5-HT obesity medication efficacy via POMC activation is maintained during aging

Autores
Burke, Luke K.; Doslikova, Barbora; D'agostino, Giuseppe; Garfield, Alastair S.; Farooq, Gala; Burdakov, Denis; Low, Malcolm J.; Rubinstein, Marcelo; Evans, Mark L.; Billups, Brian; Heisler, Lora K.
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The phenomenon commonly described as the middle-age spread is the result of elevated adiposity accumulation throughout adulthood until late middle-age. It is a clinical imperative to gain a greater understanding of the underpinnings of age-dependent obesity and, in turn, how these mechanisms may impact the efficacy of obesity treatments. In particular, both obesity and aging are associated with rewiring of a principal brain pathway modulating energy homeostasis, promoting reduced activity of satiety pro-opiomelanocortin (POMC) neurons within the arcuate nucleus of the hypothalamus (ARC). Using a selective ARC-deficient POMC mouse line, here we report that former obesity medications augmenting endogenous 5-hydroxytryptamine (5-HT) activity d-fenfluramine and sibutramine require ARC POMC neurons to elicit therapeutic appetite-suppressive effects. We next investigated whether age-related diminished ARC POMC activity therefore impacts the potency of 5-HT obesity pharmacotherapies, lorcaserin, d-fenfluramine, and sibutramine and report that all compounds reduced food intake to a comparable extent in both chow-fed young lean (3-5 months old) and middle-aged obese (12-14 months old) male and female mice. We provide a mechanism through which 5-HT anorectic potency is maintained with age, via preserved 5-HT-POMC appetitive anatomical machinery. Specifically, the abundance and signaling of the primary 5-HT receptor influencing appetite via POMC activation, the 5-HT2CR, is not perturbed with age. These data reveal that although 5-HT obesity medications require ARC POMC neurons to achieve appetitive effects, the anorectic efficacy is maintained with aging, findings of clinical significance to the global aging obese population.
Fil: Burke, Luke K.. University of Cambridge. Department of Pharmacology; Reino Unido
Fil: Doslikova, Barbora. University of Cambridge. Department of Pharmacology; Reino Unido
Fil: D'agostino, Giuseppe. University of Cambridge. Department of Pharmacology; Reino Unido. University of Aberdeen. Rowett Institute of Nutrition and Health; Reino Unido
Fil: Garfield, Alastair S.. University of Cambridge. Department of Pharmacology; Reino Unido
Fil: Farooq, Gala. University of Cambridge. Department of Pharmacology; Reino Unido
Fil: Burdakov, Denis. University of Cambridge. Department of Pharmacology; Reino Unido
Fil: Low, Malcolm J.. University of Michigan. Medical School. Department of Molecular and Integrative Physiology; Estados Unidos
Fil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina. University of Michigan. Medical School. Department of Molecular and Integrative Physiology; Estados Unidos
Fil: Evans, Mark L.. Wellcome Trust/ Medical Research Council Institute of Metabolic Science; Reino Unido
Fil: Billups, Brian. University of Cambridge. Department of Pharmacology; Reino Unido
Fil: Heisler, Lora K.. University of Cambridge. Department of Pharmacology; Reino Unido. University of Aberdeen. Rowett Institute of Nutrition and Health; Reino Unido
Materia
Serotonina
Pomc
Ratón transgénico
Obesidad
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/4006
Acceder
id CONICETDig_7330a5ccff8be23e01dbedfeb59939a4
oai_identifier_str oai:ri.conicet.gov.ar:11336/4006
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling 5-HT obesity medication efficacy via POMC activation is maintained during agingBurke, Luke K.Doslikova, BarboraD'agostino, GiuseppeGarfield, Alastair S.Farooq, GalaBurdakov, DenisLow, Malcolm J.Rubinstein, MarceloEvans, Mark L.Billups, BrianHeisler, Lora K.SerotoninaPomcRatón transgénicoObesidadhttps://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3The phenomenon commonly described as the middle-age spread is the result of elevated adiposity accumulation throughout adulthood until late middle-age. It is a clinical imperative to gain a greater understanding of the underpinnings of age-dependent obesity and, in turn, how these mechanisms may impact the efficacy of obesity treatments. In particular, both obesity and aging are associated with rewiring of a principal brain pathway modulating energy homeostasis, promoting reduced activity of satiety pro-opiomelanocortin (POMC) neurons within the arcuate nucleus of the hypothalamus (ARC). Using a selective ARC-deficient POMC mouse line, here we report that former obesity medications augmenting endogenous 5-hydroxytryptamine (5-HT) activity d-fenfluramine and sibutramine require ARC POMC neurons to elicit therapeutic appetite-suppressive effects. We next investigated whether age-related diminished ARC POMC activity therefore impacts the potency of 5-HT obesity pharmacotherapies, lorcaserin, d-fenfluramine, and sibutramine and report that all compounds reduced food intake to a comparable extent in both chow-fed young lean (3-5 months old) and middle-aged obese (12-14 months old) male and female mice. We provide a mechanism through which 5-HT anorectic potency is maintained with age, via preserved 5-HT-POMC appetitive anatomical machinery. Specifically, the abundance and signaling of the primary 5-HT receptor influencing appetite via POMC activation, the 5-HT2CR, is not perturbed with age. These data reveal that although 5-HT obesity medications require ARC POMC neurons to achieve appetitive effects, the anorectic efficacy is maintained with aging, findings of clinical significance to the global aging obese population.Fil: Burke, Luke K.. University of Cambridge. Department of Pharmacology; Reino UnidoFil: Doslikova, Barbora. University of Cambridge. Department of Pharmacology; Reino UnidoFil: D'agostino, Giuseppe. University of Cambridge. Department of Pharmacology; Reino Unido. University of Aberdeen. Rowett Institute of Nutrition and Health; Reino UnidoFil: Garfield, Alastair S.. University of Cambridge. Department of Pharmacology; Reino UnidoFil: Farooq, Gala. University of Cambridge. Department of Pharmacology; Reino UnidoFil: Burdakov, Denis. University of Cambridge. Department of Pharmacology; Reino UnidoFil: Low, Malcolm J.. University of Michigan. Medical School. Department of Molecular and Integrative Physiology; Estados UnidosFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina. University of Michigan. Medical School. Department of Molecular and Integrative Physiology; Estados UnidosFil: Evans, Mark L.. Wellcome Trust/ Medical Research Council Institute of Metabolic Science; Reino UnidoFil: Billups, Brian. University of Cambridge. Department of Pharmacology; Reino UnidoFil: Heisler, Lora K.. University of Cambridge. Department of Pharmacology; Reino Unido. University of Aberdeen. Rowett Institute of Nutrition and Health; Reino UnidoEndocrine Society2014-07-22info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/4006Burke, Luke K.; Doslikova, Barbora; D'agostino, Giuseppe; Garfield, Alastair S.; Farooq, Gala; et al.; 5-HT obesity medication efficacy via POMC activation is maintained during aging; Endocrine Society; Endocrinology; 155; 10; 22-7-2014; 3732-37380013-7227enginfo:eu-repo/semantics/altIdentifier/url/http://press.endocrine.org/doi/ref/10.1210/en.2014-1223info:eu-repo/semantics/altIdentifier/doi/10.1210/en.2014-1223info:eu-repo/semantics/altIdentifier/url/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4164923/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-10T13:23:24Zoai:ri.conicet.gov.ar:11336/4006instacron: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:34982025-09-10 13:23:24.485CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv 5-HT obesity medication efficacy via POMC activation is maintained during aging
title 5-HT obesity medication efficacy via POMC activation is maintained during aging
spellingShingle 5-HT obesity medication efficacy via POMC activation is maintained during aging
Burke, Luke K.
Serotonina
Pomc
Ratón transgénico
Obesidad
title_short 5-HT obesity medication efficacy via POMC activation is maintained during aging
title_full 5-HT obesity medication efficacy via POMC activation is maintained during aging
title_fullStr 5-HT obesity medication efficacy via POMC activation is maintained during aging
title_full_unstemmed 5-HT obesity medication efficacy via POMC activation is maintained during aging
title_sort 5-HT obesity medication efficacy via POMC activation is maintained during aging
dc.creator.none.fl_str_mv Burke, Luke K.
Doslikova, Barbora
D'agostino, Giuseppe
Garfield, Alastair S.
Farooq, Gala
Burdakov, Denis
Low, Malcolm J.
Rubinstein, Marcelo
Evans, Mark L.
Billups, Brian
Heisler, Lora K.
author Burke, Luke K.
author_facet Burke, Luke K.
Doslikova, Barbora
D'agostino, Giuseppe
Garfield, Alastair S.
Farooq, Gala
Burdakov, Denis
Low, Malcolm J.
Rubinstein, Marcelo
Evans, Mark L.
Billups, Brian
Heisler, Lora K.
author_role author
author2 Doslikova, Barbora
D'agostino, Giuseppe
Garfield, Alastair S.
Farooq, Gala
Burdakov, Denis
Low, Malcolm J.
Rubinstein, Marcelo
Evans, Mark L.
Billups, Brian
Heisler, Lora K.
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Serotonina
Pomc
Ratón transgénico
Obesidad
topic Serotonina
Pomc
Ratón transgénico
Obesidad
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv The phenomenon commonly described as the middle-age spread is the result of elevated adiposity accumulation throughout adulthood until late middle-age. It is a clinical imperative to gain a greater understanding of the underpinnings of age-dependent obesity and, in turn, how these mechanisms may impact the efficacy of obesity treatments. In particular, both obesity and aging are associated with rewiring of a principal brain pathway modulating energy homeostasis, promoting reduced activity of satiety pro-opiomelanocortin (POMC) neurons within the arcuate nucleus of the hypothalamus (ARC). Using a selective ARC-deficient POMC mouse line, here we report that former obesity medications augmenting endogenous 5-hydroxytryptamine (5-HT) activity d-fenfluramine and sibutramine require ARC POMC neurons to elicit therapeutic appetite-suppressive effects. We next investigated whether age-related diminished ARC POMC activity therefore impacts the potency of 5-HT obesity pharmacotherapies, lorcaserin, d-fenfluramine, and sibutramine and report that all compounds reduced food intake to a comparable extent in both chow-fed young lean (3-5 months old) and middle-aged obese (12-14 months old) male and female mice. We provide a mechanism through which 5-HT anorectic potency is maintained with age, via preserved 5-HT-POMC appetitive anatomical machinery. Specifically, the abundance and signaling of the primary 5-HT receptor influencing appetite via POMC activation, the 5-HT2CR, is not perturbed with age. These data reveal that although 5-HT obesity medications require ARC POMC neurons to achieve appetitive effects, the anorectic efficacy is maintained with aging, findings of clinical significance to the global aging obese population.
Fil: Burke, Luke K.. University of Cambridge. Department of Pharmacology; Reino Unido
Fil: Doslikova, Barbora. University of Cambridge. Department of Pharmacology; Reino Unido
Fil: D'agostino, Giuseppe. University of Cambridge. Department of Pharmacology; Reino Unido. University of Aberdeen. Rowett Institute of Nutrition and Health; Reino Unido
Fil: Garfield, Alastair S.. University of Cambridge. Department of Pharmacology; Reino Unido
Fil: Farooq, Gala. University of Cambridge. Department of Pharmacology; Reino Unido
Fil: Burdakov, Denis. University of Cambridge. Department of Pharmacology; Reino Unido
Fil: Low, Malcolm J.. University of Michigan. Medical School. Department of Molecular and Integrative Physiology; Estados Unidos
Fil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina. University of Michigan. Medical School. Department of Molecular and Integrative Physiology; Estados Unidos
Fil: Evans, Mark L.. Wellcome Trust/ Medical Research Council Institute of Metabolic Science; Reino Unido
Fil: Billups, Brian. University of Cambridge. Department of Pharmacology; Reino Unido
Fil: Heisler, Lora K.. University of Cambridge. Department of Pharmacology; Reino Unido. University of Aberdeen. Rowett Institute of Nutrition and Health; Reino Unido
description The phenomenon commonly described as the middle-age spread is the result of elevated adiposity accumulation throughout adulthood until late middle-age. It is a clinical imperative to gain a greater understanding of the underpinnings of age-dependent obesity and, in turn, how these mechanisms may impact the efficacy of obesity treatments. In particular, both obesity and aging are associated with rewiring of a principal brain pathway modulating energy homeostasis, promoting reduced activity of satiety pro-opiomelanocortin (POMC) neurons within the arcuate nucleus of the hypothalamus (ARC). Using a selective ARC-deficient POMC mouse line, here we report that former obesity medications augmenting endogenous 5-hydroxytryptamine (5-HT) activity d-fenfluramine and sibutramine require ARC POMC neurons to elicit therapeutic appetite-suppressive effects. We next investigated whether age-related diminished ARC POMC activity therefore impacts the potency of 5-HT obesity pharmacotherapies, lorcaserin, d-fenfluramine, and sibutramine and report that all compounds reduced food intake to a comparable extent in both chow-fed young lean (3-5 months old) and middle-aged obese (12-14 months old) male and female mice. We provide a mechanism through which 5-HT anorectic potency is maintained with age, via preserved 5-HT-POMC appetitive anatomical machinery. Specifically, the abundance and signaling of the primary 5-HT receptor influencing appetite via POMC activation, the 5-HT2CR, is not perturbed with age. These data reveal that although 5-HT obesity medications require ARC POMC neurons to achieve appetitive effects, the anorectic efficacy is maintained with aging, findings of clinical significance to the global aging obese population.
publishDate 2014
dc.date.none.fl_str_mv 2014-07-22
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/11336/4006
Burke, Luke K.; Doslikova, Barbora; D'agostino, Giuseppe; Garfield, Alastair S.; Farooq, Gala; et al.; 5-HT obesity medication efficacy via POMC activation is maintained during aging; Endocrine Society; Endocrinology; 155; 10; 22-7-2014; 3732-3738
0013-7227
url http://hdl.handle.net/11336/4006
identifier_str_mv Burke, Luke K.; Doslikova, Barbora; D'agostino, Giuseppe; Garfield, Alastair S.; Farooq, Gala; et al.; 5-HT obesity medication efficacy via POMC activation is maintained during aging; Endocrine Society; Endocrinology; 155; 10; 22-7-2014; 3732-3738
0013-7227
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://press.endocrine.org/doi/ref/10.1210/en.2014-1223
info:eu-repo/semantics/altIdentifier/doi/10.1210/en.2014-1223
info:eu-repo/semantics/altIdentifier/url/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4164923/
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
dc.publisher.none.fl_str_mv Endocrine Society
publisher.none.fl_str_mv Endocrine Society
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_ 1842981292054937600
score 12.48226

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