An evolutionary trade-off between host immunity and metabolism drives fatty liver in male mice
Adaptations to infectious and dietary pressures shape mammalian physiology and disease risk. How such adaptations affect sex-biased diseases remains insufficiently studied. In this study, we show that sex-dependent hepatic gene programs confer a robust (~300%) survival advantage for male mice during...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2022-10, Vol.378 (6617), p.290-295 |
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| creator | Nikkanen, Joni Leong, Yew Ann Krause, William C Dermadi, Denis Maschek, J Alan Van Ry, Tyler Cox, James E Weiss, Ethan J Gokcumen, Omer Chawla, Ajay Ingraham, Holly A |
| description | Adaptations to infectious and dietary pressures shape mammalian physiology and disease risk. How such adaptations affect sex-biased diseases remains insufficiently studied. In this study, we show that sex-dependent hepatic gene programs confer a robust (~300%) survival advantage for male mice during lethal bacterial infection. The transcription factor B cell lymphoma 6 (BCL6), which masculinizes hepatic gene expression at puberty, is essential for this advantage. However, protection by BCL6 protein comes at a cost during conditions of dietary excess, which result in overt fatty liver and glucose intolerance in males. Deleting hepatic BCL6 reverses these phenotypes but markedly lowers male survival during infection, thus establishing a sex-dependent trade-off between host defense and metabolic systems. Our findings offer strong evidence that some current sex-biased diseases are rooted in ancient evolutionary trade-offs between immunity and metabolism. |
| doi_str_mv | 10.1126/science.abn9886 |
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How such adaptations affect sex-biased diseases remains insufficiently studied. In this study, we show that sex-dependent hepatic gene programs confer a robust (~300%) survival advantage for male mice during lethal bacterial infection. The transcription factor B cell lymphoma 6 (BCL6), which masculinizes hepatic gene expression at puberty, is essential for this advantage. However, protection by BCL6 protein comes at a cost during conditions of dietary excess, which result in overt fatty liver and glucose intolerance in males. Deleting hepatic BCL6 reverses these phenotypes but markedly lowers male survival during infection, thus establishing a sex-dependent trade-off between host defense and metabolic systems. Our findings offer strong evidence that some current sex-biased diseases are rooted in ancient evolutionary trade-offs between immunity and metabolism.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.abn9886</identifier><identifier>PMID: 36264814</identifier><language>eng</language><publisher>United States: The American Association for the Advancement of Science</publisher><subject>Animals ; Bacterial Infections - genetics ; Bacterial Infections - immunology ; Bcl-6 protein ; Biological Evolution ; Fatty liver ; Fatty Liver - genetics ; Fatty Liver - metabolism ; Females ; Gene Deletion ; Gene Expression Regulation ; Host Adaptation - genetics ; Host Adaptation - immunology ; Liver - metabolism ; Male ; Males ; Metabolic disorders ; Mice ; Proto-Oncogene Proteins c-bcl-6 - genetics ; Proto-Oncogene Proteins c-bcl-6 - physiology ; Sex Factors</subject><ispartof>Science (American Association for the Advancement of Science), 2022-10, Vol.378 (6617), p.290-295</ispartof><rights>Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. 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How such adaptations affect sex-biased diseases remains insufficiently studied. In this study, we show that sex-dependent hepatic gene programs confer a robust (~300%) survival advantage for male mice during lethal bacterial infection. The transcription factor B cell lymphoma 6 (BCL6), which masculinizes hepatic gene expression at puberty, is essential for this advantage. However, protection by BCL6 protein comes at a cost during conditions of dietary excess, which result in overt fatty liver and glucose intolerance in males. Deleting hepatic BCL6 reverses these phenotypes but markedly lowers male survival during infection, thus establishing a sex-dependent trade-off between host defense and metabolic systems. Our findings offer strong evidence that some current sex-biased diseases are rooted in ancient evolutionary trade-offs between immunity and metabolism.</description><subject>Animals</subject><subject>Bacterial Infections - genetics</subject><subject>Bacterial Infections - immunology</subject><subject>Bcl-6 protein</subject><subject>Biological Evolution</subject><subject>Fatty liver</subject><subject>Fatty Liver - genetics</subject><subject>Fatty Liver - metabolism</subject><subject>Females</subject><subject>Gene Deletion</subject><subject>Gene Expression Regulation</subject><subject>Host Adaptation - genetics</subject><subject>Host Adaptation - immunology</subject><subject>Liver - metabolism</subject><subject>Male</subject><subject>Males</subject><subject>Metabolic disorders</subject><subject>Mice</subject><subject>Proto-Oncogene Proteins c-bcl-6 - genetics</subject><subject>Proto-Oncogene Proteins c-bcl-6 - physiology</subject><subject>Sex Factors</subject><issn>0036-8075</issn><issn>1095-9203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUU1LxDAQDaLo-nH2JgHP1aTpJs1FEPELBC96NSTpVCNtokm6sv_eLLuKnmaY9-bNx0PomJIzSmt-nqwDb-FMGy_blm-hGSVyXsmasG00I4TxqiVivof2U3onpGCS7aI9xmvetLSZoZdLj2ERhim74HVc4hx1B1Xoe2wgfwF4_BZSxm4cJ-_yEmvf4RGyNmFwacRddAtIuNe5YEPJI3Yej3oAPDoLh2in10OCo008QM83109Xd9XD4-391eVDZZtW5MrUrbVgjBaC9WQuJejOEEFryQG0kYJrokEaoI2FxnLT9IJxw2BVaShlB-hirfsxmRE6C77cMaiP6MZylAraqf-Id2_qNSyUbAUhjSgCpxuBGD4nSFm9hyn6srOqRc1l-SJhhXW-ZtkYUorQ_06gRK0MURtD1MaQ0nHyd7Ff_o8D7BvnFoy2</recordid><startdate>20221021</startdate><enddate>20221021</enddate><creator>Nikkanen, Joni</creator><creator>Leong, Yew Ann</creator><creator>Krause, William C</creator><creator>Dermadi, Denis</creator><creator>Maschek, J Alan</creator><creator>Van Ry, Tyler</creator><creator>Cox, James E</creator><creator>Weiss, Ethan J</creator><creator>Gokcumen, Omer</creator><creator>Chawla, Ajay</creator><creator>Ingraham, Holly A</creator><general>The American Association for the Advancement of Science</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>7QF</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QQ</scope><scope>7QR</scope><scope>7SC</scope><scope>7SE</scope><scope>7SN</scope><scope>7SP</scope><scope>7SR</scope><scope>7SS</scope><scope>7T7</scope><scope>7TA</scope><scope>7TB</scope><scope>7TK</scope><scope>7TM</scope><scope>7U5</scope><scope>7U9</scope><scope>8BQ</scope><scope>8FD</scope><scope>C1K</scope><scope>F28</scope><scope>FR3</scope><scope>H8D</scope><scope>H8G</scope><scope>H94</scope><scope>JG9</scope><scope>JQ2</scope><scope>K9.</scope><scope>KR7</scope><scope>L7M</scope><scope>L~C</scope><scope>L~D</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-7099-4061</orcidid><orcidid>https://orcid.org/0000-0002-5977-2350</orcidid><orcidid>https://orcid.org/0000-0003-4371-679X</orcidid><orcidid>https://orcid.org/0000-0001-6268-4178</orcidid><orcidid>https://orcid.org/0000-0001-6739-2967</orcidid><orcidid>https://orcid.org/0000-0001-8514-4975</orcidid><orcidid>https://orcid.org/0000-0003-3217-2299</orcidid><orcidid>https://orcid.org/0000-0001-9936-5816</orcidid></search><sort><creationdate>20221021</creationdate><title>An evolutionary trade-off between host immunity and metabolism drives fatty liver in male mice</title><author>Nikkanen, Joni ; Leong, Yew Ann ; Krause, William C ; Dermadi, Denis ; Maschek, J Alan ; Van Ry, Tyler ; Cox, James E ; Weiss, Ethan J ; Gokcumen, Omer ; Chawla, Ajay ; Ingraham, Holly A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c487t-b28ccebba773f0599eadb071296eeab976a0ae9be14ce4c6b4f736b3ebe144113</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Animals</topic><topic>Bacterial Infections - 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How such adaptations affect sex-biased diseases remains insufficiently studied. In this study, we show that sex-dependent hepatic gene programs confer a robust (~300%) survival advantage for male mice during lethal bacterial infection. The transcription factor B cell lymphoma 6 (BCL6), which masculinizes hepatic gene expression at puberty, is essential for this advantage. However, protection by BCL6 protein comes at a cost during conditions of dietary excess, which result in overt fatty liver and glucose intolerance in males. Deleting hepatic BCL6 reverses these phenotypes but markedly lowers male survival during infection, thus establishing a sex-dependent trade-off between host defense and metabolic systems. 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| subjects | Animals Bacterial Infections - genetics Bacterial Infections - immunology Bcl-6 protein Biological Evolution Fatty liver Fatty Liver - genetics Fatty Liver - metabolism Females Gene Deletion Gene Expression Regulation Host Adaptation - genetics Host Adaptation - immunology Liver - metabolism Male Males Metabolic disorders Mice Proto-Oncogene Proteins c-bcl-6 - genetics Proto-Oncogene Proteins c-bcl-6 - physiology Sex Factors |
| title | An evolutionary trade-off between host immunity and metabolism drives fatty liver in male mice |
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