Protective effect of FGF21 on type 1 diabetes-induced testicular apoptotic cell death probably via both mitochondrial- and endoplasmic reticulum stress-dependent pathways in the mouse model

Jiang, Xin; Zhang, Chi; Xin, Ying; Huang, Zhifeng; Tan, Yi; Huang, Yadong; Wang, Yonggang; Feng, Wenke; Li, Xiaokun; Li, Wei; Qu, Yaqin; Cai, Lu

doi:10.1016/j.toxlet.2013.02.022

Cited by 77 publications

(65 citation statements)

References 40 publications

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“…Of even more interest, there was no increase in caspase-8 cleavage in the testis of STZ-induced T1DM mice compared with their age-matched controls (19). We demonstrated here for the first time that the level of caspase-8 cleavage was increased significantly in the testis of IDS-T2DM mice (Fig.…”

Section: Discussionmentioning

confidence: 47%

Sulforaphane reduction of testicular apoptotic cell death in diabetic mice is associated with the upregulation of Nrf2 expression and function

Wang

Zhang

Guo

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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L. Sulforaphane reduction of testicular apoptotic cell death in diabetic mice is associated with the upregulation of Nrf2 expression and function. Am J Physiol Endocrinol Metab 307: E14 -E23, 2014. First published May 6, 2014 doi:10.1152/ajpendo.00702.2013.-Diabetes-induced testicular cell death is due predominantly to oxidative stress. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is an important transcription factor in controlling the antioxidative system and is inducible by sulforaphane (SFN). To test whether SFN prevents diabetes-induced testicular cell death, an insulin-defective stage of type 2 diabetes (IDS-T2DM) was induced in mice. This was accomplished by feeding them a high-fat diet (HFD) for 3 mo to induce insulin resistance and then giving one intraperitoneal injection of streptozotocin to induce hyperglycemia while age-matched control mice were fed a normal diet (ND). IDS-T2DM and ND-fed control mice were then further subdivided into those with or without 4-mo SFN treatment. IDS-T2DM induced significant increases in testicular cell death presumably through receptor and mitochondrial pathways, shown by increased ratio of Bax/Bcl2 expression and cleavage of caspase-3 and caspase-8 without significant change of endoplasmic reticulum stress. Diabetes also significantly increased testicular oxidative damage and inflammation. All of these diabetic effects were significantly prevented by SFN treatment with upregulated Nrf2 expression. These results suggest that IDS-T2DM induces testicular cell death presumably through caspase-8 activation and mitochondria-mediated cell death pathways and also by significantly downregulating testicular Nrf2 expression and function. SFN upregulates testicular Nrf2 expression and its target antioxidant expression, which was associated with significant protection of the testis from IDS-T2DM-induced germ cell death. male germ cell death; sulforaphane; nuclear factor (erythroid-derived 2)-like 2; type 2 diabetes; high-fat diet

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Section: Discussionmentioning

confidence: 47%

Sulforaphane reduction of testicular apoptotic cell death in diabetic mice is associated with the upregulation of Nrf2 expression and function

Wang

Zhang

Guo

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…Oxidative stress stimulates FGF19 expression only in vitro. Secreted FGF21 has been reported to ameliorate oxidative damage (39) and inhibit the expression of genes related to lipogenesis that are increased by a leucine-deficient diet (33). These observations are physiologically relevant; hence, FGF21 expression is regulated by oxidative stress and amino acid deprivation.…”

Section: Discussionmentioning

confidence: 98%

Selective Regulation of FGF19 and FGF21 Expression by Cellular and Nutritional Stress

Shimizu

Morimoto

Maruyama

et al. 2015

J Nutr Sci Vitaminol

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Summary Fibroblast growth factor 19 (FGF19) and FGF21 are members of a subfamily of the FGFs called endocrine FGFs. FGF19 regulates the bile acid synthetic pathway. FGF19 expression is induced by farnesoid X receptor (FXR), a nuclear hormone receptor activated by bile acids in the small intestine. FGF21 plays an important role in lipolysis that occurs in white adipose tissue. FGF21 expression is stimulated by the nuclear fatty acid receptor peroxisome proliferator-activated receptor a (PPARa) in the liver. FGF19 and FGF21 were recently identified as targets of activating transcription factor 4 (ATF4), which is activated in response to endoplasmic reticulum (ER) stress. ATF4 is also activated by oxidative stress and amino acid deprivation. In this study, we investigated FGF19 and FGF21 expression in response to oxidative stress and amino acid deprivation. We found that FGF19 mRNA is induced by oxidative stress inducers in Caco-2 cells, which are derived from the human intestinal epithelium, and rat intestinal epithelial IEC6 cells. In contrast, ileal FGF15 expression, the rodent ortholog of human FGF19, is not increased by oxidative stress. No notable changes in expression of FGF15/19 took place under amino acid deprivation either in vitro or in vivo. In contrast, FGF21 expression is induced by oxidative stress and amino acid deprivation both in vitro and in vivo. These results indicate distinctive patterns of regulation of FGF19 expression by ER stress, and FGF21 expression by ER stress, oxidative stress, and amino acid deprivation through ATF4 activation.

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“…The most frequent effects of DM on the male reproductive system include decreased levels of testosterone, lower testicular weight, abnormal spermatogenesis, alterations in sperm count and motility, and histopathological changes in testis tissue components [2][3][4][5] . Abnormalities in spermatogenesis due to increased apoptosis have been demonstrated in certain studies 2,3,[6][7][8][9][10] . Testicular apoptosis may be the major component of the infertility.…”

Section: Introductionmentioning

confidence: 99%

MAPK immunoreactivity in streptozotocin-induced diabetic rat testis

2014

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PURPOSE:To evaluate the alterations of two mitogen-activated protein kinases (MAPK)s, extracellular signal regulated kinase (ERK) and c-Jun NH2 terminal kinase (JNK), in the testes of male rats with experimental diabetes. METHODS:Twenty males Sprague-Dawley rats were randomly divided into a control group (n=8) and a diabetes group (administration of 40 mg/kg/day streptozotocin (STZ) for five sequential days, n=12). After six weeks, testicular biopsy samples were obtained for light microscopy and immunohistochemical methods. RESULTS:The PCNA (proliferating cell nuclear antigen) index was significantly decreased in the diabetes group (p=0.004) when compared to the control group. Both total (t)-ERK and phosphor (p)-ERK immunoreactivities were significantly decreased in the diabetes group (p=0.004, p<0.001, respectively). The t-JNK immunoreactivity was unchanged in both groups (p=0.125), while p-JNK immunoreactivity was significantly increased in the diabetic group (p=0.002). CONCLUSIONS:The decrease of androgen levels in the course of diabetes may contribute to the decrease of the immunoreactivities of t-ERK and p-ERK. JNK may be activated due to the changes in various cytokines and chemochines that participate in the oxidative stress process of diabetes. Therefore, testicular apoptosis may occur and lead to infertility associated with diabetes.

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Protective effect of FGF21 on type 1 diabetes-induced testicular apoptotic cell death probably via both mitochondrial- and endoplasmic reticulum stress-dependent pathways in the mouse model

Cited by 77 publications

References 40 publications

Sulforaphane reduction of testicular apoptotic cell death in diabetic mice is associated with the upregulation of Nrf2 expression and function

Sulforaphane reduction of testicular apoptotic cell death in diabetic mice is associated with the upregulation of Nrf2 expression and function

Selective Regulation of FGF19 and FGF21 Expression by Cellular and Nutritional Stress

MAPK immunoreactivity in streptozotocin-induced diabetic rat testis

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