Mineralocorticoid receptor activates postnatal adiposity in zebrafish lacking proopiomelanocortin
The proopiomelanocortin (Pomc)‐derived peptides, including adrenocorticotropic hormone and α‐melanocyte stimulating hormone (α‐Msh), play both a central and a peripheral role in modulating the stress response. The central role is predominantly associated with nutrient homeostasis, while peripherally...
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description | The proopiomelanocortin (Pomc)‐derived peptides, including adrenocorticotropic hormone and α‐melanocyte stimulating hormone (α‐Msh), play both a central and a peripheral role in modulating the stress response. The central role is predominantly associated with nutrient homeostasis, while peripherally they play an important role in the synthesis of glucocorticoids (GCs) in response to stress. Pomc mutations are a major risk factor in the development of early‐onset childhood obesity in humans. This is attributed primarily to their central effects on melanocortin receptor dysfunction leading to hyperphagia and reduced energy expenditure, while the peripheral mechanism contributing to obesity has largely been unexplored. Here, we tested the hypothesis that Pomc mutation‐mediated adrenal insufficiency and the associated changes in GC signaling contribute to postnatal adiposity using zebrafish as a model. We generated a ubiquitous Pomc knockout zebrafish that mimicked the mammalian mutant phenotype of adrenal insufficiency and enhanced adiposity. The loss of Pomc inhibited stress‐induced cortisol production and reprogrammed GC signaling by reducing glucocorticoid receptor responsiveness, whereas the mineralocorticoid receptor (Mr) signaling was enhanced. Larval feeding led to enhanced growth and adipogenesis in the Pomc mutants, and this was inhibited by eplerenone, an Mr antagonist. Altogether, our results underscore a key role for Mr signaling in early developmental adipogenesis and a possible target for therapeutic intervention for early‐onset childhood obesity due to Pomc dysfunction. |
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The central role is predominantly associated with nutrient homeostasis, while peripherally they play an important role in the synthesis of glucocorticoids (GCs) in response to stress. Pomc mutations are a major risk factor in the development of early‐onset childhood obesity in humans. This is attributed primarily to their central effects on melanocortin receptor dysfunction leading to hyperphagia and reduced energy expenditure, while the peripheral mechanism contributing to obesity has largely been unexplored. Here, we tested the hypothesis that Pomc mutation‐mediated adrenal insufficiency and the associated changes in GC signaling contribute to postnatal adiposity using zebrafish as a model. We generated a ubiquitous Pomc knockout zebrafish that mimicked the mammalian mutant phenotype of adrenal insufficiency and enhanced adiposity. The loss of Pomc inhibited stress‐induced cortisol production and reprogrammed GC signaling by reducing glucocorticoid receptor responsiveness, whereas the mineralocorticoid receptor (Mr) signaling was enhanced. Larval feeding led to enhanced growth and adipogenesis in the Pomc mutants, and this was inhibited by eplerenone, an Mr antagonist. Altogether, our results underscore a key role for Mr signaling in early developmental adipogenesis and a possible target for therapeutic intervention for early‐onset childhood obesity due to Pomc dysfunction.</description><identifier>ISSN: 0021-9541</identifier><identifier>ISSN: 1097-4652</identifier><identifier>EISSN: 1097-4652</identifier><identifier>DOI: 10.1002/jcp.31428</identifier><identifier>PMID: 39238189</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>Adipogenesis ; Adipogenesis - genetics ; Adipose tissue ; Adiposity - genetics ; Adrenal Insufficiency - genetics ; Adrenal Insufficiency - metabolism ; Adrenocorticotropic hormone ; Animals ; Animals, Genetically Modified ; Children ; corticosteroid receptors ; cortisol ; Danio rerio ; Energy expenditure ; Glucocorticoid receptors ; Glucocorticoids ; Glucocorticoids - metabolism ; Homeostasis ; Hydrocortisone - metabolism ; Hyperphagia ; Melanocortin ; Mineralocorticoid receptors ; Mutants ; Mutation ; Mutation - genetics ; Obesity ; Obesity - genetics ; Obesity - metabolism ; Peptides ; Phenotypes ; pomca ; Postpartum period ; Pro-Opiomelanocortin - genetics ; Pro-Opiomelanocortin - metabolism ; Proopiomelanocortin ; Receptors ; Receptors, Glucocorticoid - genetics ; Receptors, Glucocorticoid - metabolism ; Receptors, Mineralocorticoid - genetics ; Receptors, Mineralocorticoid - metabolism ; Risk factors ; Signal Transduction ; stress ; Stress response ; Zebrafish ; Zebrafish - genetics ; Zebrafish Proteins - genetics ; Zebrafish Proteins - metabolism</subject><ispartof>Journal of cellular physiology, 2024-09, Vol.239 (12), p.e31428-n/a</ispartof><rights>2024 The Author(s). published by Wiley Periodicals LLC.</rights><rights>2024 The Author(s). Journal of Cellular Physiology published by Wiley Periodicals LLC.</rights><rights>2024. This article is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c3348-d1e7aeeedd3e24225262c7c643141c296a498788fef618a768af60d0e3aa20683</cites><orcidid>0000-0002-4300-1965</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.31428$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjcp.31428$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39238189$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rajeswari, Jithine J.</creatorcontrib><creatorcontrib>Faught, Erin</creatorcontrib><creatorcontrib>Santos, Helio</creatorcontrib><creatorcontrib>Vijayan, Mathilakath M.</creatorcontrib><title>Mineralocorticoid receptor activates postnatal adiposity in zebrafish lacking proopiomelanocortin</title><title>Journal of cellular physiology</title><addtitle>J Cell Physiol</addtitle><description>The proopiomelanocortin (Pomc)‐derived peptides, including adrenocorticotropic hormone and α‐melanocyte stimulating hormone (α‐Msh), play both a central and a peripheral role in modulating the stress response. The central role is predominantly associated with nutrient homeostasis, while peripherally they play an important role in the synthesis of glucocorticoids (GCs) in response to stress. Pomc mutations are a major risk factor in the development of early‐onset childhood obesity in humans. This is attributed primarily to their central effects on melanocortin receptor dysfunction leading to hyperphagia and reduced energy expenditure, while the peripheral mechanism contributing to obesity has largely been unexplored. Here, we tested the hypothesis that Pomc mutation‐mediated adrenal insufficiency and the associated changes in GC signaling contribute to postnatal adiposity using zebrafish as a model. We generated a ubiquitous Pomc knockout zebrafish that mimicked the mammalian mutant phenotype of adrenal insufficiency and enhanced adiposity. The loss of Pomc inhibited stress‐induced cortisol production and reprogrammed GC signaling by reducing glucocorticoid receptor responsiveness, whereas the mineralocorticoid receptor (Mr) signaling was enhanced. Larval feeding led to enhanced growth and adipogenesis in the Pomc mutants, and this was inhibited by eplerenone, an Mr antagonist. Altogether, our results underscore a key role for Mr signaling in early developmental adipogenesis and a possible target for therapeutic intervention for early‐onset childhood obesity due to Pomc dysfunction.</description><subject>Adipogenesis</subject><subject>Adipogenesis - genetics</subject><subject>Adipose tissue</subject><subject>Adiposity - genetics</subject><subject>Adrenal Insufficiency - genetics</subject><subject>Adrenal Insufficiency - metabolism</subject><subject>Adrenocorticotropic hormone</subject><subject>Animals</subject><subject>Animals, Genetically Modified</subject><subject>Children</subject><subject>corticosteroid receptors</subject><subject>cortisol</subject><subject>Danio rerio</subject><subject>Energy expenditure</subject><subject>Glucocorticoid receptors</subject><subject>Glucocorticoids</subject><subject>Glucocorticoids - metabolism</subject><subject>Homeostasis</subject><subject>Hydrocortisone - metabolism</subject><subject>Hyperphagia</subject><subject>Melanocortin</subject><subject>Mineralocorticoid receptors</subject><subject>Mutants</subject><subject>Mutation</subject><subject>Mutation - genetics</subject><subject>Obesity</subject><subject>Obesity - genetics</subject><subject>Obesity - metabolism</subject><subject>Peptides</subject><subject>Phenotypes</subject><subject>pomca</subject><subject>Postpartum period</subject><subject>Pro-Opiomelanocortin - genetics</subject><subject>Pro-Opiomelanocortin - metabolism</subject><subject>Proopiomelanocortin</subject><subject>Receptors</subject><subject>Receptors, Glucocorticoid - genetics</subject><subject>Receptors, Glucocorticoid - metabolism</subject><subject>Receptors, Mineralocorticoid - genetics</subject><subject>Receptors, Mineralocorticoid - metabolism</subject><subject>Risk factors</subject><subject>Signal Transduction</subject><subject>stress</subject><subject>Stress response</subject><subject>Zebrafish</subject><subject>Zebrafish - genetics</subject><subject>Zebrafish Proteins - genetics</subject><subject>Zebrafish Proteins - metabolism</subject><issn>0021-9541</issn><issn>1097-4652</issn><issn>1097-4652</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><recordid>eNp1kU1v1DAQhi1ERZfCgT-AInGBQ1p_xbFPqFrxVRXBAc7W1Jm0XrJ2sL1Fy6-vIaWiSJxGo3n0aF69hDxj9JhRyk82bj4WTHL9gKwYNX0rVccfklW9sdZ0kh2SxzlvKKXGCPGIHArDhWbarAh89AETTNHFVLyLfmgSOpxLTA244q-hYG7mmEuAAlMDg6-LL_vGh-YnXiQYfb5qJnDffLhs5hTj7OMWJwiLMjwhByNMGZ_eziPy9e2bL-v37fmndx_Wp-etE0LqdmDYAyIOg0AuOe-44q53StZgzHGjQBrdaz3iqJiGXmkYFR0oCgBOlRZH5PXinXcXWxwchlJz2Tn5LaS9jeDt_UvwV_YyXlvGlDSmM9Xw8taQ4vcd5mK3PjucahaMu2wFo4wLZjiv6It_0E3cpVDzVUp2vBeyY5V6tVAuxZwTjnffMGp_NWdrc_Z3c5V9_vf7d-SfqipwsgA__IT7_5vs2frzorwBYG6lQQ</recordid><startdate>20240905</startdate><enddate>20240905</enddate><creator>Rajeswari, Jithine J.</creator><creator>Faught, Erin</creator><creator>Santos, Helio</creator><creator>Vijayan, Mathilakath M.</creator><general>Wiley Subscription Services, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><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><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-4300-1965</orcidid></search><sort><creationdate>20240905</creationdate><title>Mineralocorticoid receptor activates postnatal adiposity in zebrafish lacking proopiomelanocortin</title><author>Rajeswari, Jithine J. ; Faught, Erin ; Santos, Helio ; Vijayan, Mathilakath M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3348-d1e7aeeedd3e24225262c7c643141c296a498788fef618a768af60d0e3aa20683</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Adipogenesis</topic><topic>Adipogenesis - genetics</topic><topic>Adipose tissue</topic><topic>Adiposity - genetics</topic><topic>Adrenal Insufficiency - genetics</topic><topic>Adrenal Insufficiency - metabolism</topic><topic>Adrenocorticotropic hormone</topic><topic>Animals</topic><topic>Animals, Genetically Modified</topic><topic>Children</topic><topic>corticosteroid receptors</topic><topic>cortisol</topic><topic>Danio rerio</topic><topic>Energy expenditure</topic><topic>Glucocorticoid receptors</topic><topic>Glucocorticoids</topic><topic>Glucocorticoids - metabolism</topic><topic>Homeostasis</topic><topic>Hydrocortisone - metabolism</topic><topic>Hyperphagia</topic><topic>Melanocortin</topic><topic>Mineralocorticoid receptors</topic><topic>Mutants</topic><topic>Mutation</topic><topic>Mutation - genetics</topic><topic>Obesity</topic><topic>Obesity - genetics</topic><topic>Obesity - metabolism</topic><topic>Peptides</topic><topic>Phenotypes</topic><topic>pomca</topic><topic>Postpartum period</topic><topic>Pro-Opiomelanocortin - genetics</topic><topic>Pro-Opiomelanocortin - metabolism</topic><topic>Proopiomelanocortin</topic><topic>Receptors</topic><topic>Receptors, Glucocorticoid - genetics</topic><topic>Receptors, Glucocorticoid - metabolism</topic><topic>Receptors, Mineralocorticoid - genetics</topic><topic>Receptors, Mineralocorticoid - metabolism</topic><topic>Risk factors</topic><topic>Signal Transduction</topic><topic>stress</topic><topic>Stress response</topic><topic>Zebrafish</topic><topic>Zebrafish - genetics</topic><topic>Zebrafish Proteins - genetics</topic><topic>Zebrafish Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rajeswari, Jithine J.</creatorcontrib><creatorcontrib>Faught, Erin</creatorcontrib><creatorcontrib>Santos, Helio</creatorcontrib><creatorcontrib>Vijayan, Mathilakath M.</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>Wiley Online Library (Open Access Collection)</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of cellular physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rajeswari, Jithine J.</au><au>Faught, Erin</au><au>Santos, Helio</au><au>Vijayan, Mathilakath M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mineralocorticoid receptor activates postnatal adiposity in zebrafish lacking proopiomelanocortin</atitle><jtitle>Journal of cellular physiology</jtitle><addtitle>J Cell Physiol</addtitle><date>2024-09-05</date><risdate>2024</risdate><volume>239</volume><issue>12</issue><spage>e31428</spage><epage>n/a</epage><pages>e31428-n/a</pages><issn>0021-9541</issn><issn>1097-4652</issn><eissn>1097-4652</eissn><abstract>The proopiomelanocortin (Pomc)‐derived peptides, including adrenocorticotropic hormone and α‐melanocyte stimulating hormone (α‐Msh), play both a central and a peripheral role in modulating the stress response. The central role is predominantly associated with nutrient homeostasis, while peripherally they play an important role in the synthesis of glucocorticoids (GCs) in response to stress. Pomc mutations are a major risk factor in the development of early‐onset childhood obesity in humans. This is attributed primarily to their central effects on melanocortin receptor dysfunction leading to hyperphagia and reduced energy expenditure, while the peripheral mechanism contributing to obesity has largely been unexplored. Here, we tested the hypothesis that Pomc mutation‐mediated adrenal insufficiency and the associated changes in GC signaling contribute to postnatal adiposity using zebrafish as a model. We generated a ubiquitous Pomc knockout zebrafish that mimicked the mammalian mutant phenotype of adrenal insufficiency and enhanced adiposity. The loss of Pomc inhibited stress‐induced cortisol production and reprogrammed GC signaling by reducing glucocorticoid receptor responsiveness, whereas the mineralocorticoid receptor (Mr) signaling was enhanced. Larval feeding led to enhanced growth and adipogenesis in the Pomc mutants, and this was inhibited by eplerenone, an Mr antagonist. Altogether, our results underscore a key role for Mr signaling in early developmental adipogenesis and a possible target for therapeutic intervention for early‐onset childhood obesity due to Pomc dysfunction.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>39238189</pmid><doi>10.1002/jcp.31428</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0002-4300-1965</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Adipogenesis Adipogenesis - genetics Adipose tissue Adiposity - genetics Adrenal Insufficiency - genetics Adrenal Insufficiency - metabolism Adrenocorticotropic hormone Animals Animals, Genetically Modified Children corticosteroid receptors cortisol Danio rerio Energy expenditure Glucocorticoid receptors Glucocorticoids Glucocorticoids - metabolism Homeostasis Hydrocortisone - metabolism Hyperphagia Melanocortin Mineralocorticoid receptors Mutants Mutation Mutation - genetics Obesity Obesity - genetics Obesity - metabolism Peptides Phenotypes pomca Postpartum period Pro-Opiomelanocortin - genetics Pro-Opiomelanocortin - metabolism Proopiomelanocortin Receptors Receptors, Glucocorticoid - genetics Receptors, Glucocorticoid - metabolism Receptors, Mineralocorticoid - genetics Receptors, Mineralocorticoid - metabolism Risk factors Signal Transduction stress Stress response Zebrafish Zebrafish - genetics Zebrafish Proteins - genetics Zebrafish Proteins - metabolism |
title | Mineralocorticoid receptor activates postnatal adiposity in zebrafish lacking proopiomelanocortin |
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