In vivo glucoregulation and tissue-specific glucose uptake in female Akt substrate 160 kDa knockout rats
The Rab GTPase activating protein known as Akt substrate of 160 kDa (AS160 or TBC1D4) regulates insulin-stimulated glucose uptake in skeletal muscle, the heart, and white adipose tissue (WAT). A novel rat AS160-knockout (AS160-KO) was created with CRISPR/Cas9 technology. Because female AS160-KO vers...
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| description | The Rab GTPase activating protein known as Akt substrate of 160 kDa (AS160 or TBC1D4) regulates insulin-stimulated glucose uptake in skeletal muscle, the heart, and white adipose tissue (WAT). A novel rat AS160-knockout (AS160-KO) was created with CRISPR/Cas9 technology. Because female AS160-KO versus wild type (WT) rats had not been previously evaluated, the primary objective of this study was to compare female AS160-KO rats with WT controls for multiple, important metabolism-related endpoints. Body mass and composition, physical activity, and energy expenditure were not different between genotypes. AS160-KO versus WT rats were glucose intolerant based on an oral glucose tolerance test (P |
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A novel rat AS160-knockout (AS160-KO) was created with CRISPR/Cas9 technology. Because female AS160-KO versus wild type (WT) rats had not been previously evaluated, the primary objective of this study was to compare female AS160-KO rats with WT controls for multiple, important metabolism-related endpoints. Body mass and composition, physical activity, and energy expenditure were not different between genotypes. AS160-KO versus WT rats were glucose intolerant based on an oral glucose tolerance test (P<0.001) and insulin resistant based on a hyperinsulinemic-euglycemic clamp (HEC; P<0.001). Tissue glucose uptake during the HEC of female AS160-KO versus WT rats was: 1) significantly lower in epitrochlearis (P<0.05) and extensor digitorum longus (EDL; P<0.01) muscles of AS160-KO compared to WT rats; 2) not different in soleus, gastrocnemius or WAT; and 3) ~3-fold greater in the heart (P<0.05). GLUT4 protein content was reduced in AS160-KO versus WT rats in the epitrochlearis (P<0.05), EDL (P<0.05), gastrocnemius (P<0.05), soleus (P<0.05), WAT (P<0.05), and the heart (P<0.005). Insulin-stimulated glucose uptake by isolated epitrochlearis and soleus muscles was lower (P<0.001) in AS160-KO versus WT rats. Akt phosphorylation of insulin-stimulated tissues was not different between the genotypes. A secondary objective was to probe processes that might account for the genotype-related increase in myocardial glucose uptake, including glucose transporter protein abundance (GLUT1, GLUT4, GLUT8, SGLT1), hexokinase II protein abundance, and stimulation of the AMP-activated protein kinase (AMPK) pathway. None of these parameters differed between genotypes. Metabolic phenotyping in the current study revealed AS160 deficiency produced a profound glucoregulatory phenotype in female AS160-KO rats that was strikingly similar to the results previously reported in male AS160-KO rats.]]></description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0223340</identifier><identifier>PMID: 32053588</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Abundance ; Adipose tissue ; AKT protein ; AMP ; AMP-activated protein kinase ; AMP-Activated Protein Kinases - metabolism ; Animals ; Biology and Life Sciences ; Body mass ; CRISPR ; Disease Models, Animal ; Energy expenditure ; Female ; Genotypes ; Gluconeogenesis - genetics ; Glucose ; Glucose - metabolism ; Glucose Clamp Technique ; Glucose tolerance ; Glucose Tolerance Test ; Glucose Transport Proteins, Facilitative - metabolism ; Glucose transporter ; GTPase-Activating Proteins - deficiency ; GTPase-Activating Proteins - genetics ; Guanosine triphosphatases ; Hexokinase ; Humans ; In vivo methods and tests ; Insulin ; Insulin resistance ; Insulin Resistance - genetics ; Kinases ; Liver - metabolism ; Medicine and Health Sciences ; Metabolism ; Muscle, Skeletal - metabolism ; Muscles ; Phenotypes ; Phenotyping ; Phosphorylation ; Physical activity ; Physical Conditioning, Animal ; Physical Sciences ; Protein folding ; Protein transport ; Proteins ; Rats ; Rats, Transgenic ; Rats, Wistar ; Rodents ; Signal Transduction ; Skeletal muscle ; Substrates</subject><ispartof>PloS one, 2020-02, Vol.15 (2), p.e0223340-e0223340</ispartof><rights>2020 Zheng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 Zheng et al 2020 Zheng et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-10b93ee92e65bca0e936a2c85e60b9a6ba34721a599217c747b4a516ce62eab53</citedby><cites>FETCH-LOGICAL-c526t-10b93ee92e65bca0e936a2c85e60b9a6ba34721a599217c747b4a516ce62eab53</cites><orcidid>0000-0003-2015-101X ; 0000-0001-5311-1722</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018090/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018090/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32053588$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Sánchez-Margalet, Víctor</contributor><creatorcontrib>Zheng, Xiaohua</creatorcontrib><creatorcontrib>Arias, Edward B</creatorcontrib><creatorcontrib>Qi, Nathan R</creatorcontrib><creatorcontrib>Saunders, Thomas L</creatorcontrib><creatorcontrib>Cartee, Gregory D</creatorcontrib><title>In vivo glucoregulation and tissue-specific glucose uptake in female Akt substrate 160 kDa knockout rats</title><title>PloS one</title><addtitle>PLoS One</addtitle><description><![CDATA[The Rab GTPase activating protein known as Akt substrate of 160 kDa (AS160 or TBC1D4) regulates insulin-stimulated glucose uptake in skeletal muscle, the heart, and white adipose tissue (WAT). A novel rat AS160-knockout (AS160-KO) was created with CRISPR/Cas9 technology. Because female AS160-KO versus wild type (WT) rats had not been previously evaluated, the primary objective of this study was to compare female AS160-KO rats with WT controls for multiple, important metabolism-related endpoints. Body mass and composition, physical activity, and energy expenditure were not different between genotypes. AS160-KO versus WT rats were glucose intolerant based on an oral glucose tolerance test (P<0.001) and insulin resistant based on a hyperinsulinemic-euglycemic clamp (HEC; P<0.001). Tissue glucose uptake during the HEC of female AS160-KO versus WT rats was: 1) significantly lower in epitrochlearis (P<0.05) and extensor digitorum longus (EDL; P<0.01) muscles of AS160-KO compared to WT rats; 2) not different in soleus, gastrocnemius or WAT; and 3) ~3-fold greater in the heart (P<0.05). GLUT4 protein content was reduced in AS160-KO versus WT rats in the epitrochlearis (P<0.05), EDL (P<0.05), gastrocnemius (P<0.05), soleus (P<0.05), WAT (P<0.05), and the heart (P<0.005). Insulin-stimulated glucose uptake by isolated epitrochlearis and soleus muscles was lower (P<0.001) in AS160-KO versus WT rats. Akt phosphorylation of insulin-stimulated tissues was not different between the genotypes. A secondary objective was to probe processes that might account for the genotype-related increase in myocardial glucose uptake, including glucose transporter protein abundance (GLUT1, GLUT4, GLUT8, SGLT1), hexokinase II protein abundance, and stimulation of the AMP-activated protein kinase (AMPK) pathway. None of these parameters differed between genotypes. Metabolic phenotyping in the current study revealed AS160 deficiency produced a profound glucoregulatory phenotype in female AS160-KO rats that was strikingly similar to the results previously reported in male AS160-KO rats.]]></description><subject>Abundance</subject><subject>Adipose tissue</subject><subject>AKT protein</subject><subject>AMP</subject><subject>AMP-activated protein kinase</subject><subject>AMP-Activated Protein Kinases - metabolism</subject><subject>Animals</subject><subject>Biology and Life Sciences</subject><subject>Body mass</subject><subject>CRISPR</subject><subject>Disease Models, Animal</subject><subject>Energy expenditure</subject><subject>Female</subject><subject>Genotypes</subject><subject>Gluconeogenesis - genetics</subject><subject>Glucose</subject><subject>Glucose - metabolism</subject><subject>Glucose Clamp Technique</subject><subject>Glucose tolerance</subject><subject>Glucose Tolerance Test</subject><subject>Glucose Transport Proteins, Facilitative - metabolism</subject><subject>Glucose transporter</subject><subject>GTPase-Activating Proteins - deficiency</subject><subject>GTPase-Activating Proteins - genetics</subject><subject>Guanosine triphosphatases</subject><subject>Hexokinase</subject><subject>Humans</subject><subject>In vivo methods and tests</subject><subject>Insulin</subject><subject>Insulin resistance</subject><subject>Insulin Resistance - genetics</subject><subject>Kinases</subject><subject>Liver - metabolism</subject><subject>Medicine and Health Sciences</subject><subject>Metabolism</subject><subject>Muscle, Skeletal - metabolism</subject><subject>Muscles</subject><subject>Phenotypes</subject><subject>Phenotyping</subject><subject>Phosphorylation</subject><subject>Physical activity</subject><subject>Physical Conditioning, Animal</subject><subject>Physical Sciences</subject><subject>Protein folding</subject><subject>Protein transport</subject><subject>Proteins</subject><subject>Rats</subject><subject>Rats, Transgenic</subject><subject>Rats, Wistar</subject><subject>Rodents</subject><subject>Signal Transduction</subject><subject>Skeletal muscle</subject><subject>Substrates</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNptUk1v1DAQjRCIlsI_QGCJC5cs_ogd54JUtQVWqsQFztbEO9l6k7UX21mp_57sblq1iJNHM--9-fAriveMLpio2ZdNGKOHYbELHheUcyEq-qI4Z43gpeJUvHwSnxVvUtpQKoVW6nVxJvgUSq3Pi7ulJ3u3D2Q9jDZEXI8DZBc8Ab8i2aU0Ypl2aF3n7AmTkIy7DD0S50mHWxiQXPaZpLFNOUJGwhQl_TWQ3gfbhzGTKZveFq86GBK-m9-L4ve3m19XP8rbn9-XV5e3pZVc5ZLRthGIDUclWwsUG6GAWy1RTRVQLYiq5gxk03BW27qq2wokUxYVR2iluCg-nnR3Q0hmPlIyXMiqroQWB8TyhFgF2JhddFuI9yaAM8dEiGsDMTs7oOFaYweMNkzzaqUrbaniLVeqo5rWDZ20vs7dxnaLK4t-OsHwTPR5xbs7sw57U1Om6VHg8ywQw58RUzZblywOA3gM43Fu2Uy_VosJ-ukf6P-3q04oG0NKEbvHYRg1B-M8sMzBOGY2zkT78HSRR9KDU8RfJTjA4g</recordid><startdate>20200213</startdate><enddate>20200213</enddate><creator>Zheng, Xiaohua</creator><creator>Arias, Edward B</creator><creator>Qi, Nathan R</creator><creator>Saunders, Thomas L</creator><creator>Cartee, Gregory D</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0003-2015-101X</orcidid><orcidid>https://orcid.org/0000-0001-5311-1722</orcidid></search><sort><creationdate>20200213</creationdate><title>In vivo glucoregulation and tissue-specific glucose uptake in female Akt substrate 160 kDa knockout rats</title><author>Zheng, Xiaohua ; Arias, Edward B ; Qi, Nathan R ; Saunders, Thomas L ; Cartee, Gregory D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-10b93ee92e65bca0e936a2c85e60b9a6ba34721a599217c747b4a516ce62eab53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Abundance</topic><topic>Adipose tissue</topic><topic>AKT protein</topic><topic>AMP</topic><topic>AMP-activated protein kinase</topic><topic>AMP-Activated Protein Kinases - metabolism</topic><topic>Animals</topic><topic>Biology and Life Sciences</topic><topic>Body mass</topic><topic>CRISPR</topic><topic>Disease Models, Animal</topic><topic>Energy expenditure</topic><topic>Female</topic><topic>Genotypes</topic><topic>Gluconeogenesis - genetics</topic><topic>Glucose</topic><topic>Glucose - metabolism</topic><topic>Glucose Clamp Technique</topic><topic>Glucose tolerance</topic><topic>Glucose Tolerance Test</topic><topic>Glucose Transport Proteins, Facilitative - metabolism</topic><topic>Glucose transporter</topic><topic>GTPase-Activating Proteins - deficiency</topic><topic>GTPase-Activating Proteins - genetics</topic><topic>Guanosine triphosphatases</topic><topic>Hexokinase</topic><topic>Humans</topic><topic>In vivo methods and tests</topic><topic>Insulin</topic><topic>Insulin resistance</topic><topic>Insulin Resistance - genetics</topic><topic>Kinases</topic><topic>Liver - metabolism</topic><topic>Medicine and Health Sciences</topic><topic>Metabolism</topic><topic>Muscle, Skeletal - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zheng, Xiaohua</au><au>Arias, Edward B</au><au>Qi, Nathan R</au><au>Saunders, Thomas L</au><au>Cartee, Gregory D</au><au>Sánchez-Margalet, Víctor</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>In vivo glucoregulation and tissue-specific glucose uptake in female Akt substrate 160 kDa knockout rats</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2020-02-13</date><risdate>2020</risdate><volume>15</volume><issue>2</issue><spage>e0223340</spage><epage>e0223340</epage><pages>e0223340-e0223340</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract><![CDATA[The Rab GTPase activating protein known as Akt substrate of 160 kDa (AS160 or TBC1D4) regulates insulin-stimulated glucose uptake in skeletal muscle, the heart, and white adipose tissue (WAT). A novel rat AS160-knockout (AS160-KO) was created with CRISPR/Cas9 technology. Because female AS160-KO versus wild type (WT) rats had not been previously evaluated, the primary objective of this study was to compare female AS160-KO rats with WT controls for multiple, important metabolism-related endpoints. Body mass and composition, physical activity, and energy expenditure were not different between genotypes. AS160-KO versus WT rats were glucose intolerant based on an oral glucose tolerance test (P<0.001) and insulin resistant based on a hyperinsulinemic-euglycemic clamp (HEC; P<0.001). Tissue glucose uptake during the HEC of female AS160-KO versus WT rats was: 1) significantly lower in epitrochlearis (P<0.05) and extensor digitorum longus (EDL; P<0.01) muscles of AS160-KO compared to WT rats; 2) not different in soleus, gastrocnemius or WAT; and 3) ~3-fold greater in the heart (P<0.05). GLUT4 protein content was reduced in AS160-KO versus WT rats in the epitrochlearis (P<0.05), EDL (P<0.05), gastrocnemius (P<0.05), soleus (P<0.05), WAT (P<0.05), and the heart (P<0.005). Insulin-stimulated glucose uptake by isolated epitrochlearis and soleus muscles was lower (P<0.001) in AS160-KO versus WT rats. Akt phosphorylation of insulin-stimulated tissues was not different between the genotypes. A secondary objective was to probe processes that might account for the genotype-related increase in myocardial glucose uptake, including glucose transporter protein abundance (GLUT1, GLUT4, GLUT8, SGLT1), hexokinase II protein abundance, and stimulation of the AMP-activated protein kinase (AMPK) pathway. None of these parameters differed between genotypes. Metabolic phenotyping in the current study revealed AS160 deficiency produced a profound glucoregulatory phenotype in female AS160-KO rats that was strikingly similar to the results previously reported in male AS160-KO rats.]]></abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>32053588</pmid><doi>10.1371/journal.pone.0223340</doi><orcidid>https://orcid.org/0000-0003-2015-101X</orcidid><orcidid>https://orcid.org/0000-0001-5311-1722</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | PloS one, 2020-02, Vol.15 (2), p.e0223340-e0223340 |
| issn | 1932-6203 1932-6203 |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Abundance Adipose tissue AKT protein AMP AMP-activated protein kinase AMP-Activated Protein Kinases - metabolism Animals Biology and Life Sciences Body mass CRISPR Disease Models, Animal Energy expenditure Female Genotypes Gluconeogenesis - genetics Glucose Glucose - metabolism Glucose Clamp Technique Glucose tolerance Glucose Tolerance Test Glucose Transport Proteins, Facilitative - metabolism Glucose transporter GTPase-Activating Proteins - deficiency GTPase-Activating Proteins - genetics Guanosine triphosphatases Hexokinase Humans In vivo methods and tests Insulin Insulin resistance Insulin Resistance - genetics Kinases Liver - metabolism Medicine and Health Sciences Metabolism Muscle, Skeletal - metabolism Muscles Phenotypes Phenotyping Phosphorylation Physical activity Physical Conditioning, Animal Physical Sciences Protein folding Protein transport Proteins Rats Rats, Transgenic Rats, Wistar Rodents Signal Transduction Skeletal muscle Substrates |
| title | In vivo glucoregulation and tissue-specific glucose uptake in female Akt substrate 160 kDa knockout rats |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-26T14%3A50%3A03IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=In%20vivo%20glucoregulation%20and%20tissue-specific%20glucose%20uptake%20in%20female%20Akt%20substrate%20160%20kDa%20knockout%20rats&rft.jtitle=PloS%20one&rft.au=Zheng,%20Xiaohua&rft.date=2020-02-13&rft.volume=15&rft.issue=2&rft.spage=e0223340&rft.epage=e0223340&rft.pages=e0223340-e0223340&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0223340&rft_dat=%3Cproquest_plos_%3E2355938673%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2354743835&rft_id=info:pmid/32053588&rft_doaj_id=oai_doaj_org_article_288efa1091824d848c062b266f080790&rfr_iscdi=true |