Lorcaserin improves glycemic control via a melanocortin neurocircuit

Autores
Burke, Luke K.; Ogunnowo-Bada, Emmanuel; Georgescu, Teodora; Cristiano, Claudia; de Morentin, Pablo B. Martinez; Valencia Torres, Lourdes; D'Agostino, Giuseppe; Riches, Christine; Heeley, Nicholas; Ruan, Yue; Rubinstein, Marcelo; Low, Malcolm J.; Myers, Martin G.; Rochford, Justin J.; Evans, Mark L.; Heisler, Lora K.
Año de publicación
2017
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Objective: The increasing prevalence of type 2 diabetes (T2D) and associated morbidity and mortality emphasizes the need for a more complete understanding of the mechanisms mediating glucose homeostasis to accelerate the identification of new medications. Recent reports indicate that the obesity medication lorcaserin, a 5-hydroxytryptamine (5-HT, serotonin) 2C receptor (5-HT2CR) agonist, improves glycemic control in association with weight loss in obese patients with T2D. Here we evaluate whether lorcaserin has an effect on glycemia without body weight loss and how this effect is achieved. Methods: Murine models of common and genetic T2D were utilized to probe the direct effect of lorcaserin on glycemic control. Results: Lorcaserin dose-dependently improves glycemic control in mouse models of T2D in the absence of reductions in food intake or body weight. Examining the mechanism of this effect, we reveal a necessary and sufficient neurochemical mediator of lorcaserin's glucoregulatory effects, brain pro-opiomelanocortin (POMC) peptides. To clarify further lorcaserin's therapeutic brain circuit, we examined the receptor target of POMC peptides. We demonstrate that lorcaserin requires functional melanocortin4 receptors on cholinergic preganglionic neurons (MC4RChAT) to exert its effects on glucose homeostasis. In contrast, MC4RChAT signaling did not impact lorcaserin's effects on feeding, indicating a divergence in the neurocircuitry underpinning lorcaserin's therapeutic glycemic and anorectic effects. Hyperinsulinemic-euglycemic clamp studies reveal that lorcaserin reduces hepatic glucose production, increases glucose disposal and improves insulin sensitivity. Conclusions: These data suggest that lorcaserin's action within the brain represents a mechanistically novel treatment for T2D: findings of significance to a prevalent global disease.
Fil: Burke, Luke K.. University of Cambridge; Estados Unidos
Fil: Ogunnowo-Bada, Emmanuel. University of Cambridge; Estados Unidos
Fil: Georgescu, Teodora. University of Aberdeen; Reino Unido
Fil: Cristiano, Claudia. University of Aberdeen; Reino Unido
Fil: de Morentin, Pablo B. Martinez. University of Aberdeen; Reino Unido
Fil: Valencia Torres, Lourdes. University of Aberdeen; Reino Unido. University of Cambridge; Estados Unidos
Fil: D'Agostino, Giuseppe. University of Cambridge; Estados Unidos. University of Aberdeen; Reino Unido
Fil: Riches, Christine. University of Cambridge; Estados Unidos
Fil: Heeley, Nicholas. University of Cambridge; Estados Unidos
Fil: Ruan, Yue. University of Cambridge; Estados Unidos
Fil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Low, Malcolm J.. University of Michigan; Estados Unidos
Fil: Myers, Martin G.. University of Michigan; Estados Unidos
Fil: Rochford, Justin J.. University of Aberdeen; Reino Unido
Fil: Evans, Mark L.. University of Cambridge; Estados Unidos
Fil: Heisler, Lora K.. University of Aberdeen; Reino Unido. University of Cambridge; Estados Unidos
Materia
5-HT2C RECEPTOR
HYPOTHALAMUS
LORCASERIN
MELANOCORTIN4 RECEPTOR (MC4R)
PRO-OPIOMELANOCORTIN (POMC)
TYPE 2 DIABETES
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:11336/65596

id CONICETDig_785157d52bc00d872d8cb68f2cbff3e9
oai_identifier_str oai:ri.conicet.gov.ar:11336/65596
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Lorcaserin improves glycemic control via a melanocortin neurocircuitBurke, Luke K.Ogunnowo-Bada, EmmanuelGeorgescu, TeodoraCristiano, Claudiade Morentin, Pablo B. MartinezValencia Torres, LourdesD'Agostino, GiuseppeRiches, ChristineHeeley, NicholasRuan, YueRubinstein, MarceloLow, Malcolm J.Myers, Martin G.Rochford, Justin J.Evans, Mark L.Heisler, Lora K.5-HT2C RECEPTORHYPOTHALAMUSLORCASERINMELANOCORTIN4 RECEPTOR (MC4R)PRO-OPIOMELANOCORTIN (POMC)TYPE 2 DIABETEShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Objective: The increasing prevalence of type 2 diabetes (T2D) and associated morbidity and mortality emphasizes the need for a more complete understanding of the mechanisms mediating glucose homeostasis to accelerate the identification of new medications. Recent reports indicate that the obesity medication lorcaserin, a 5-hydroxytryptamine (5-HT, serotonin) 2C receptor (5-HT2CR) agonist, improves glycemic control in association with weight loss in obese patients with T2D. Here we evaluate whether lorcaserin has an effect on glycemia without body weight loss and how this effect is achieved. Methods: Murine models of common and genetic T2D were utilized to probe the direct effect of lorcaserin on glycemic control. Results: Lorcaserin dose-dependently improves glycemic control in mouse models of T2D in the absence of reductions in food intake or body weight. Examining the mechanism of this effect, we reveal a necessary and sufficient neurochemical mediator of lorcaserin's glucoregulatory effects, brain pro-opiomelanocortin (POMC) peptides. To clarify further lorcaserin's therapeutic brain circuit, we examined the receptor target of POMC peptides. We demonstrate that lorcaserin requires functional melanocortin4 receptors on cholinergic preganglionic neurons (MC4RChAT) to exert its effects on glucose homeostasis. In contrast, MC4RChAT signaling did not impact lorcaserin's effects on feeding, indicating a divergence in the neurocircuitry underpinning lorcaserin's therapeutic glycemic and anorectic effects. Hyperinsulinemic-euglycemic clamp studies reveal that lorcaserin reduces hepatic glucose production, increases glucose disposal and improves insulin sensitivity. Conclusions: These data suggest that lorcaserin's action within the brain represents a mechanistically novel treatment for T2D: findings of significance to a prevalent global disease.Fil: Burke, Luke K.. University of Cambridge; Estados UnidosFil: Ogunnowo-Bada, Emmanuel. University of Cambridge; Estados UnidosFil: Georgescu, Teodora. University of Aberdeen; Reino UnidoFil: Cristiano, Claudia. University of Aberdeen; Reino UnidoFil: de Morentin, Pablo B. Martinez. University of Aberdeen; Reino UnidoFil: Valencia Torres, Lourdes. University of Aberdeen; Reino Unido. University of Cambridge; Estados UnidosFil: D'Agostino, Giuseppe. University of Cambridge; Estados Unidos. University of Aberdeen; Reino UnidoFil: Riches, Christine. University of Cambridge; Estados UnidosFil: Heeley, Nicholas. University of Cambridge; Estados UnidosFil: Ruan, Yue. University of Cambridge; Estados UnidosFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Low, Malcolm J.. University of Michigan; Estados UnidosFil: Myers, Martin G.. University of Michigan; Estados UnidosFil: Rochford, Justin J.. University of Aberdeen; Reino UnidoFil: Evans, Mark L.. University of Cambridge; Estados UnidosFil: Heisler, Lora K.. University of Aberdeen; Reino Unido. University of Cambridge; Estados UnidosElsevier Gmbh2017-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/65596Burke, Luke K.; Ogunnowo-Bada, Emmanuel; Georgescu, Teodora; Cristiano, Claudia; de Morentin, Pablo B. Martinez; et al.; Lorcaserin improves glycemic control via a melanocortin neurocircuit; Elsevier Gmbh; Molecular Metabolism; 6; 10; 10-2017; 1092-11022212-8778CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.molmet.2017.07.004info:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S2212877817304258info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:10:51Zoai:ri.conicet.gov.ar:11336/65596instacron: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 10:10:52.282CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Lorcaserin improves glycemic control via a melanocortin neurocircuit
title Lorcaserin improves glycemic control via a melanocortin neurocircuit
spellingShingle Lorcaserin improves glycemic control via a melanocortin neurocircuit
Burke, Luke K.
5-HT2C RECEPTOR
HYPOTHALAMUS
LORCASERIN
MELANOCORTIN4 RECEPTOR (MC4R)
PRO-OPIOMELANOCORTIN (POMC)
TYPE 2 DIABETES
title_short Lorcaserin improves glycemic control via a melanocortin neurocircuit
title_full Lorcaserin improves glycemic control via a melanocortin neurocircuit
title_fullStr Lorcaserin improves glycemic control via a melanocortin neurocircuit
title_full_unstemmed Lorcaserin improves glycemic control via a melanocortin neurocircuit
title_sort Lorcaserin improves glycemic control via a melanocortin neurocircuit
dc.creator.none.fl_str_mv Burke, Luke K.
Ogunnowo-Bada, Emmanuel
Georgescu, Teodora
Cristiano, Claudia
de Morentin, Pablo B. Martinez
Valencia Torres, Lourdes
D'Agostino, Giuseppe
Riches, Christine
Heeley, Nicholas
Ruan, Yue
Rubinstein, Marcelo
Low, Malcolm J.
Myers, Martin G.
Rochford, Justin J.
Evans, Mark L.
Heisler, Lora K.
author Burke, Luke K.
author_facet Burke, Luke K.
Ogunnowo-Bada, Emmanuel
Georgescu, Teodora
Cristiano, Claudia
de Morentin, Pablo B. Martinez
Valencia Torres, Lourdes
D'Agostino, Giuseppe
Riches, Christine
Heeley, Nicholas
Ruan, Yue
Rubinstein, Marcelo
Low, Malcolm J.
Myers, Martin G.
Rochford, Justin J.
Evans, Mark L.
Heisler, Lora K.
author_role author
author2 Ogunnowo-Bada, Emmanuel
Georgescu, Teodora
Cristiano, Claudia
de Morentin, Pablo B. Martinez
Valencia Torres, Lourdes
D'Agostino, Giuseppe
Riches, Christine
Heeley, Nicholas
Ruan, Yue
Rubinstein, Marcelo
Low, Malcolm J.
Myers, Martin G.
Rochford, Justin J.
Evans, Mark L.
Heisler, Lora K.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv 5-HT2C RECEPTOR
HYPOTHALAMUS
LORCASERIN
MELANOCORTIN4 RECEPTOR (MC4R)
PRO-OPIOMELANOCORTIN (POMC)
TYPE 2 DIABETES
topic 5-HT2C RECEPTOR
HYPOTHALAMUS
LORCASERIN
MELANOCORTIN4 RECEPTOR (MC4R)
PRO-OPIOMELANOCORTIN (POMC)
TYPE 2 DIABETES
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Objective: The increasing prevalence of type 2 diabetes (T2D) and associated morbidity and mortality emphasizes the need for a more complete understanding of the mechanisms mediating glucose homeostasis to accelerate the identification of new medications. Recent reports indicate that the obesity medication lorcaserin, a 5-hydroxytryptamine (5-HT, serotonin) 2C receptor (5-HT2CR) agonist, improves glycemic control in association with weight loss in obese patients with T2D. Here we evaluate whether lorcaserin has an effect on glycemia without body weight loss and how this effect is achieved. Methods: Murine models of common and genetic T2D were utilized to probe the direct effect of lorcaserin on glycemic control. Results: Lorcaserin dose-dependently improves glycemic control in mouse models of T2D in the absence of reductions in food intake or body weight. Examining the mechanism of this effect, we reveal a necessary and sufficient neurochemical mediator of lorcaserin's glucoregulatory effects, brain pro-opiomelanocortin (POMC) peptides. To clarify further lorcaserin's therapeutic brain circuit, we examined the receptor target of POMC peptides. We demonstrate that lorcaserin requires functional melanocortin4 receptors on cholinergic preganglionic neurons (MC4RChAT) to exert its effects on glucose homeostasis. In contrast, MC4RChAT signaling did not impact lorcaserin's effects on feeding, indicating a divergence in the neurocircuitry underpinning lorcaserin's therapeutic glycemic and anorectic effects. Hyperinsulinemic-euglycemic clamp studies reveal that lorcaserin reduces hepatic glucose production, increases glucose disposal and improves insulin sensitivity. Conclusions: These data suggest that lorcaserin's action within the brain represents a mechanistically novel treatment for T2D: findings of significance to a prevalent global disease.
Fil: Burke, Luke K.. University of Cambridge; Estados Unidos
Fil: Ogunnowo-Bada, Emmanuel. University of Cambridge; Estados Unidos
Fil: Georgescu, Teodora. University of Aberdeen; Reino Unido
Fil: Cristiano, Claudia. University of Aberdeen; Reino Unido
Fil: de Morentin, Pablo B. Martinez. University of Aberdeen; Reino Unido
Fil: Valencia Torres, Lourdes. University of Aberdeen; Reino Unido. University of Cambridge; Estados Unidos
Fil: D'Agostino, Giuseppe. University of Cambridge; Estados Unidos. University of Aberdeen; Reino Unido
Fil: Riches, Christine. University of Cambridge; Estados Unidos
Fil: Heeley, Nicholas. University of Cambridge; Estados Unidos
Fil: Ruan, Yue. University of Cambridge; Estados Unidos
Fil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Low, Malcolm J.. University of Michigan; Estados Unidos
Fil: Myers, Martin G.. University of Michigan; Estados Unidos
Fil: Rochford, Justin J.. University of Aberdeen; Reino Unido
Fil: Evans, Mark L.. University of Cambridge; Estados Unidos
Fil: Heisler, Lora K.. University of Aberdeen; Reino Unido. University of Cambridge; Estados Unidos
description Objective: The increasing prevalence of type 2 diabetes (T2D) and associated morbidity and mortality emphasizes the need for a more complete understanding of the mechanisms mediating glucose homeostasis to accelerate the identification of new medications. Recent reports indicate that the obesity medication lorcaserin, a 5-hydroxytryptamine (5-HT, serotonin) 2C receptor (5-HT2CR) agonist, improves glycemic control in association with weight loss in obese patients with T2D. Here we evaluate whether lorcaserin has an effect on glycemia without body weight loss and how this effect is achieved. Methods: Murine models of common and genetic T2D were utilized to probe the direct effect of lorcaserin on glycemic control. Results: Lorcaserin dose-dependently improves glycemic control in mouse models of T2D in the absence of reductions in food intake or body weight. Examining the mechanism of this effect, we reveal a necessary and sufficient neurochemical mediator of lorcaserin's glucoregulatory effects, brain pro-opiomelanocortin (POMC) peptides. To clarify further lorcaserin's therapeutic brain circuit, we examined the receptor target of POMC peptides. We demonstrate that lorcaserin requires functional melanocortin4 receptors on cholinergic preganglionic neurons (MC4RChAT) to exert its effects on glucose homeostasis. In contrast, MC4RChAT signaling did not impact lorcaserin's effects on feeding, indicating a divergence in the neurocircuitry underpinning lorcaserin's therapeutic glycemic and anorectic effects. Hyperinsulinemic-euglycemic clamp studies reveal that lorcaserin reduces hepatic glucose production, increases glucose disposal and improves insulin sensitivity. Conclusions: These data suggest that lorcaserin's action within the brain represents a mechanistically novel treatment for T2D: findings of significance to a prevalent global disease.
publishDate 2017
dc.date.none.fl_str_mv 2017-10
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/11336/65596
Burke, Luke K.; Ogunnowo-Bada, Emmanuel; Georgescu, Teodora; Cristiano, Claudia; de Morentin, Pablo B. Martinez; et al.; Lorcaserin improves glycemic control via a melanocortin neurocircuit; Elsevier Gmbh; Molecular Metabolism; 6; 10; 10-2017; 1092-1102
2212-8778
CONICET Digital
CONICET
url http://hdl.handle.net/11336/65596
identifier_str_mv Burke, Luke K.; Ogunnowo-Bada, Emmanuel; Georgescu, Teodora; Cristiano, Claudia; de Morentin, Pablo B. Martinez; et al.; Lorcaserin improves glycemic control via a melanocortin neurocircuit; Elsevier Gmbh; Molecular Metabolism; 6; 10; 10-2017; 1092-1102
2212-8778
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.molmet.2017.07.004
info:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S2212877817304258
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 Elsevier Gmbh
publisher.none.fl_str_mv Elsevier Gmbh
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_ 1842270135374577664
score 13.13397