL/6 mice with the dose of 500 μg/kg/day BPA by once-a-day oral administration for 8 weeks displayed a NAFLD-like phenotype. RNA-Seq analysis of preadipocytes showed that BPA exposure affected multiple biological processes including glycosphingolipid biosynthesis, regulation of lipolysis in adipocytes, PPAR signaling pathway and fatty acid metabolism. The dysregulation in a series of genes of mice was associated to de novo lipogenesis and lipid transport, which was linked to obesity. Importantly, we also found a significant expression increase of stearoyl-CoA desaturase 1 (SCD1) and a significant decrease of apolipoprotein D (APOD) in both fat (p < 0.01) and livers (p < 0.01) of male mice. Besides, the dysregulation of pro-inflammatory genes (TNF-α,IL-6 and SAA3) showed that BPA exposure promoted progression of hepatic inflammation. In conclusion, this study elucidated a novel mechanism in which obesity associated with BPA exposure by targeting SCD1. Exposure to BPA should be carefully examined in the chronic liver metabolic diseases.
Afficher plus [+] Moins [-]Endoplasmic reticulum (ER) stress and cAMP/PKA pathway mediated Zn-induced hepatic lipolysis
2017
Song, Yu–Feng | Hogstrand, Christer | Wei, Chuan-Chuan | Wu, Kun | Pan, Ya–Xiong | Luo, Zhi
The present study was performed to determine the effect of Zn exposure influencing endoplasmic reticulum (ER) stress, explore the underlying molecular mechanism of Zn-induced hepatic lipolysis in a fish species of significance for aquaculture, yellow catfish Pelteobagrus fulvidraco. We found that waterborne Zn exposure evoked ER stress and unfolded protein response (UPR), and activated cAMP/PKA pathway, and up-regulated hepatic lipolysis. The increase in ER stress and lipolysis were associated with activation of cAMP/PKA signaling pathway. Zn also induced an increase in intracellular Ca2+ level, which could be partially prevented by dantrolene (RyR receptor inhibitor) and 2-APB (IP3 receptor inhibitor), demonstrating that the disturbed Ca2+ homeostasis in ER contributed to ER stress and dysregulation of lipolysis. Inhibition of ER stress by PBA attenuated UPR, inhibited the activation of cAMP/PKA pathway and resulted in down-regulation of lipolysis. Inhibition of protein kinase RNA-activated-like ER kinase (PERK) by GSK2656157 and inositol-requiring enzyme (IRE) by STF-083010 differentially influenced Zn-induced changes of lipolytic metabolism, indicating that PERK and IRE pathways played different regulatory roles in Zn-induced lipolysis. Inhibition of PKA by H89 blocked the Zn-induced activation of cAMP/PKA pathway with a concomitant inhibition of ER stress-mediated lipolysis. Taken together, our findings highlight the importance of the ER stress–cAMP/PKA axis in Zn-induced lipolysis, which provides new insights into Zn toxicology in fish and probably in other vertebrates.
Afficher plus [+] Moins [-]Long-term exposure to environmental levels of phenanthrene induces emaciation-thirst disease-like syndromes in female mice
2022
Fang, Lu | Ou, Kunlin | Huang, Jie | Zhang, Shenli | Zhang, Ying | Zhao, Hezhen | Chen, Meng | Wang, Chonggang
Phenanthrene (Phe) is a polycyclic aromatic hydrocarbon widely present in foods and drinking water. To explore the detrimental effects of Phe on body metabolism, female Kunming mice were treated with Phe in drinking water at concentrations of 0.05, 0.5 and 5 ng/mL. After exposure for 270 d, the animals exhibited dose-dependent reduced body weight and increased water consumption. The dose-dependent accumulation of Phe in the brain decreased hypothalamic neuron numbers, upregulated hypothalamic expression of anaplastic lymphoma kinase, elevated norepinephrine levels in white adipose tissue (WAT) and further activated lipolysis in WAT, leading to a reduction in fat mass. Brown adipose tissue formation was reduced, accompanied by the inhibition of the bone morphogenetic protein signaling pathway. A simultaneous reduced serum levels of antidiuretic hormone (arginine vasopressin) might be one of the reasons for increased water consumption. The present results indicate an environmental etiology and prevention way for the development of emaciation-thirst disease.
Afficher plus [+] Moins [-]Lipid metabolic adaption to long-term ambient PM2.5 exposure in mice
2021
Emerging evidence has demonstrated that exposure to fine particulate matter (PM₂.₅) is a risk factor for lipid metabolic disorders in the liver. However, the effects of PM₂.₅ exposure time duration on hepatic lipid metabolism remain unknown. In this study, C57BL/6 mice were randomly divided into ambient PM₂.₅ (PM) or filtered air (FA) exposure chamber for short-term (4 weeks) or long-term (24 weeks) exposure via a whole body exposure system. We measured hepatic triglyceride and free fatty acid levels and analyzed the alteration of lipometabolism-related molecules in the liver. We found that triglyceride levels were significantly elevated in both short-term and long-term PM₂.₅-exposed mice and free fatty acid levels were increased after long-term PM₂.₅ exposure. Besides, enzymes for lipolysis and fatty acid oxidation in the liver were inhibited after short-term PM₂.₅ exposure but adaptively enhanced after long-term PM₂.₅ exposure. Furthermore, molecules for fatty acid uptake were down-regulated in the short-term PM₂.₅-exposed mice whereas molecules for lipid export were induced after long-term PM₂.₅ exposure. Therefore, ambient PM₂.₅ exposure disturbed hepatic lipid metabolism and the effects varied in different exposure duration. These findings in mice provide new insight into the biological basis of PM₂.₅-induced human metabolic dysfunction and specific strategies may be applied based on different exposure time periods.
Afficher plus [+] Moins [-]Multigenerational study of the obesogen effects of bisphenol S after a perinatal exposure in C57BL6/J mice fed a high fat diet
2021
Brulport, Axelle | Le Corre, Ludovic | Maquart, Guillaume | Barbet, Virginie | Dastugue, Aurélie | Severin, Isabelle | Vaiman, Daniel | Chagnon, Marie-Christine
Bisphenol S is an endocrine disruptor exhibiting metabolic disturbances, especially following perinatal exposures. To date, no data are available on the obesogen effects of BPS in a mutligenerational issue.We investigated obesogen effects of BPS in a multigenerational study by focusing on body weight, adipose tissue and plasma parameters in male and female mice.Pregnant C57BL6/J mice were exposed to BPS (1.5 μg/kg bw/day ie a human equivalent dose of 0.12 μg/kg bw/day) by drinking water from gestational day 0 to post natal day 21. All offsprings were fed with a high fat diet during 15 weeks. Body weight was monitored weekly and fat mass was measured before euthanasia. At euthanasia, blood glucose, insuline, triglyceride, cholesterol and no esterified fatty acid plasma levels were determined and gene expressions in visceral adipose tissue were assessed. F1 males and females were mated to obtain the F2 generation. Likewise, the F2 mice were cross-bred to obtain F3. The same analyses were performed.In F1 BPS induced an overweight in male mice associated to lipolysis gene expressions upregulation. In F1 females, dyslipidemia was observed. In F2, BPS exposure was associated to an increase in body weight, fat and VAT masses in males and females. Several plasma parameters were increased but with a sex related pattern (blood glucose, triglycerides and cholesterol in males and NEFA in females). We observed a down-regulation in mRNA expression of gene involved in lipogenesis and in lipolysis for females but only in the lipogenesis for males. In F3, a decrease in VAT mass and an upregulation of lipogenesis gene expression occurred only in females.BPS perinatal exposure induced sex-dependent obesogen multigenerational effects, the F2 generation being the most impacted. Transgenerational disturbances persisted only in females.
Afficher plus [+] Moins [-]Environmentally relevant concentrations of oxytetracycline and copper increased liver lipid deposition through inducing oxidative stress and mitochondria dysfunction in grass carp Ctenopharyngodon idella
2021
Xu, Yi-Huan | Hogstrand, Christer | Xu, Yi-Chuang | Zhao, Tao | Zheng, Hua | Luo, Zhi
Oxytetracycline (OTC) and Cu are prevalent in aquatic ecosystems and their pollution are issues of serious concern. The present working hypothesis is that the toxicity of Cu and OTC mixture on physiological activity of fish was different from single OTC and Cu alone. The present study indicated that, compared to single OTC or Cu alone, Cu+OTC mixture reduced growth performance and feed utilization of grass carp, escalated the contents of Cu, OTC and TG, increased lipogenesis, induced oxidative stress, damaged the mitochondrial structure and functions and inhibited the lipolysis in the liver tissues and hepatocytes of grass carp. Cu+OTC co-treatment significantly increased the mRNA abundances and protein expression of Nrf2. Moreover, we found that Cu+OTC mixture-induced oxidative stress promoted Nrf2 recruitment to the SREBP-1 promoter and increased SREBP-1-mediated lipogenesis; Nrf2 sited at the crossroads of oxidative stress and lipid metabolism, and mediated the regulation of oxidative stress and lipid metabolism. Our findings clearly indicated that OTC and Cu mixture differed in environmental risks from single antibiotic or metal element itself, and thus posed different toxicological responses to aquatic animals. Moreover, our findings suggested that Nrf2 functioned as an important antioxidant regulator linking oxidative stress to lipogenic metabolism, and thus elucidated a novel regulatory mechanism for lipid metabolism.
Afficher plus [+] Moins [-]Excess iron supplementation induced hepatopancreas lipolysis, destroyed intestinal function in Pacific white shrimp Litopenaeus vannamei
2022
Jiao, Lefei | Dai, Tianmeng | Lu, Jingjing | Tao, Xinyue | Jin, Min | Sun, Peng | Zhou, Qicun
So far, the adverse effects of excess Fe in shrimp have been ignored for years as it was thought that extra Fe supplementation was not needed in the practical diets. Nowadays, Fe concentration in commercial shrimp feed from feed enterprises could be around 301.34–545.5 mg/kg, which is mainly due to the fish meal containing up to 1500 mg/kg Fe. Therefore, the purpose of this experiment was to investigate the effects of Fe supplementation on the growth performance, tissue Fe deposition, hepatopancreas lipid metabolism, intestinal function in L. vannamei. The results showed that although growth performance was not influenced by the dietary Fe supplementation, excess Fe supplementation (955.00 mg/kg) significantly increased hepatopancreas Fe deposition and induced lipolysis. Moreover, excess Fe supplementation impaired intestinal immune function and disrupted microbiota homeostasis. These findings might provide partial theoretical evidence for the effect of dietary Fe supplementation on physiological metabolism in L. vannamei.
Afficher plus [+] Moins [-]Bisphenol A disturbs metabolism of primary rat adipocytes without affecting adipokine secretion
2021
Szkudelska, Katarzyna | Okulicz, Monika | Szkudelski, Tomasz
Bisphenol A (BPA) is an ubiquitous synthetic chemical exerting numerous adverse effects. Results of rodent studies show that BPA negatively affects adipose tissue. However, the short-term influence of this compound addressing adipocyte metabolism and adipokine secretion is unknown. In the present study, isolated rat adipocytes were exposed for 2 h to 1 and 10 nM BPA. Insulin-induced glucose conversion to lipids along with glucose transport was significantly increased in the presence of BPA. However, basal glucose conversion to lipids, glucose oxidation, and formation of lipids from acetate were unchanged in adipocytes incubated with BPA. It was also shown that BPA significantly increases lipolytic response of adipocytes to epinephrine. However, lipolysis stimulated by dibutyryl-cAMP (a direct activator of protein kinase A) and the antilipolytic action of insulin were not affected by BPA. Moreover, BPA did not influence leptin and adiponectin secretion from adipocytes. Our new results show that BPA is capable of disturbing processes related to lipid accumulation in isolated rat adipocytes. This is associated with the potentiation of insulin and epinephrine action. The effects of BPA appear already after short-term exposure to low doses of this compound. However, BPA fails to change adipokine secretion.
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