scholarly journals High-Fat Diet Causes Lipotoxicity Responses in Cumulus–Oocyte Complexes and Decreased Fertilization Rates

Endocrinology ◽  
2010 ◽  
Vol 151 (11) ◽  
pp. 5438-5445 ◽  
Author(s):  
Linda Lin-Yan Wu ◽  
Kylie R. Dunning ◽  
Xing Yang ◽  
Darryl L. Russell ◽  
Michelle Lane ◽  
...  
Keyword(s):  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Granulosa Cells ◽  
Follicular Fluid ◽  
High Fat Diet ◽  
Marker Genes ◽  
Obese Women ◽  
High Fat ◽  
Fertilization Rates ◽  
Ovarian Cells

In obesity, accumulation of lipid in nonadipose tissues, or lipotoxicity, is associated with endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and ultimately apoptosis. We have previously shown that obese women have increased triglycerides in follicular fluid; thus, the present study examined whether high-fat diet–induced obesity causes lipotoxicity in granulosa cells and the cumulus–oocyte complex (COC). Oocytes of mice fed a high-fat diet had dramatically increased lipid content and reduced mitochondrial membrane potential compared to those of mice fed a control diet. COCs from mice fed a high-fat diet had increased expression of ER stress marker genes ATF4 and GRP78. Apoptosis was increased in granulosa and cumulus cells of mice fed a high-fat diet. Mice fed a high-fat diet also exhibited increased anovulation and decreased in vivo fertilization rates. Thus, lipid accumulation, ER stress, mitochondrial dysfunction, and apoptosis are markedly increased in ovarian cells of mice fed a high-fat diet. ER stress markers were also analyzed in granulosa cells and follicular fluid from women with varying body mass indices (BMI). ATF4 was increased in granulosa cells and [Ca2+] in follicular fluid from obese women compared to nonobese women. These results indicate that lipotoxicity may be occurring in ovarian cells of obese women and may contribute to the reduced pregnancy rates observed in response to obesity.

151. LIPOTOXICITY MEDIATED ENDOPLASMIC RETICULUM STRESS, MITOCHONDRIAL DYSFUNCTION AND APOPTOSIS CONTRIBUTE IMPAIRED OOCYTE QUALITY IN RESPONSE TO OBESITY

2009 ◽  
Vol 21 (9) ◽  
pp. 69
Author(s):  
L. L. Y. Wu ◽  
X. Yang ◽  
K. R. Dunning ◽  
R. J. Norman ◽  
R. L. Robker
Keyword(s):  
Endoplasmic Reticulum ◽  
Membrane Potential ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Granulosa Cells ◽  
Oocyte Quality ◽  
Developmental Competence ◽  
Tunel Staining ◽  
Marker Genes ◽  
Er Homeostasis

In obesity, accumulation of lipid in non-adipose tissues, a process termed lipotoxicity, is associated with endoplasmic reticulum (ER) stress, mitochondrial dysfunction and ultimately apoptosis . We have previously shown that diet-induced obesity in mice causes impaired oocyte developmental competence, but whether this is due to activation of lipotoxicity pathways in the ovary is not known. The present study examined the hypothesis that diet-induced lipid accumulation in the cumulus oocyte complex (COC) disrupts ER homeostasis and mitochondrial membrane potential which leads to apoptosis. COCs and mural granulosa cells were collected from ovaries of adult mice fed a high fat (HFD) or control diet for 4 weeks. ER homeostasis was assessed by measuring expression of known ER stress marker genes, GRP78, ATF4 and CHOP. COCs from mice fed HFD showed significantly increased expression of GRP78 and ATF4. There was a similar trend towards increased expression in granulosa cells. Mitochondrial function was assessed by measuring membrane potential using the dual emission probe JC-1. In COCs from mice fed HFD there were reduced numbers of active mitochondria but instead large aggregated clusters of inactive mitochondria. Apoptosis in granulosa cells was determined by DNA laddering assay which showed significantly increased DNA fragmentation in cells from mice fed HFD. Apoptosis was also assessed by TUNEL staining of paraffin embedded ovaries from identical treatment groups. Ovaries from HFD mice appeared to have increased TUNEL positivity in both granulosa and cumulus cells. Our results demonstrate that the ER stress, mitochondrial dysfunction and apoptosis are markedly increased in granulosa cells and COCs from mice fed HFD, suggesting that lipotoxicity contributes to the impaired oocyte quality and reduced fertility observed in response to obesity.

LXRs Protect DRG Neurons from High-Fat Diet–Induced ER Stress and Allodynia

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 553-P
Author(s):  
VIRGINIE AUBERT
Keyword(s):  
Er Stress ◽  
High Fat Diet ◽  
High Fat ◽  
Drg Neurons

Hyperbaric oxygen therapy attenuates D-galactose-induced-age-related cardiac dysfunction through mitigating cardiac mitochondrial dysfunction in pre-diabetic rats

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
C Bo-Htay ◽  
T Shwe ◽  
S Palee ◽  
T Pattarasakulchai ◽  
K Shinlapawittayatorn ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
High Fat Diet ◽  
Diabetic Rats ◽  
Normal Diet ◽  
Lv Function ◽  
High Fat ◽  
Insulin Resistant ◽  
Lv Dysfunction ◽  
Age Related ◽  
Mitochondrial Functions

Abstract Background D-galactose (D-gal) induced ageing has been shown to exacerbate left ventricular (LV) dysfunction via worsening of apoptosis and mitochondrial dysfunction in the heart of obese rats. Hyperbaric oxygen therapy (HBOT) has been demonstrated to exert anti-inflammatory and anti-apoptotic effects in multiple neurological disorders. However, the cardioprotective effect of HBOT on inflammation, apoptosis, LV and mitochondrial functions in D-gal induced ageing rats in the presence of obese-insulin resistant condition has never been investigated. Purpose We sought to determine the effect of HBOT on inflammation, apoptosis, mitochondrial functions and LV function in pre-diabetic rats with D-gal induced ageing. We hypothesized that HBOT attenuates D-gal induced cardiac mitochondrial dysfunctions and reduces inflammation and apoptosis, leading to improved LV function in pre-diabetic rats. Methods Forty-eight male Wistar rats were fed with either normal diet or high-fat diet for 12 weeks. Then, rats were treated with either vehicle groups (0.9% NSS, subcutaneous injection (SC)) or D-gal groups (150 mg/kg/day, SC) for 8 weeks. At week 21, rats in each group were equally divided into 6 sub-groups: normal diet fed rats treated with vehicle (NDV) sham, normal diet fed rats treated with D-gal (NDDg) sham, high fat diet fed rats treated with D-gal (HFDg) sham, high fat diet fed rats treated with vehicle (HFV) + HBOT, NDDg + HBOT and HFDg + HBOT. Sham treated rats were given normal concentration of O2 (flow rate of 80 L/min, 1 ATA for 60 minutes), whereas HBOT treated rats were subjected to 100% O2 (flow rate of 250 L/min, 2 ATA for 60 minutes), given once daily for 2 weeks. Results Under obese-insulin resistant condition, D-gal-induced ageing aggravated LV dysfunction (Fig 1A) and impaired cardiac mitochondrial function, increased cardiac inflammatory and apoptotic markers (Fig 1B). HBOT markedly reduced cardiac TNF-α level and TUNEL positive apoptotic cells, and improved cardiac mitochondrial function as indicated by decreased mitochondrial ROS production, mitochondrial depolarization and mitochondrial swelling, resulting in the restoration of the normal LV function in HFV and NDDg rats, compared to sham NDDg rats. In addition, in HFDg treated rats, HBOT attenuated cardiac TNF-α level, TUNEL positive apoptotic cells and cardiac mitochondrial dysfunction, compared to sham HFDg rats, leading to improved cardiac function as indicated by increased %LV ejection fraction (LVEF) (Figure 1). Conclusion HBOT efficiently alleviates D-gal-induced-age-related LV dysfunction through mitigating inflammation, apoptosis and mitochondrial dysfunction in pre-diabetic rats. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): 1. The National Science and Technology Development Agency Thailand, 2. Thailand Research Fund Grants

scholarly journals Palmitate reduces starvation-induced ER stress by inhibiting ER-phagy in hypothalamic cells

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yun Lim ◽  
Seolsong Kim ◽  
Eun-Kyoung Kim
Keyword(s):  
Er Stress ◽  
High Fat Diet ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Fat ◽  
Selective Autophagy ◽  
Induced Stress ◽  
Hypothalamic Cells ◽  
The Brain ◽  
Main Region

AbstractPalmitate is a saturated fatty acid that is well known to induce endoplasmic reticulum (ER) stress and autophagy. A high-fat diet increases the palmitate level in the hypothalamus, the main region of the brain regulating energy metabolism. Interestingly, hypothalamic palmitate level is also increased under starvation, urging the study to distinguish the effects of elevated hypothalamic palmitate level under different nutrient conditions. Herein, we show that ER-phagy (ER-targeted selective autophagy) is required for progress of ER stress and that palmitate decreases ER stress by inhibiting ER-phagy in hypothalamic cells under starvation. Palmitate inhibited starvation-induced ER-phagy by increasing the level of B-cell lymphoma 2 (Bcl-2) protein, which inhibits autophagy initiation. These findings suggest that, unlike the induction of ER stress under nutrient-rich conditions, palmitate protects hypothalamic cells from starvation-induced stress by inhibiting ER-phagy.

scholarly journals Maternal high-fat diet induces metabolic stress response disorders in offspring hypothalamus

2017 ◽  
Vol 59 (1) ◽  
pp. 81-92 ◽  
Author(s):  
Long The Nguyen ◽  
Sonia Saad ◽  
Yi Tan ◽  
Carol Pollock ◽  
Hui Chen
Keyword(s):  
Endoplasmic Reticulum ◽  
Body Weight ◽  
Er Stress ◽  
High Fat Diet ◽  
Maternal Obesity ◽  
Mrna Level ◽  
Metabolic Stress ◽  
High Fat ◽  
Chemical Chaperone ◽  
Protein Levels

Maternal obesity has been shown to increase the risk of obesity and related disorders in the offspring, which has been partially attributed to changes of appetite regulators in the offspring hypothalamus. On the other hand, endoplasmic reticulum (ER) stress and autophagy have been implicated in hypothalamic neuropeptide dysregulation, thus may also play important roles in such transgenerational effect. In this study, we show that offspring born to high-fat diet-fed dams showed significantly increased body weight and glucose intolerance, adiposity and plasma triglyceride level at weaning. Hypothalamic mRNA level of the orexigenic neuropeptide Y (NPY) was increased, while the levels of the anorexigenic pro-opiomelanocortin (POMC), NPY1 receptor (NPY1R) and melanocortin-4 receptor (MC4R) were significantly downregulated. In association, the expression of unfolded protein response (UPR) markers including glucose-regulated protein (GRP)94 and endoplasmic reticulum DNA J domain-containing protein (Erdj)4 was reduced. By contrast, protein levels of autophagy-related genes Atg5 and Atg7, as well as mitophagy marker Parkin, were slightly increased. The administration of 4-phenyl butyrate (PBA), a chemical chaperone of protein folding and UPR activator, in the offspring from postnatal day 4 significantly reduced their body weight, fat deposition, which were in association with increased activating transcription factor (ATF)4, immunoglobulin-binding protein (BiP) and Erdj4 mRNA as well as reduced Parkin, PTEN-induced putative kinase (PINK)1 and dynamin-related protein (Drp)1 protein expression levels. These results suggest that hypothalamic ER stress and mitophagy are among the regulatory factors of offspring metabolic changes due to maternal obesity.

scholarly journals 12/15-Lipoxygenase signaling in the endoplasmic reticulum stress response

2012 ◽  
Vol 302 (6) ◽  
pp. E654-E665 ◽  
Author(s):  
Banumathi K. Cole ◽  
Norine S. Kuhn ◽  
Shamina M. Green-Mitchell ◽  
Kendall A. Leone ◽  
Rebekah M. Raab ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Pancreatic Islets ◽  
High Fat Diet ◽  
Wild Type ◽  
High Fat ◽  
Stress Markers ◽  
Deficient Mice

Central obesity is associated with chronic inflammation, insulin resistance, β-cell dysfunction, and endoplasmic reticulum (ER) stress. The 12/15-lipoxygenase enzyme (12/15-LO) promotes inflammation and insulin resistance in adipose and peripheral tissues. Given that obesity is associated with ER stress and 12/15-LO is expressed in adipose tissue, we determined whether 12/15-LO could mediate ER stress signals. Addition of 12/15-LO lipid products 12(S)-HETE and 12(S)-HPETE to differentiated 3T3-L1 adipocytes induced expression and activation of ER stress markers, including BiP, XBP-1, p-PERK, and p-IRE1α. The ER stress inducer, tunicamycin, upregulated ER stress markers in adipocytes with concomitant 12/15-LO activation. Addition of a 12/15-LO inhibitor, CDC, to tunicamycin-treated adipocytes attenuated the ER stress response. Furthermore, 12/15-LO-deficient adipocytes exhibited significantly decreased tunicamycin-induced ER stress. 12/15-LO action involves upregulation of interleukin-12 (IL-12) expression. Tunicamycin significantly upregulated IL-12p40 expression in adipocytes, and IL-12 addition increased ER stress gene expression; conversely, LSF, an IL-12 signaling inhibitor, and an IL-12p40-neutralizing antibody attenuated tunicamycin-induced ER stress. Isolated adipocytes and liver from 12/15-LO-deficient mice fed a high-fat diet revealed a decrease in spliced XBP-1 expression compared with wild-type C57BL/6 mice on a high-fat diet. Furthermore, pancreatic islets from 12/15-LO-deficient mice showed reduced high-fat diet-induced ER stress genes compared with wild-type mice. These data suggest that 12/15-LO activity participates in ER stress in adipocytes, pancreatic islets, and liver. Therefore, reduction of 12/15-LO activity or expression could provide a new therapeutic target to reduce ER stress and downstream inflammation linked to obesity.

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