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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/65596
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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 |
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1842270135374577664 |
score |
13.13397 |