PACAP ameliorates fertility in obese male mice via PKA/CREB pathway‐dependent Sirt1 activation and p53 deacetylation
Obesity is strongly linked to male infertility. Testicular spermatogenic cell apoptosis plays an important role in obesity‐related male infertility. Pituitary adenylate cyclase‐activating peptide (PACAP) has been recently shown to exhibit antiapoptotic and antidiabetic effects. However, the effects...
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| Veröffentlicht in: | Journal of cellular physiology 2020-10, Vol.235 (10), p.7465-7483 |
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| creator | Yan, Qiuxia Huang, Hongke Lu, Shiyin Ou, Biqian Feng, Jia Shan, Wailan Li, Huixian Wang, Zixian Hong, An Ma, Yi |
| description | Obesity is strongly linked to male infertility. Testicular spermatogenic cell apoptosis plays an important role in obesity‐related male infertility. Pituitary adenylate cyclase‐activating peptide (PACAP) has been recently shown to exhibit antiapoptotic and antidiabetic effects. However, the effects of PACAP on obesity‐related male infertility remain unknown. The purpose of the current study is to explore the role of PACAP in obesity‐related male infertility. Here, C57BL/6 male mice were fed with a high‐fat diet to induce obesity and then treated with PACAP. PACAP treatment ameliorated obesity characteristics, including body weight, epididymal adipose weight, testes/body weight, serum lipids levels, and reproductive hormone levels in vivo. Additionally, PACAP was shown to improve the reproductive function of the obese mice, which was characterized by improved testis morphology, sperm parameters, acrosome reaction, and embryo quality after in vitro fertilization via silent information regulator 1 (Sirt1) activation and p53 deacetylation. These beneficial effects of PACAP were abolished in obese mice with testis‐specific knockdown of Sirt1. The mechanism studies showed that PACAP selectively binds to the PAC1 receptor to attenuate palmitic acid‐induced mouse spermatogenic cell (GC‐1) apoptosis via the PKA/CREB/Sirt1/p53 pathway. However, this mechanism was inhibited in GC‐1 cells lacking Sirt1. Finally, human semen studies showed that the decline in sperm quality in obese infertile men was partly due to Sirt1 downregulation and p53 acetylation. Our data suggest that PACAP could ameliorate fertility in obese male mice and may be a promising candidate drug for obesity‐induced male infertility.
Obesity can cause male infertility. PACAP could ameliorate fertility in obese male mice via PKA/CREB pathway‐dependent Sirt1 activation and p53 deacetylation and may be a promising candidate drug for obesity‐induced male infertility. |
| doi_str_mv | 10.1002/jcp.29651 |
| format | Article |
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Obesity can cause male infertility. PACAP could ameliorate fertility in obese male mice via PKA/CREB pathway‐dependent Sirt1 activation and p53 deacetylation and may be a promising candidate drug for obesity‐induced male infertility.</description><identifier>ISSN: 0021-9541</identifier><identifier>EISSN: 1097-4652</identifier><identifier>DOI: 10.1002/jcp.29651</identifier><identifier>PMID: 32159232</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>Acetylation ; Acrosome reaction ; Activation ; Animals ; Antidiabetics ; Apoptosis ; Body weight ; Cell Line - chemistry ; Cyclic AMP response element-binding protein ; Cyclic AMP Response Element-Binding Protein - metabolism ; Cyclic AMP-Dependent Protein Kinases - metabolism ; Deacetylation ; Diabetes mellitus ; Down-Regulation - physiology ; Embryos ; Fertility ; Fertility - physiology ; High fat diet ; In vitro fertilization ; Infertility ; Infertility, Male - metabolism ; Lipids ; Male ; Male infertility ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; Morphology ; Obesity ; Obesity - metabolism ; p53 ; p53 Protein ; PAC1 protein ; PACAP ; Palmitic acid ; Pituitary adenylate cyclase-activating polypeptide ; Pituitary Adenylate Cyclase-Activating Polypeptide - metabolism ; Rodents ; Semen ; Serum lipids ; Signal Transduction - physiology ; Sirt1 ; SIRT1 protein ; Sirtuin 1 - metabolism ; Sperm ; Spermatozoa - metabolism ; Testes ; Testis - metabolism ; Tumor Suppressor Protein p53 - metabolism</subject><ispartof>Journal of cellular physiology, 2020-10, Vol.235 (10), p.7465-7483</ispartof><rights>2020 Wiley Periodicals, Inc.</rights><rights>2020 Wiley Periodicals LLC</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3531-1932ea045a648c0a8d305e582de74cf198a1bab8293677c599dfdbd468fe5f083</citedby><cites>FETCH-LOGICAL-c3531-1932ea045a648c0a8d305e582de74cf198a1bab8293677c599dfdbd468fe5f083</cites><orcidid>0000-0002-7701-5126</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjcp.29651$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjcp.29651$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32159232$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yan, Qiuxia</creatorcontrib><creatorcontrib>Huang, Hongke</creatorcontrib><creatorcontrib>Lu, Shiyin</creatorcontrib><creatorcontrib>Ou, Biqian</creatorcontrib><creatorcontrib>Feng, Jia</creatorcontrib><creatorcontrib>Shan, Wailan</creatorcontrib><creatorcontrib>Li, Huixian</creatorcontrib><creatorcontrib>Wang, Zixian</creatorcontrib><creatorcontrib>Hong, An</creatorcontrib><creatorcontrib>Ma, Yi</creatorcontrib><title>PACAP ameliorates fertility in obese male mice via PKA/CREB pathway‐dependent Sirt1 activation and p53 deacetylation</title><title>Journal of cellular physiology</title><addtitle>J Cell Physiol</addtitle><description>Obesity is strongly linked to male infertility. Testicular spermatogenic cell apoptosis plays an important role in obesity‐related male infertility. Pituitary adenylate cyclase‐activating peptide (PACAP) has been recently shown to exhibit antiapoptotic and antidiabetic effects. However, the effects of PACAP on obesity‐related male infertility remain unknown. The purpose of the current study is to explore the role of PACAP in obesity‐related male infertility. Here, C57BL/6 male mice were fed with a high‐fat diet to induce obesity and then treated with PACAP. PACAP treatment ameliorated obesity characteristics, including body weight, epididymal adipose weight, testes/body weight, serum lipids levels, and reproductive hormone levels in vivo. Additionally, PACAP was shown to improve the reproductive function of the obese mice, which was characterized by improved testis morphology, sperm parameters, acrosome reaction, and embryo quality after in vitro fertilization via silent information regulator 1 (Sirt1) activation and p53 deacetylation. These beneficial effects of PACAP were abolished in obese mice with testis‐specific knockdown of Sirt1. The mechanism studies showed that PACAP selectively binds to the PAC1 receptor to attenuate palmitic acid‐induced mouse spermatogenic cell (GC‐1) apoptosis via the PKA/CREB/Sirt1/p53 pathway. However, this mechanism was inhibited in GC‐1 cells lacking Sirt1. Finally, human semen studies showed that the decline in sperm quality in obese infertile men was partly due to Sirt1 downregulation and p53 acetylation. Our data suggest that PACAP could ameliorate fertility in obese male mice and may be a promising candidate drug for obesity‐induced male infertility.
Obesity can cause male infertility. PACAP could ameliorate fertility in obese male mice via PKA/CREB pathway‐dependent Sirt1 activation and p53 deacetylation and may be a promising candidate drug for obesity‐induced male infertility.</description><subject>Acetylation</subject><subject>Acrosome reaction</subject><subject>Activation</subject><subject>Animals</subject><subject>Antidiabetics</subject><subject>Apoptosis</subject><subject>Body weight</subject><subject>Cell Line - chemistry</subject><subject>Cyclic AMP response element-binding protein</subject><subject>Cyclic AMP Response Element-Binding Protein - metabolism</subject><subject>Cyclic AMP-Dependent Protein Kinases - metabolism</subject><subject>Deacetylation</subject><subject>Diabetes mellitus</subject><subject>Down-Regulation - physiology</subject><subject>Embryos</subject><subject>Fertility</subject><subject>Fertility - physiology</subject><subject>High fat diet</subject><subject>In vitro fertilization</subject><subject>Infertility</subject><subject>Infertility, Male - metabolism</subject><subject>Lipids</subject><subject>Male</subject><subject>Male infertility</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Obese</subject><subject>Morphology</subject><subject>Obesity</subject><subject>Obesity - metabolism</subject><subject>p53</subject><subject>p53 Protein</subject><subject>PAC1 protein</subject><subject>PACAP</subject><subject>Palmitic acid</subject><subject>Pituitary adenylate cyclase-activating polypeptide</subject><subject>Pituitary Adenylate Cyclase-Activating Polypeptide - metabolism</subject><subject>Rodents</subject><subject>Semen</subject><subject>Serum lipids</subject><subject>Signal Transduction - physiology</subject><subject>Sirt1</subject><subject>SIRT1 protein</subject><subject>Sirtuin 1 - metabolism</subject><subject>Sperm</subject><subject>Spermatozoa - metabolism</subject><subject>Testes</subject><subject>Testis - metabolism</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><issn>0021-9541</issn><issn>1097-4652</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kc1u1DAQxy1ERZfCgRdAlrjAIV1_xEl83EYFCpVY8XGOJvZEeJUvbO9WufUReMY-CaZbOCBxmZFmfvppNH9CXnB2zhkT652Zz4UuFH9EVpzpMssLJR6TVdrxTKucn5KnIewYY1pL-YScSsGVFlKsyGG7qTdbCgP2bvIQMdAOfXS9iwt1I51aDEgH6FNxBunBAd1-3Kzrz5cXdIb4_QaWu9ufFmccLY6RfnE-cgomugNEN40URktnJalFMBiX_n76jJx00Ad8_tDPyLe3l1_r99n1p3dX9eY6M1JJnnEtBQLLFRR5ZRhUVjKFqhIWy9x0XFfAW2groWVRlkZpbTvb2ryoOlQdq-QZeX30zn76sccQm8EFg30PI0770AhZFukPsuAJffUPupv2fkzXNSKXTJRS5CxRb46U8VMIHrtm9m4AvzScNb_DaFIYzX0YiX35YNy3A9q_5J_vJ2B9BG5cj8v_Tc2HentU_gLUF5Lp</recordid><startdate>202010</startdate><enddate>202010</enddate><creator>Yan, Qiuxia</creator><creator>Huang, Hongke</creator><creator>Lu, Shiyin</creator><creator>Ou, Biqian</creator><creator>Feng, Jia</creator><creator>Shan, Wailan</creator><creator>Li, Huixian</creator><creator>Wang, Zixian</creator><creator>Hong, An</creator><creator>Ma, Yi</creator><general>Wiley Subscription Services, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-7701-5126</orcidid></search><sort><creationdate>202010</creationdate><title>PACAP ameliorates fertility in obese male mice via PKA/CREB pathway‐dependent Sirt1 activation and p53 deacetylation</title><author>Yan, Qiuxia ; 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Testicular spermatogenic cell apoptosis plays an important role in obesity‐related male infertility. Pituitary adenylate cyclase‐activating peptide (PACAP) has been recently shown to exhibit antiapoptotic and antidiabetic effects. However, the effects of PACAP on obesity‐related male infertility remain unknown. The purpose of the current study is to explore the role of PACAP in obesity‐related male infertility. Here, C57BL/6 male mice were fed with a high‐fat diet to induce obesity and then treated with PACAP. PACAP treatment ameliorated obesity characteristics, including body weight, epididymal adipose weight, testes/body weight, serum lipids levels, and reproductive hormone levels in vivo. Additionally, PACAP was shown to improve the reproductive function of the obese mice, which was characterized by improved testis morphology, sperm parameters, acrosome reaction, and embryo quality after in vitro fertilization via silent information regulator 1 (Sirt1) activation and p53 deacetylation. These beneficial effects of PACAP were abolished in obese mice with testis‐specific knockdown of Sirt1. The mechanism studies showed that PACAP selectively binds to the PAC1 receptor to attenuate palmitic acid‐induced mouse spermatogenic cell (GC‐1) apoptosis via the PKA/CREB/Sirt1/p53 pathway. However, this mechanism was inhibited in GC‐1 cells lacking Sirt1. Finally, human semen studies showed that the decline in sperm quality in obese infertile men was partly due to Sirt1 downregulation and p53 acetylation. Our data suggest that PACAP could ameliorate fertility in obese male mice and may be a promising candidate drug for obesity‐induced male infertility.
Obesity can cause male infertility. PACAP could ameliorate fertility in obese male mice via PKA/CREB pathway‐dependent Sirt1 activation and p53 deacetylation and may be a promising candidate drug for obesity‐induced male infertility.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>32159232</pmid><doi>10.1002/jcp.29651</doi><tpages>19</tpages><orcidid>https://orcid.org/0000-0002-7701-5126</orcidid></addata></record> |
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| subjects | Acetylation Acrosome reaction Activation Animals Antidiabetics Apoptosis Body weight Cell Line - chemistry Cyclic AMP response element-binding protein Cyclic AMP Response Element-Binding Protein - metabolism Cyclic AMP-Dependent Protein Kinases - metabolism Deacetylation Diabetes mellitus Down-Regulation - physiology Embryos Fertility Fertility - physiology High fat diet In vitro fertilization Infertility Infertility, Male - metabolism Lipids Male Male infertility Mice Mice, Inbred C57BL Mice, Obese Morphology Obesity Obesity - metabolism p53 p53 Protein PAC1 protein PACAP Palmitic acid Pituitary adenylate cyclase-activating polypeptide Pituitary Adenylate Cyclase-Activating Polypeptide - metabolism Rodents Semen Serum lipids Signal Transduction - physiology Sirt1 SIRT1 protein Sirtuin 1 - metabolism Sperm Spermatozoa - metabolism Testes Testis - metabolism Tumor Suppressor Protein p53 - metabolism |
| title | PACAP ameliorates fertility in obese male mice via PKA/CREB pathway‐dependent Sirt1 activation and p53 deacetylation |
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