Genetic or pharmacological GHSR blockade has sexually dimorphic effects in rodents on a high-fat diet
- Autores
- Lékó, András H.; Gregory Flores, Adriana; Marchette, Renata C. N.; Gomez, Juan L.; Vendruscolo, Janaina C. M.; Repunte Canonigo, Vez; Choung, Vicky; Deschaine, Sara L.; Whiting, Kimberly E.; Jackson, Shelley N.; Cornejo, María Paula; Perello, Mario; You, Zhi Bing; Eckhaus, Michael; Rasineni, Karuna; Janda, Kim D.; Zorman, Barry; Sumazin, Pavel; Koob, George F.; Michaelides, Michael; Sanna, Pietro P.; Vendruscolo, Leandro F.; Leggio, Lorenzo
- Año de publicación
- 2024
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- The stomach-derived hormone ghrelin regulates essential physiological functions. The ghrelin receptor (GHSR) has ligand-independent actions; therefore, GHSR gene deletion may be a reasonable approach to investigate the role of this system in feeding behaviors and diet-induced obesity (DIO). Here, we investigate the effects of a long-term (12-month) high-fat (HFD) versus regular diet on obesity-related measures in global GHSR-KO and wild-type (WT) Wistar male and female rats. Our main findings are that the GHSR gene deletion protects against DIO and decreases food intake during HFD in male but not in female rats. GHSR gene deletion increases thermogenesis and brain glucose uptake in male rats and modifies the effects of HFD on brain glucose metabolism in a sex-specific manner, as assessed with small animal positron emission tomography. We use RNA-sequencing to show that GHSR-KO rats have upregulated expression of genes responsible for fat oxidation in brown adipose tissue. Central administration of a novel GHSR inverse agonist, PF-5190457, attenuates ghrelin-induced food intake, but only in male, not in female mice. HFD-induced binge-like eating is reduced by inverse agonism in both sexes. Our results support GHSR as a promising target for new pharmacotherapies for obesity.
Fil: Lékó, András H.. National Institutes of Health; Estados Unidos
Fil: Gregory Flores, Adriana. National Institutes of Health; Estados Unidos
Fil: Marchette, Renata C. N.. National Institutes of Health; Estados Unidos
Fil: Gomez, Juan L.. National Institutes of Health; Estados Unidos
Fil: Vendruscolo, Janaina C. M.. National Institutes of Health; Estados Unidos
Fil: Repunte Canonigo, Vez. The Scripps Research Institute; Estados Unidos
Fil: Choung, Vicky. National Institutes of Health; Estados Unidos
Fil: Deschaine, Sara L.. National Institutes of Health; Estados Unidos
Fil: Whiting, Kimberly E.. National Institutes of Health; Estados Unidos
Fil: Jackson, Shelley N.. National Institutes of Health; Estados Unidos
Fil: Cornejo, María Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina
Fil: Perello, Mario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina
Fil: You, Zhi Bing. National Institutes of Health; Estados Unidos
Fil: Eckhaus, Michael. National Institutes of Health; Estados Unidos
Fil: Rasineni, Karuna. Veterans Affairs Nebraska-Western Iowa Health Care System; Estados Unidos. University of Nebraska; Estados Unidos
Fil: Janda, Kim D.. The Scripps Research Institute; Estados Unidos
Fil: Zorman, Barry. Baylor College of Medicine; Estados Unidos
Fil: Sumazin, Pavel. Baylor College of Medicine; Estados Unidos
Fil: Koob, George F.. National Institutes of Health; Estados Unidos
Fil: Michaelides, Michael. National Institutes of Health; Estados Unidos
Fil: Sanna, Pietro P.. The Scripps Research Institute; Estados Unidos
Fil: Vendruscolo, Leandro F.. National Institutes of Health; Estados Unidos
Fil: Leggio, Lorenzo. National Institutes of Health; Estados Unidos. Brown University; Estados Unidos. University Of Georgetown; Estados Unidos. University Johns Hopkins; Estados Unidos - Materia
-
GHSR
Obesity
HFD
Ghrelin - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by/2.5/ar/
- Repositorio
.jpg)
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/266600
Ver los metadatos del registro completo
| id |
CONICETDig_61ec69ee1ed68c60f8bea42924a47f8e |
|---|---|
| oai_identifier_str |
oai:ri.conicet.gov.ar:11336/266600 |
| network_acronym_str |
CONICETDig |
| repository_id_str |
3498 |
| network_name_str |
CONICET Digital (CONICET) |
| spelling |
Genetic or pharmacological GHSR blockade has sexually dimorphic effects in rodents on a high-fat dietLékó, András H.Gregory Flores, AdrianaMarchette, Renata C. N.Gomez, Juan L.Vendruscolo, Janaina C. M.Repunte Canonigo, VezChoung, VickyDeschaine, Sara L.Whiting, Kimberly E.Jackson, Shelley N.Cornejo, María PaulaPerello, MarioYou, Zhi BingEckhaus, MichaelRasineni, KarunaJanda, Kim D.Zorman, BarrySumazin, PavelKoob, George F.Michaelides, MichaelSanna, Pietro P.Vendruscolo, Leandro F.Leggio, LorenzoGHSRObesityHFDGhrelinhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3The stomach-derived hormone ghrelin regulates essential physiological functions. The ghrelin receptor (GHSR) has ligand-independent actions; therefore, GHSR gene deletion may be a reasonable approach to investigate the role of this system in feeding behaviors and diet-induced obesity (DIO). Here, we investigate the effects of a long-term (12-month) high-fat (HFD) versus regular diet on obesity-related measures in global GHSR-KO and wild-type (WT) Wistar male and female rats. Our main findings are that the GHSR gene deletion protects against DIO and decreases food intake during HFD in male but not in female rats. GHSR gene deletion increases thermogenesis and brain glucose uptake in male rats and modifies the effects of HFD on brain glucose metabolism in a sex-specific manner, as assessed with small animal positron emission tomography. We use RNA-sequencing to show that GHSR-KO rats have upregulated expression of genes responsible for fat oxidation in brown adipose tissue. Central administration of a novel GHSR inverse agonist, PF-5190457, attenuates ghrelin-induced food intake, but only in male, not in female mice. HFD-induced binge-like eating is reduced by inverse agonism in both sexes. Our results support GHSR as a promising target for new pharmacotherapies for obesity.Fil: Lékó, András H.. National Institutes of Health; Estados UnidosFil: Gregory Flores, Adriana. National Institutes of Health; Estados UnidosFil: Marchette, Renata C. N.. National Institutes of Health; Estados UnidosFil: Gomez, Juan L.. National Institutes of Health; Estados UnidosFil: Vendruscolo, Janaina C. M.. National Institutes of Health; Estados UnidosFil: Repunte Canonigo, Vez. The Scripps Research Institute; Estados UnidosFil: Choung, Vicky. National Institutes of Health; Estados UnidosFil: Deschaine, Sara L.. National Institutes of Health; Estados UnidosFil: Whiting, Kimberly E.. National Institutes of Health; Estados UnidosFil: Jackson, Shelley N.. National Institutes of Health; Estados UnidosFil: Cornejo, María Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; ArgentinaFil: Perello, Mario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; ArgentinaFil: You, Zhi Bing. National Institutes of Health; Estados UnidosFil: Eckhaus, Michael. National Institutes of Health; Estados UnidosFil: Rasineni, Karuna. Veterans Affairs Nebraska-Western Iowa Health Care System; Estados Unidos. University of Nebraska; Estados UnidosFil: Janda, Kim D.. The Scripps Research Institute; Estados UnidosFil: Zorman, Barry. Baylor College of Medicine; Estados UnidosFil: Sumazin, Pavel. Baylor College of Medicine; Estados UnidosFil: Koob, George F.. National Institutes of Health; Estados UnidosFil: Michaelides, Michael. National Institutes of Health; Estados UnidosFil: Sanna, Pietro P.. The Scripps Research Institute; Estados UnidosFil: Vendruscolo, Leandro F.. National Institutes of Health; Estados UnidosFil: Leggio, Lorenzo. National Institutes of Health; Estados Unidos. Brown University; Estados Unidos. University Of Georgetown; Estados Unidos. University Johns Hopkins; Estados UnidosNature2024-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/266600Lékó, András H.; Gregory Flores, Adriana; Marchette, Renata C. N.; Gomez, Juan L.; Vendruscolo, Janaina C. M.; et al.; Genetic or pharmacological GHSR blockade has sexually dimorphic effects in rodents on a high-fat diet; Nature; Communications Biology; 7; 1; 5-2024; 1-152399-3642CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s42003-024-06303-5info:eu-repo/semantics/altIdentifier/doi/10.1038/s42003-024-06303-5info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:06:40Zoai:ri.conicet.gov.ar:11336/266600instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 10:06:40.986CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
| dc.title.none.fl_str_mv |
Genetic or pharmacological GHSR blockade has sexually dimorphic effects in rodents on a high-fat diet |
| title |
Genetic or pharmacological GHSR blockade has sexually dimorphic effects in rodents on a high-fat diet |
| spellingShingle |
Genetic or pharmacological GHSR blockade has sexually dimorphic effects in rodents on a high-fat diet Lékó, András H. GHSR Obesity HFD Ghrelin |
| title_short |
Genetic or pharmacological GHSR blockade has sexually dimorphic effects in rodents on a high-fat diet |
| title_full |
Genetic or pharmacological GHSR blockade has sexually dimorphic effects in rodents on a high-fat diet |
| title_fullStr |
Genetic or pharmacological GHSR blockade has sexually dimorphic effects in rodents on a high-fat diet |
| title_full_unstemmed |
Genetic or pharmacological GHSR blockade has sexually dimorphic effects in rodents on a high-fat diet |
| title_sort |
Genetic or pharmacological GHSR blockade has sexually dimorphic effects in rodents on a high-fat diet |
| dc.creator.none.fl_str_mv |
Lékó, András H. Gregory Flores, Adriana Marchette, Renata C. N. Gomez, Juan L. Vendruscolo, Janaina C. M. Repunte Canonigo, Vez Choung, Vicky Deschaine, Sara L. Whiting, Kimberly E. Jackson, Shelley N. Cornejo, María Paula Perello, Mario You, Zhi Bing Eckhaus, Michael Rasineni, Karuna Janda, Kim D. Zorman, Barry Sumazin, Pavel Koob, George F. Michaelides, Michael Sanna, Pietro P. Vendruscolo, Leandro F. Leggio, Lorenzo |
| author |
Lékó, András H. |
| author_facet |
Lékó, András H. Gregory Flores, Adriana Marchette, Renata C. N. Gomez, Juan L. Vendruscolo, Janaina C. M. Repunte Canonigo, Vez Choung, Vicky Deschaine, Sara L. Whiting, Kimberly E. Jackson, Shelley N. Cornejo, María Paula Perello, Mario You, Zhi Bing Eckhaus, Michael Rasineni, Karuna Janda, Kim D. Zorman, Barry Sumazin, Pavel Koob, George F. Michaelides, Michael Sanna, Pietro P. Vendruscolo, Leandro F. Leggio, Lorenzo |
| author_role |
author |
| author2 |
Gregory Flores, Adriana Marchette, Renata C. N. Gomez, Juan L. Vendruscolo, Janaina C. M. Repunte Canonigo, Vez Choung, Vicky Deschaine, Sara L. Whiting, Kimberly E. Jackson, Shelley N. Cornejo, María Paula Perello, Mario You, Zhi Bing Eckhaus, Michael Rasineni, Karuna Janda, Kim D. Zorman, Barry Sumazin, Pavel Koob, George F. Michaelides, Michael Sanna, Pietro P. Vendruscolo, Leandro F. Leggio, Lorenzo |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
GHSR Obesity HFD Ghrelin |
| topic |
GHSR Obesity HFD Ghrelin |
| purl_subject.fl_str_mv |
https://purl.org/becyt/ford/3.1 https://purl.org/becyt/ford/3 |
| dc.description.none.fl_txt_mv |
The stomach-derived hormone ghrelin regulates essential physiological functions. The ghrelin receptor (GHSR) has ligand-independent actions; therefore, GHSR gene deletion may be a reasonable approach to investigate the role of this system in feeding behaviors and diet-induced obesity (DIO). Here, we investigate the effects of a long-term (12-month) high-fat (HFD) versus regular diet on obesity-related measures in global GHSR-KO and wild-type (WT) Wistar male and female rats. Our main findings are that the GHSR gene deletion protects against DIO and decreases food intake during HFD in male but not in female rats. GHSR gene deletion increases thermogenesis and brain glucose uptake in male rats and modifies the effects of HFD on brain glucose metabolism in a sex-specific manner, as assessed with small animal positron emission tomography. We use RNA-sequencing to show that GHSR-KO rats have upregulated expression of genes responsible for fat oxidation in brown adipose tissue. Central administration of a novel GHSR inverse agonist, PF-5190457, attenuates ghrelin-induced food intake, but only in male, not in female mice. HFD-induced binge-like eating is reduced by inverse agonism in both sexes. Our results support GHSR as a promising target for new pharmacotherapies for obesity. Fil: Lékó, András H.. National Institutes of Health; Estados Unidos Fil: Gregory Flores, Adriana. National Institutes of Health; Estados Unidos Fil: Marchette, Renata C. N.. National Institutes of Health; Estados Unidos Fil: Gomez, Juan L.. National Institutes of Health; Estados Unidos Fil: Vendruscolo, Janaina C. M.. National Institutes of Health; Estados Unidos Fil: Repunte Canonigo, Vez. The Scripps Research Institute; Estados Unidos Fil: Choung, Vicky. National Institutes of Health; Estados Unidos Fil: Deschaine, Sara L.. National Institutes of Health; Estados Unidos Fil: Whiting, Kimberly E.. National Institutes of Health; Estados Unidos Fil: Jackson, Shelley N.. National Institutes of Health; Estados Unidos Fil: Cornejo, María Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina Fil: Perello, Mario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina Fil: You, Zhi Bing. National Institutes of Health; Estados Unidos Fil: Eckhaus, Michael. National Institutes of Health; Estados Unidos Fil: Rasineni, Karuna. Veterans Affairs Nebraska-Western Iowa Health Care System; Estados Unidos. University of Nebraska; Estados Unidos Fil: Janda, Kim D.. The Scripps Research Institute; Estados Unidos Fil: Zorman, Barry. Baylor College of Medicine; Estados Unidos Fil: Sumazin, Pavel. Baylor College of Medicine; Estados Unidos Fil: Koob, George F.. National Institutes of Health; Estados Unidos Fil: Michaelides, Michael. National Institutes of Health; Estados Unidos Fil: Sanna, Pietro P.. The Scripps Research Institute; Estados Unidos Fil: Vendruscolo, Leandro F.. National Institutes of Health; Estados Unidos Fil: Leggio, Lorenzo. National Institutes of Health; Estados Unidos. Brown University; Estados Unidos. University Of Georgetown; Estados Unidos. University Johns Hopkins; Estados Unidos |
| description |
The stomach-derived hormone ghrelin regulates essential physiological functions. The ghrelin receptor (GHSR) has ligand-independent actions; therefore, GHSR gene deletion may be a reasonable approach to investigate the role of this system in feeding behaviors and diet-induced obesity (DIO). Here, we investigate the effects of a long-term (12-month) high-fat (HFD) versus regular diet on obesity-related measures in global GHSR-KO and wild-type (WT) Wistar male and female rats. Our main findings are that the GHSR gene deletion protects against DIO and decreases food intake during HFD in male but not in female rats. GHSR gene deletion increases thermogenesis and brain glucose uptake in male rats and modifies the effects of HFD on brain glucose metabolism in a sex-specific manner, as assessed with small animal positron emission tomography. We use RNA-sequencing to show that GHSR-KO rats have upregulated expression of genes responsible for fat oxidation in brown adipose tissue. Central administration of a novel GHSR inverse agonist, PF-5190457, attenuates ghrelin-induced food intake, but only in male, not in female mice. HFD-induced binge-like eating is reduced by inverse agonism in both sexes. Our results support GHSR as a promising target for new pharmacotherapies for obesity. |
| publishDate |
2024 |
| dc.date.none.fl_str_mv |
2024-05 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/266600 Lékó, András H.; Gregory Flores, Adriana; Marchette, Renata C. N.; Gomez, Juan L.; Vendruscolo, Janaina C. M.; et al.; Genetic or pharmacological GHSR blockade has sexually dimorphic effects in rodents on a high-fat diet; Nature; Communications Biology; 7; 1; 5-2024; 1-15 2399-3642 CONICET Digital CONICET |
| url |
http://hdl.handle.net/11336/266600 |
| identifier_str_mv |
Lékó, András H.; Gregory Flores, Adriana; Marchette, Renata C. N.; Gomez, Juan L.; Vendruscolo, Janaina C. M.; et al.; Genetic or pharmacological GHSR blockade has sexually dimorphic effects in rodents on a high-fat diet; Nature; Communications Biology; 7; 1; 5-2024; 1-15 2399-3642 CONICET Digital CONICET |
| dc.language.none.fl_str_mv |
eng |
| language |
eng |
| dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s42003-024-06303-5 info:eu-repo/semantics/altIdentifier/doi/10.1038/s42003-024-06303-5 |
| dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by/2.5/ar/ |
| eu_rights_str_mv |
openAccess |
| rights_invalid_str_mv |
https://creativecommons.org/licenses/by/2.5/ar/ |
| dc.format.none.fl_str_mv |
application/pdf application/pdf application/pdf |
| dc.publisher.none.fl_str_mv |
Nature |
| publisher.none.fl_str_mv |
Nature |
| dc.source.none.fl_str_mv |
reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
| reponame_str |
CONICET Digital (CONICET) |
| collection |
CONICET Digital (CONICET) |
| instname_str |
Consejo Nacional de Investigaciones Científicas y Técnicas |
| repository.name.fl_str_mv |
CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
| repository.mail.fl_str_mv |
dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
| _version_ |
1842269969532846080 |
| score |
13.13397 |