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Hepatic lipogenesis marked by GCKR‐modulated triglycerides increases serum FGF21 in children/teens with obesity
Aims Fibroblast growth factor 21 (FGF21) decreases hepatic lipogenesis in animal models, and FGF21 analogues decrease serum triglycerides (TG) in adults in phase‐2 trials. On the other hand, serum FGF21 is associated with higher TG in observational studies of people with obesity, raising a sort of p...
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| Published in: | Diabetes, obesity & metabolism obesity & metabolism, 2025-02, Vol.27 (2), p.825-834 |
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| container_title | Diabetes, obesity & metabolism |
| container_volume | 27 |
| creator | Maffeis, Claudio Morandi, Anita Zusi, Chiara Olivieri, Francesca Fornari, Elena Cavarzere, Paolo Piona, Claudia Corradi, Massimiliano Emiliani, Federica Da Ros, Alessandro Berni Canani, Roberto Mantovani, Alessandro Targher, Giovanni |
| description | Aims
Fibroblast growth factor 21 (FGF21) decreases hepatic lipogenesis in animal models, and FGF21 analogues decrease serum triglycerides (TG) in adults in phase‐2 trials. On the other hand, serum FGF21 is associated with higher TG in observational studies of people with obesity, raising a sort of paradox. We tested the hypothesis that FGF21 is induced by TG in youth with obesity, as a compensatory mechanism.
Materials and Methods
We recruited 159 children/adolescents with obesity (80 males, 12.7 ± 2.1 years). Besides serum FGF21 and lipid dosages, we genotyped the Pro446Leu variant at glucokinase regulator (GCKR) as a known marker of genetically increased hepatic de novo lipogenesis, and we used it as an instrumental variable to establish a cause‐and‐effect relationship between FGF21 and TG, according to a Mendelian randomization analysis.
Results
The Pro446Leu variant increased circulating TG (β = +0.35, p |
| doi_str_mv | 10.1111/dom.16081 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_11701186</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3151984010</sourcerecordid><originalsourceid>FETCH-LOGICAL-c2991-107becfa89ec2dd3ffc3ff725f8e17b32b11512b6421fc5466fcf3c035e40b3d3</originalsourceid><addsrcrecordid>eNp1kcFu1DAQhi0EoqVw4AWQJS5wSNdjO05yQmjLblGLKiE4W4k92XVJ4q2dtMqNR-AZeRJMt1QFCUuWR-NPn2b0E_IS2DGks7C-PwbFSnhEDkEqkYHg6vFtzbOyYvyAPIvxkjEmRVk8JQeiUgAc5CG5OsVdPTpDO7fzGxwwukj7OnxDS5uZrpdnn39-_9F7O3X1mHpjcJtuNhicxUjdYALWMVURw9TT1XrFIXWp2brOBhwWI-IQ6Y0bt9Q3ST7Oz8mTtu4ivrh7j8jX1Ycvy9Ps_GL9cfn-PDO8qiADVjRo2rqs0HBrRduadAuetyVC0QjeAOTAGyU5tCaXSrWmFYaJHCVrhBVH5N3eu5uaHq3BYQx1p3fBpfVm7Wun__4Z3FZv_LUGKBhAqZLhzZ0h-KsJ46h7Fw12XT2gn6IWICRTlZB5Ql__g176KQxpv0TlUJWSAUvU2z1lgo8xYHs_DTD9O0mdktS3SSb21cPx78k_0SVgsQduXIfz_0365OLTXvkLI6yqiQ</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>3151984010</pqid></control><display><type>article</type><title>Hepatic lipogenesis marked by GCKR‐modulated triglycerides increases serum FGF21 in children/teens with obesity</title><source>Wiley-Blackwell Read & Publish Collection</source><creator>Maffeis, Claudio ; Morandi, Anita ; Zusi, Chiara ; Olivieri, Francesca ; Fornari, Elena ; Cavarzere, Paolo ; Piona, Claudia ; Corradi, Massimiliano ; Emiliani, Federica ; Da Ros, Alessandro ; Berni Canani, Roberto ; Mantovani, Alessandro ; Targher, Giovanni</creator><creatorcontrib>Maffeis, Claudio ; Morandi, Anita ; Zusi, Chiara ; Olivieri, Francesca ; Fornari, Elena ; Cavarzere, Paolo ; Piona, Claudia ; Corradi, Massimiliano ; Emiliani, Federica ; Da Ros, Alessandro ; Berni Canani, Roberto ; Mantovani, Alessandro ; Targher, Giovanni</creatorcontrib><description>Aims
Fibroblast growth factor 21 (FGF21) decreases hepatic lipogenesis in animal models, and FGF21 analogues decrease serum triglycerides (TG) in adults in phase‐2 trials. On the other hand, serum FGF21 is associated with higher TG in observational studies of people with obesity, raising a sort of paradox. We tested the hypothesis that FGF21 is induced by TG in youth with obesity, as a compensatory mechanism.
Materials and Methods
We recruited 159 children/adolescents with obesity (80 males, 12.7 ± 2.1 years). Besides serum FGF21 and lipid dosages, we genotyped the Pro446Leu variant at glucokinase regulator (GCKR) as a known marker of genetically increased hepatic de novo lipogenesis, and we used it as an instrumental variable to establish a cause‐and‐effect relationship between FGF21 and TG, according to a Mendelian randomization analysis.
Results
The Pro446Leu variant increased circulating TG (β = +0.35, p < 0.001), which was positively associated with circulating FGF21 (β = +0.42, p < 0.001). The Pro446Leu variant increased FGF‐21 (β = +0.14, p = 0.031) with the expected slope (β‐coefficient) in case of association entirely mediated by TG: 0.35 (slope between Pro446Ala and TG) × 0.42 (slope between TG and FGF21) = 0.14.
Conclusions
Hepatic lipogenesis, marked by GCKR‐modulated triglycerides, is significantly associated with increased serum FGF‐21 in children/adolescents with obesity.</description><identifier>ISSN: 1462-8902</identifier><identifier>ISSN: 1463-1326</identifier><identifier>EISSN: 1463-1326</identifier><identifier>DOI: 10.1111/dom.16081</identifier><identifier>PMID: 39611214</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Adolescents ; Animal models ; Children ; Fibroblast growth factors ; Glucokinase ; insulin resistance ; lipid‐lowering therapy ; Lipogenesis ; Liver ; Obesity ; obesity care ; Original ; Teenagers ; Triglycerides</subject><ispartof>Diabetes, obesity & metabolism, 2025-02, Vol.27 (2), p.825-834</ispartof><rights>2024 The Author(s). published by John Wiley & Sons Ltd.</rights><rights>2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.</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-c2991-107becfa89ec2dd3ffc3ff725f8e17b32b11512b6421fc5466fcf3c035e40b3d3</cites><orcidid>0000-0002-4325-3900 ; 0000-0001-5168-8317 ; 0000-0002-2631-9330</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27898,27899</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39611214$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Maffeis, Claudio</creatorcontrib><creatorcontrib>Morandi, Anita</creatorcontrib><creatorcontrib>Zusi, Chiara</creatorcontrib><creatorcontrib>Olivieri, Francesca</creatorcontrib><creatorcontrib>Fornari, Elena</creatorcontrib><creatorcontrib>Cavarzere, Paolo</creatorcontrib><creatorcontrib>Piona, Claudia</creatorcontrib><creatorcontrib>Corradi, Massimiliano</creatorcontrib><creatorcontrib>Emiliani, Federica</creatorcontrib><creatorcontrib>Da Ros, Alessandro</creatorcontrib><creatorcontrib>Berni Canani, Roberto</creatorcontrib><creatorcontrib>Mantovani, Alessandro</creatorcontrib><creatorcontrib>Targher, Giovanni</creatorcontrib><title>Hepatic lipogenesis marked by GCKR‐modulated triglycerides increases serum FGF21 in children/teens with obesity</title><title>Diabetes, obesity & metabolism</title><addtitle>Diabetes Obes Metab</addtitle><description>Aims
Fibroblast growth factor 21 (FGF21) decreases hepatic lipogenesis in animal models, and FGF21 analogues decrease serum triglycerides (TG) in adults in phase‐2 trials. On the other hand, serum FGF21 is associated with higher TG in observational studies of people with obesity, raising a sort of paradox. We tested the hypothesis that FGF21 is induced by TG in youth with obesity, as a compensatory mechanism.
Materials and Methods
We recruited 159 children/adolescents with obesity (80 males, 12.7 ± 2.1 years). Besides serum FGF21 and lipid dosages, we genotyped the Pro446Leu variant at glucokinase regulator (GCKR) as a known marker of genetically increased hepatic de novo lipogenesis, and we used it as an instrumental variable to establish a cause‐and‐effect relationship between FGF21 and TG, according to a Mendelian randomization analysis.
Results
The Pro446Leu variant increased circulating TG (β = +0.35, p < 0.001), which was positively associated with circulating FGF21 (β = +0.42, p < 0.001). The Pro446Leu variant increased FGF‐21 (β = +0.14, p = 0.031) with the expected slope (β‐coefficient) in case of association entirely mediated by TG: 0.35 (slope between Pro446Ala and TG) × 0.42 (slope between TG and FGF21) = 0.14.
Conclusions
Hepatic lipogenesis, marked by GCKR‐modulated triglycerides, is significantly associated with increased serum FGF‐21 in children/adolescents with obesity.</description><subject>Adolescents</subject><subject>Animal models</subject><subject>Children</subject><subject>Fibroblast growth factors</subject><subject>Glucokinase</subject><subject>insulin resistance</subject><subject>lipid‐lowering therapy</subject><subject>Lipogenesis</subject><subject>Liver</subject><subject>Obesity</subject><subject>obesity care</subject><subject>Original</subject><subject>Teenagers</subject><subject>Triglycerides</subject><issn>1462-8902</issn><issn>1463-1326</issn><issn>1463-1326</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2025</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><recordid>eNp1kcFu1DAQhi0EoqVw4AWQJS5wSNdjO05yQmjLblGLKiE4W4k92XVJ4q2dtMqNR-AZeRJMt1QFCUuWR-NPn2b0E_IS2DGks7C-PwbFSnhEDkEqkYHg6vFtzbOyYvyAPIvxkjEmRVk8JQeiUgAc5CG5OsVdPTpDO7fzGxwwukj7OnxDS5uZrpdnn39-_9F7O3X1mHpjcJtuNhicxUjdYALWMVURw9TT1XrFIXWp2brOBhwWI-IQ6Y0bt9Q3ST7Oz8mTtu4ivrh7j8jX1Ycvy9Ps_GL9cfn-PDO8qiADVjRo2rqs0HBrRduadAuetyVC0QjeAOTAGyU5tCaXSrWmFYaJHCVrhBVH5N3eu5uaHq3BYQx1p3fBpfVm7Wun__4Z3FZv_LUGKBhAqZLhzZ0h-KsJ46h7Fw12XT2gn6IWICRTlZB5Ql__g176KQxpv0TlUJWSAUvU2z1lgo8xYHs_DTD9O0mdktS3SSb21cPx78k_0SVgsQduXIfz_0365OLTXvkLI6yqiQ</recordid><startdate>202502</startdate><enddate>202502</enddate><creator>Maffeis, Claudio</creator><creator>Morandi, Anita</creator><creator>Zusi, Chiara</creator><creator>Olivieri, Francesca</creator><creator>Fornari, Elena</creator><creator>Cavarzere, Paolo</creator><creator>Piona, Claudia</creator><creator>Corradi, Massimiliano</creator><creator>Emiliani, Federica</creator><creator>Da Ros, Alessandro</creator><creator>Berni Canani, Roberto</creator><creator>Mantovani, Alessandro</creator><creator>Targher, Giovanni</creator><general>Blackwell Publishing Ltd</general><general>Wiley Subscription Services, Inc</general><scope>24P</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>7TK</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-4325-3900</orcidid><orcidid>https://orcid.org/0000-0001-5168-8317</orcidid><orcidid>https://orcid.org/0000-0002-2631-9330</orcidid></search><sort><creationdate>202502</creationdate><title>Hepatic lipogenesis marked by GCKR‐modulated triglycerides increases serum FGF21 in children/teens with obesity</title><author>Maffeis, Claudio ; Morandi, Anita ; Zusi, Chiara ; Olivieri, Francesca ; Fornari, Elena ; Cavarzere, Paolo ; Piona, Claudia ; Corradi, Massimiliano ; Emiliani, Federica ; Da Ros, Alessandro ; Berni Canani, Roberto ; Mantovani, Alessandro ; Targher, Giovanni</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c2991-107becfa89ec2dd3ffc3ff725f8e17b32b11512b6421fc5466fcf3c035e40b3d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2025</creationdate><topic>Adolescents</topic><topic>Animal models</topic><topic>Children</topic><topic>Fibroblast growth factors</topic><topic>Glucokinase</topic><topic>insulin resistance</topic><topic>lipid‐lowering therapy</topic><topic>Lipogenesis</topic><topic>Liver</topic><topic>Obesity</topic><topic>obesity care</topic><topic>Original</topic><topic>Teenagers</topic><topic>Triglycerides</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Maffeis, Claudio</creatorcontrib><creatorcontrib>Morandi, Anita</creatorcontrib><creatorcontrib>Zusi, Chiara</creatorcontrib><creatorcontrib>Olivieri, Francesca</creatorcontrib><creatorcontrib>Fornari, Elena</creatorcontrib><creatorcontrib>Cavarzere, Paolo</creatorcontrib><creatorcontrib>Piona, Claudia</creatorcontrib><creatorcontrib>Corradi, Massimiliano</creatorcontrib><creatorcontrib>Emiliani, Federica</creatorcontrib><creatorcontrib>Da Ros, Alessandro</creatorcontrib><creatorcontrib>Berni Canani, Roberto</creatorcontrib><creatorcontrib>Mantovani, Alessandro</creatorcontrib><creatorcontrib>Targher, Giovanni</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Diabetes, obesity & metabolism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Maffeis, Claudio</au><au>Morandi, Anita</au><au>Zusi, Chiara</au><au>Olivieri, Francesca</au><au>Fornari, Elena</au><au>Cavarzere, Paolo</au><au>Piona, Claudia</au><au>Corradi, Massimiliano</au><au>Emiliani, Federica</au><au>Da Ros, Alessandro</au><au>Berni Canani, Roberto</au><au>Mantovani, Alessandro</au><au>Targher, Giovanni</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hepatic lipogenesis marked by GCKR‐modulated triglycerides increases serum FGF21 in children/teens with obesity</atitle><jtitle>Diabetes, obesity & metabolism</jtitle><addtitle>Diabetes Obes Metab</addtitle><date>2025-02</date><risdate>2025</risdate><volume>27</volume><issue>2</issue><spage>825</spage><epage>834</epage><pages>825-834</pages><issn>1462-8902</issn><issn>1463-1326</issn><eissn>1463-1326</eissn><abstract>Aims
Fibroblast growth factor 21 (FGF21) decreases hepatic lipogenesis in animal models, and FGF21 analogues decrease serum triglycerides (TG) in adults in phase‐2 trials. On the other hand, serum FGF21 is associated with higher TG in observational studies of people with obesity, raising a sort of paradox. We tested the hypothesis that FGF21 is induced by TG in youth with obesity, as a compensatory mechanism.
Materials and Methods
We recruited 159 children/adolescents with obesity (80 males, 12.7 ± 2.1 years). Besides serum FGF21 and lipid dosages, we genotyped the Pro446Leu variant at glucokinase regulator (GCKR) as a known marker of genetically increased hepatic de novo lipogenesis, and we used it as an instrumental variable to establish a cause‐and‐effect relationship between FGF21 and TG, according to a Mendelian randomization analysis.
Results
The Pro446Leu variant increased circulating TG (β = +0.35, p < 0.001), which was positively associated with circulating FGF21 (β = +0.42, p < 0.001). The Pro446Leu variant increased FGF‐21 (β = +0.14, p = 0.031) with the expected slope (β‐coefficient) in case of association entirely mediated by TG: 0.35 (slope between Pro446Ala and TG) × 0.42 (slope between TG and FGF21) = 0.14.
Conclusions
Hepatic lipogenesis, marked by GCKR‐modulated triglycerides, is significantly associated with increased serum FGF‐21 in children/adolescents with obesity.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>39611214</pmid><doi>10.1111/dom.16081</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-4325-3900</orcidid><orcidid>https://orcid.org/0000-0001-5168-8317</orcidid><orcidid>https://orcid.org/0000-0002-2631-9330</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Diabetes, obesity & metabolism, 2025-02, Vol.27 (2), p.825-834 |
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| source | Wiley-Blackwell Read & Publish Collection |
| subjects | Adolescents Animal models Children Fibroblast growth factors Glucokinase insulin resistance lipid‐lowering therapy Lipogenesis Liver Obesity obesity care Original Teenagers Triglycerides |
| title | Hepatic lipogenesis marked by GCKR‐modulated triglycerides increases serum FGF21 in children/teens with obesity |
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