Inhibition of the RPS6KA1/FoxO1 signaling axis by hydroxycitric acid attenuates HFD-induced obesity through MCE suppression
Because obesity is associated with a hyperplasia-mediated increase in adipose tissue, inhibiting cell proliferation during mitotic clonal expansion (MCE) is a leading strategy for preventing obesity. Although (–)-hydroxycitric acid (HCA) is used to control obesity, the molecular mechanisms underlyin...
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| Veröffentlicht in: | Phytomedicine (Stuttgart) 2024-06, Vol.128, p.155551-155551, Article 155551 |
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| creator | Lee, Hyung-Won Karki, Rajendra Han, Joo-Hui |
| description | Because obesity is associated with a hyperplasia-mediated increase in adipose tissue, inhibiting cell proliferation during mitotic clonal expansion (MCE) is a leading strategy for preventing obesity. Although (–)-hydroxycitric acid (HCA) is used to control obesity, the molecular mechanisms underlying its effects on MCE are poorly understood.
This study aimed to investigate the potential effects of HCA on MCE and underlying molecular mechanisms affecting adipogenesis and obesity improvements.
Preadipocyte cell line, 3T3-L1, were treated with HCA; oil red O, cell proliferation, cell cycle, and related alterations in signaling pathways were examined. High-fat diet (HFD)-fed mice were administered HCA for 12 weeks; body and adipose tissues weights were evaluated, and the regulation of signaling pathways in epidydimal white adipose tissue were examined in vivo.
Here, we report that during MCE, HCA attenuates the proliferation of the preadipocyte cell line, 3T3-L1, by arresting the cell cycle at the G0/G1 phase. In addition, HCA markedly inhibits Forkhead Box O1 (FoxO1) phosphorylation, thereby inducing the expression of cyclin-dependent kinase inhibitor 1B and suppressing the levels of cyclin-dependent kinase 2, cyclin E1, proliferating cell nuclear antigen, and phosphorylated retinoblastoma. Importantly, we found that ribosomal protein S6 kinase A1 (RPS6KA1) influences HCA-mediated inactivation of FoxO1 and its nuclear exclusion. An animal model of obesity revealed that HCA reduced high-fat diet-induced obesity by suppressing adipocyte numbers as well as epididymal and mesenteric white adipose tissue mass, which is attributed to the regulation of RPS6KA1, FoxO1, CDKN1B and PCNA that had been consistently identified in vitro.
These findings provide novel insights into the mechanism by which HCA regulates adipogenesis and highlight the RPS6KA1/FoxO1 signaling axis as a therapeutic target for obesity.
[Display omitted] |
| doi_str_mv | 10.1016/j.phymed.2024.155551 |
| format | Article |
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This study aimed to investigate the potential effects of HCA on MCE and underlying molecular mechanisms affecting adipogenesis and obesity improvements.
Preadipocyte cell line, 3T3-L1, were treated with HCA; oil red O, cell proliferation, cell cycle, and related alterations in signaling pathways were examined. High-fat diet (HFD)-fed mice were administered HCA for 12 weeks; body and adipose tissues weights were evaluated, and the regulation of signaling pathways in epidydimal white adipose tissue were examined in vivo.
Here, we report that during MCE, HCA attenuates the proliferation of the preadipocyte cell line, 3T3-L1, by arresting the cell cycle at the G0/G1 phase. In addition, HCA markedly inhibits Forkhead Box O1 (FoxO1) phosphorylation, thereby inducing the expression of cyclin-dependent kinase inhibitor 1B and suppressing the levels of cyclin-dependent kinase 2, cyclin E1, proliferating cell nuclear antigen, and phosphorylated retinoblastoma. Importantly, we found that ribosomal protein S6 kinase A1 (RPS6KA1) influences HCA-mediated inactivation of FoxO1 and its nuclear exclusion. An animal model of obesity revealed that HCA reduced high-fat diet-induced obesity by suppressing adipocyte numbers as well as epididymal and mesenteric white adipose tissue mass, which is attributed to the regulation of RPS6KA1, FoxO1, CDKN1B and PCNA that had been consistently identified in vitro.
These findings provide novel insights into the mechanism by which HCA regulates adipogenesis and highlight the RPS6KA1/FoxO1 signaling axis as a therapeutic target for obesity.
[Display omitted]</description><identifier>ISSN: 0944-7113</identifier><identifier>EISSN: 1618-095X</identifier><identifier>DOI: 10.1016/j.phymed.2024.155551</identifier><identifier>PMID: 38569293</identifier><language>eng</language><publisher>Germany: Elsevier GmbH</publisher><subject>3T3-L1 Cells ; Adipocytes - drug effects ; Adipocytes - metabolism ; Adipogenesis ; Adipogenesis - drug effects ; Adipose Tissue, White - drug effects ; Adipose Tissue, White - metabolism ; Animals ; Cell Proliferation - drug effects ; Citrates ; Diet, High-Fat - adverse effects ; Forkhead Box Protein O1 - metabolism ; FoxO1 ; Hydroxycitric acid ; Male ; Mice ; Mice, Inbred C57BL ; Mitosis - drug effects ; Mitotic clonal expansion ; Obesity ; Obesity - drug therapy ; Obesity - metabolism ; Ribosomal Protein S6 Kinases, 90-kDa - metabolism ; RPS6KA1 ; Signal Transduction - drug effects</subject><ispartof>Phytomedicine (Stuttgart), 2024-06, Vol.128, p.155551-155551, Article 155551</ispartof><rights>2024 Elsevier GmbH</rights><rights>Copyright © 2024 Elsevier GmbH. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c311t-5eea8d83ffc1c8b17e7c8386e5ed5313bb265a73985362ec1ec68b73875f09d33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0944711324002162$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,65309</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38569293$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lee, Hyung-Won</creatorcontrib><creatorcontrib>Karki, Rajendra</creatorcontrib><creatorcontrib>Han, Joo-Hui</creatorcontrib><title>Inhibition of the RPS6KA1/FoxO1 signaling axis by hydroxycitric acid attenuates HFD-induced obesity through MCE suppression</title><title>Phytomedicine (Stuttgart)</title><addtitle>Phytomedicine</addtitle><description>Because obesity is associated with a hyperplasia-mediated increase in adipose tissue, inhibiting cell proliferation during mitotic clonal expansion (MCE) is a leading strategy for preventing obesity. Although (–)-hydroxycitric acid (HCA) is used to control obesity, the molecular mechanisms underlying its effects on MCE are poorly understood.
This study aimed to investigate the potential effects of HCA on MCE and underlying molecular mechanisms affecting adipogenesis and obesity improvements.
Preadipocyte cell line, 3T3-L1, were treated with HCA; oil red O, cell proliferation, cell cycle, and related alterations in signaling pathways were examined. High-fat diet (HFD)-fed mice were administered HCA for 12 weeks; body and adipose tissues weights were evaluated, and the regulation of signaling pathways in epidydimal white adipose tissue were examined in vivo.
Here, we report that during MCE, HCA attenuates the proliferation of the preadipocyte cell line, 3T3-L1, by arresting the cell cycle at the G0/G1 phase. In addition, HCA markedly inhibits Forkhead Box O1 (FoxO1) phosphorylation, thereby inducing the expression of cyclin-dependent kinase inhibitor 1B and suppressing the levels of cyclin-dependent kinase 2, cyclin E1, proliferating cell nuclear antigen, and phosphorylated retinoblastoma. Importantly, we found that ribosomal protein S6 kinase A1 (RPS6KA1) influences HCA-mediated inactivation of FoxO1 and its nuclear exclusion. An animal model of obesity revealed that HCA reduced high-fat diet-induced obesity by suppressing adipocyte numbers as well as epididymal and mesenteric white adipose tissue mass, which is attributed to the regulation of RPS6KA1, FoxO1, CDKN1B and PCNA that had been consistently identified in vitro.
These findings provide novel insights into the mechanism by which HCA regulates adipogenesis and highlight the RPS6KA1/FoxO1 signaling axis as a therapeutic target for obesity.
[Display omitted]</description><subject>3T3-L1 Cells</subject><subject>Adipocytes - drug effects</subject><subject>Adipocytes - metabolism</subject><subject>Adipogenesis</subject><subject>Adipogenesis - drug effects</subject><subject>Adipose Tissue, White - drug effects</subject><subject>Adipose Tissue, White - metabolism</subject><subject>Animals</subject><subject>Cell Proliferation - drug effects</subject><subject>Citrates</subject><subject>Diet, High-Fat - adverse effects</subject><subject>Forkhead Box Protein O1 - metabolism</subject><subject>FoxO1</subject><subject>Hydroxycitric acid</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mitosis - drug effects</subject><subject>Mitotic clonal expansion</subject><subject>Obesity</subject><subject>Obesity - drug therapy</subject><subject>Obesity - metabolism</subject><subject>Ribosomal Protein S6 Kinases, 90-kDa - metabolism</subject><subject>RPS6KA1</subject><subject>Signal Transduction - drug effects</subject><issn>0944-7113</issn><issn>1618-095X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1v1DAQhi0EokvhHyDkI5dsPXGcOBekaunSiqIiPiRulmNPNl7txsF20Eb8ebJKe2Uuc5j3Q_MQ8hbYGhiUV_v10E1HtOuc5cUaxDzwjKygBJmxWvx6TlasLoqsAuAX5FWMe8agqCv2klxwKco6r_mK_L3rO9e45HxPfUtTh_Tb1-_l52u42vrTA9Dodr0-uH5H9clF2ky0m2zwp8m4FJyh2jhLdUrYjzphpLfbj5nr7WjQUt9gdGmaU4Mfdx39srmhcRyGgDHOha_Ji1YfIr553Jfk5_bmx-Y2u3_4dLe5vs8MB0iZQNTSSt62BoxsoMLKSC5LFGgFB940eSl0xWspeJmjATSlbCouK9Gy2nJ-Sd4vuUPwv0eMSR1dNHg46B79GBVnnDNWlyBmabFITfAxBmzVENxRh0kBU2fsaq8W7OqMXS3YZ9u7x4axOd-eTE-cZ8GHRYDzn38cBhWNw36G5AKapKx3_2_4BwAnllo</recordid><startdate>202406</startdate><enddate>202406</enddate><creator>Lee, Hyung-Won</creator><creator>Karki, Rajendra</creator><creator>Han, Joo-Hui</creator><general>Elsevier GmbH</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>7X8</scope></search><sort><creationdate>202406</creationdate><title>Inhibition of the RPS6KA1/FoxO1 signaling axis by hydroxycitric acid attenuates HFD-induced obesity through MCE suppression</title><author>Lee, Hyung-Won ; Karki, Rajendra ; Han, Joo-Hui</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c311t-5eea8d83ffc1c8b17e7c8386e5ed5313bb265a73985362ec1ec68b73875f09d33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>3T3-L1 Cells</topic><topic>Adipocytes - drug effects</topic><topic>Adipocytes - metabolism</topic><topic>Adipogenesis</topic><topic>Adipogenesis - drug effects</topic><topic>Adipose Tissue, White - drug effects</topic><topic>Adipose Tissue, White - metabolism</topic><topic>Animals</topic><topic>Cell Proliferation - drug effects</topic><topic>Citrates</topic><topic>Diet, High-Fat - adverse effects</topic><topic>Forkhead Box Protein O1 - metabolism</topic><topic>FoxO1</topic><topic>Hydroxycitric acid</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mitosis - drug effects</topic><topic>Mitotic clonal expansion</topic><topic>Obesity</topic><topic>Obesity - drug therapy</topic><topic>Obesity - metabolism</topic><topic>Ribosomal Protein S6 Kinases, 90-kDa - metabolism</topic><topic>RPS6KA1</topic><topic>Signal Transduction - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lee, Hyung-Won</creatorcontrib><creatorcontrib>Karki, Rajendra</creatorcontrib><creatorcontrib>Han, Joo-Hui</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Phytomedicine (Stuttgart)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lee, Hyung-Won</au><au>Karki, Rajendra</au><au>Han, Joo-Hui</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of the RPS6KA1/FoxO1 signaling axis by hydroxycitric acid attenuates HFD-induced obesity through MCE suppression</atitle><jtitle>Phytomedicine (Stuttgart)</jtitle><addtitle>Phytomedicine</addtitle><date>2024-06</date><risdate>2024</risdate><volume>128</volume><spage>155551</spage><epage>155551</epage><pages>155551-155551</pages><artnum>155551</artnum><issn>0944-7113</issn><eissn>1618-095X</eissn><abstract>Because obesity is associated with a hyperplasia-mediated increase in adipose tissue, inhibiting cell proliferation during mitotic clonal expansion (MCE) is a leading strategy for preventing obesity. Although (–)-hydroxycitric acid (HCA) is used to control obesity, the molecular mechanisms underlying its effects on MCE are poorly understood.
This study aimed to investigate the potential effects of HCA on MCE and underlying molecular mechanisms affecting adipogenesis and obesity improvements.
Preadipocyte cell line, 3T3-L1, were treated with HCA; oil red O, cell proliferation, cell cycle, and related alterations in signaling pathways were examined. High-fat diet (HFD)-fed mice were administered HCA for 12 weeks; body and adipose tissues weights were evaluated, and the regulation of signaling pathways in epidydimal white adipose tissue were examined in vivo.
Here, we report that during MCE, HCA attenuates the proliferation of the preadipocyte cell line, 3T3-L1, by arresting the cell cycle at the G0/G1 phase. In addition, HCA markedly inhibits Forkhead Box O1 (FoxO1) phosphorylation, thereby inducing the expression of cyclin-dependent kinase inhibitor 1B and suppressing the levels of cyclin-dependent kinase 2, cyclin E1, proliferating cell nuclear antigen, and phosphorylated retinoblastoma. Importantly, we found that ribosomal protein S6 kinase A1 (RPS6KA1) influences HCA-mediated inactivation of FoxO1 and its nuclear exclusion. An animal model of obesity revealed that HCA reduced high-fat diet-induced obesity by suppressing adipocyte numbers as well as epididymal and mesenteric white adipose tissue mass, which is attributed to the regulation of RPS6KA1, FoxO1, CDKN1B and PCNA that had been consistently identified in vitro.
These findings provide novel insights into the mechanism by which HCA regulates adipogenesis and highlight the RPS6KA1/FoxO1 signaling axis as a therapeutic target for obesity.
[Display omitted]</abstract><cop>Germany</cop><pub>Elsevier GmbH</pub><pmid>38569293</pmid><doi>10.1016/j.phymed.2024.155551</doi><tpages>1</tpages></addata></record> |
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| subjects | 3T3-L1 Cells Adipocytes - drug effects Adipocytes - metabolism Adipogenesis Adipogenesis - drug effects Adipose Tissue, White - drug effects Adipose Tissue, White - metabolism Animals Cell Proliferation - drug effects Citrates Diet, High-Fat - adverse effects Forkhead Box Protein O1 - metabolism FoxO1 Hydroxycitric acid Male Mice Mice, Inbred C57BL Mitosis - drug effects Mitotic clonal expansion Obesity Obesity - drug therapy Obesity - metabolism Ribosomal Protein S6 Kinases, 90-kDa - metabolism RPS6KA1 Signal Transduction - drug effects |
| title | Inhibition of the RPS6KA1/FoxO1 signaling axis by hydroxycitric acid attenuates HFD-induced obesity through MCE suppression |
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