Mackenzie K. Fitzpatrick, Alexandria Szalanczy, Angela Beeson, Anusha Vora, Christina Scott, Michael Grzybowski, Jason Klotz, Nataley Der, Rong Chen, Aron M. Geurts, Leah C. Solberg Woods
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Wild-type, <i>Adcy3</i><sup>+/−</sup>, and <i>Adcy3</i><sup>mut/mut</sup> rats were fed a high-fat diet for 12 weeks. We measured body weight, fat mass, glucose tolerance, food intake, metabolism, emotion-like behaviors, memory, and downstream proteins.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p><i>Adcy3</i><sup>+/−</sup> and <i>Adcy3</i><sup>mut/mut</sup> rats weighed more than wild-type rats due to increased fat mass. There were key sex differences: adiposity was driven by increased food intake in males but by decreased energy expenditure in females. <i>Adcy3</i><sup>mut/mut</sup> males displayed increased passive coping and decreased memory, whereas <i>Adcy3</i><sup>mut/mut</sup> females displayed increased anxiety-like behavior. <i>Adcy3</i><sup>mut/mut</sup> males had decreased hypothalamic cAMP-response element binding protein (CREB) signaling, with decreased phospho-AMP-activated protein kinase (p-AMPK) signaling in both sexes.</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>The ADCY3 TM domain plays a role in protein function via p-AMPK and CREB signaling. <i>Adcy3</i> may contribute to the relationship between obesity and major depressive disorder, and sex influences the relationships between <i>Adcy3</i>, metabolism, and behavior.</p>\n </section>\n </div>","PeriodicalId":215,"journal":{"name":"Obesity","volume":"33 1","pages":"91-103"},"PeriodicalIF":4.2000,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Protein-coding mutation in Adcy3 increases adiposity and alters emotional behaviors sex-dependently in rats\",\"authors\":\"Mackenzie K. Fitzpatrick, Alexandria Szalanczy, Angela Beeson, Anusha Vora, Christina Scott, Michael Grzybowski, Jason Klotz, Nataley Der, Rong Chen, Aron M. Geurts, Leah C. Solberg Woods\",\"doi\":\"10.1002/oby.24178\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Objective</h3>\\n \\n <p>Adenylate cyclase 3 (<i>Adcy3</i>) has been linked to both obesity and major depressive disorder. We identified a protein-coding variant in the transmembrane (TM) helix of <i>Adcy3</i> in rats; similar obesity variants have been identified in humans. This study investigates the role of a TM variant in adiposity and behavior.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>We mutated the TM domain of <i>Adcy3</i> (<i>Adcy3</i><sup>mut/mut</sup>) and created a heterozygous knockout (<i>Adcy3</i><sup>+/−</sup>) in Wistar Kyoto (WKY) rats. Wild-type, <i>Adcy3</i><sup>+/−</sup>, and <i>Adcy3</i><sup>mut/mut</sup> rats were fed a high-fat diet for 12 weeks. We measured body weight, fat mass, glucose tolerance, food intake, metabolism, emotion-like behaviors, memory, and downstream proteins.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p><i>Adcy3</i><sup>+/−</sup> and <i>Adcy3</i><sup>mut/mut</sup> rats weighed more than wild-type rats due to increased fat mass. There were key sex differences: adiposity was driven by increased food intake in males but by decreased energy expenditure in females. <i>Adcy3</i><sup>mut/mut</sup> males displayed increased passive coping and decreased memory, whereas <i>Adcy3</i><sup>mut/mut</sup> females displayed increased anxiety-like behavior. <i>Adcy3</i><sup>mut/mut</sup> males had decreased hypothalamic cAMP-response element binding protein (CREB) signaling, with decreased phospho-AMP-activated protein kinase (p-AMPK) signaling in both sexes.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusions</h3>\\n \\n <p>The ADCY3 TM domain plays a role in protein function via p-AMPK and CREB signaling. <i>Adcy3</i> may contribute to the relationship between obesity and major depressive disorder, and sex influences the relationships between <i>Adcy3</i>, metabolism, and behavior.</p>\\n </section>\\n </div>\",\"PeriodicalId\":215,\"journal\":{\"name\":\"Obesity\",\"volume\":\"33 1\",\"pages\":\"91-103\"},\"PeriodicalIF\":4.2000,\"publicationDate\":\"2024-12-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Obesity\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/oby.24178\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Obesity","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/oby.24178","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
Protein-coding mutation in Adcy3 increases adiposity and alters emotional behaviors sex-dependently in rats
Objective
Adenylate cyclase 3 (Adcy3) has been linked to both obesity and major depressive disorder. We identified a protein-coding variant in the transmembrane (TM) helix of Adcy3 in rats; similar obesity variants have been identified in humans. This study investigates the role of a TM variant in adiposity and behavior.
Methods
We mutated the TM domain of Adcy3 (Adcy3mut/mut) and created a heterozygous knockout (Adcy3+/−) in Wistar Kyoto (WKY) rats. Wild-type, Adcy3+/−, and Adcy3mut/mut rats were fed a high-fat diet for 12 weeks. We measured body weight, fat mass, glucose tolerance, food intake, metabolism, emotion-like behaviors, memory, and downstream proteins.
Results
Adcy3+/− and Adcy3mut/mut rats weighed more than wild-type rats due to increased fat mass. There were key sex differences: adiposity was driven by increased food intake in males but by decreased energy expenditure in females. Adcy3mut/mut males displayed increased passive coping and decreased memory, whereas Adcy3mut/mut females displayed increased anxiety-like behavior. Adcy3mut/mut males had decreased hypothalamic cAMP-response element binding protein (CREB) signaling, with decreased phospho-AMP-activated protein kinase (p-AMPK) signaling in both sexes.
Conclusions
The ADCY3 TM domain plays a role in protein function via p-AMPK and CREB signaling. Adcy3 may contribute to the relationship between obesity and major depressive disorder, and sex influences the relationships between Adcy3, metabolism, and behavior.
期刊介绍：
Obesity is the official journal of The Obesity Society and is the premier source of information for increasing knowledge, fostering translational research from basic to population science, and promoting better treatment for people with obesity. Obesity publishes important peer-reviewed research and cutting-edge reviews, commentaries, and public health and medical developments.
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