Lorcaserin improves glycemic control via a melanocortin neurocircuit

Luke K. Burke; Emmanuel Ogunnowo-Bada; Teodora Georgescu; Claudia Cristiano; Pablo B. Martinez De Morentin; Lourdes Valencia-Torres; Giuseppe D'Agostino; Christine Riches; Nicholas Heeley; Yue Ruan; Marcelo Rubinstein; Malcolm J. Low; Martin G. Myers; Justin J. Rochford; Mark L. Evans; Lora K. Heisler

doi:10.1016/j.molmet.2017.07.004

Lorcaserin improves glycemic control via a melanocortin neurocircuit

Luke K. Burke, Emmanuel Ogunnowo-Bada, Teodora Georgescu, Claudia Cristiano, Pablo B. Martinez De Morentin, Lourdes Valencia-Torres, Giuseppe D'Agostino, Christine Riches, Nicholas Heeley, Yue Ruan, Marcelo Rubinstein, Malcolm J. Low, Martin G. Myers, Justin J. Rochford, Mark L. Evans, Lora K. Heisler^* (Corresponding Author)

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

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 that 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.

Original language	English
Pages (from-to)	1092-1102
Number of pages	11
Journal	Molecular Metabolism
Volume	6
Issue number	10
Early online date	21 Jul 2017
DOIs	https://doi.org/10.1016/j.molmet.2017.07.004
Publication status	Published - 31 Oct 2017

Bibliographical note

Authors wish to thank members of staff of the Medical Research Facility University of Aberdeen, Ms Raffaella Chianese, Ms Pat Bain, Dr Samuel Virtue and Dr Guenievre Roussel for technical assistance. Work was supported by the Wellcome Trust (LKH: WT098012, WT081713; LKH/LKB: 093566/Z/10/A; JJR/GD'A/PBMM: 100574/Z/12/Z), Diabetes UK (MLE: 13/0004680), Biotechnology and Biological Sciences Research Council (LKH: BB/K001418/1, BB/NO17838/1 and JJR: BB/K017772/1), the Medical Research Council (JJR: MR/L002620/1; LKH: MC/PC/15077; GD'A: MR/P009824/1), the Cambridge MRC Centre for Study of Obesity and Related Disorders (MRC-CORD) to LKH, MLE and LKB, European Commission (PBMM/LKH 660219-NeuroEE), Genomics/Transcriptomics Core Facilities, the Neuroscience Graduate Program, the National Institutes of Health (MJL: DK066604; MJL/MR: DK068400; MGM: DK056731) and the Marilyn H. Vincent Foundation to MGM.

Keywords

5-HT2c receptor
Type 2 diabetes
Hypothalamus
Lorcaserin
Pro-opiomelanocortin (POMC)
Melanocortin4 receptor (Mc4r)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Lorcaserin improves glycemic control via a melanocortin neurocircuit
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Lora Heisler
- School of Medicine, Medical Sciences & Nutrition, Aberdeen Cardiovascular and Diabetes Centre
- School of Medicine, Medical Sciences & Nutrition, The Rowett Institute of Nutrition and Health - Chair in Human Nutrition
Person: Academic
Justin Rochford
- School of Medicine, Medical Sciences & Nutrition, The Rowett Institute of Nutrition and Health - Personal Chair
- School of Medicine, Medical Sciences & Nutrition, Aberdeen Cardiovascular and Diabetes Centre
Person: Academic

Cite this

Burke, L. K., Ogunnowo-Bada, E., Georgescu, T., Cristiano, C., Martinez De Morentin, P. B., Valencia-Torres, L., D'Agostino, G., Riches, C., Heeley, N., Ruan, Y., Rubinstein, M., Low, M. J., Myers, M. G., Rochford, J. J., Evans, M. L., & Heisler, L. K. (2017). Lorcaserin improves glycemic control via a melanocortin neurocircuit. Molecular Metabolism, 6(10), 1092-1102. https://doi.org/10.1016/j.molmet.2017.07.004

Burke, LK, Ogunnowo-Bada, E, Georgescu, T, Cristiano, C, Martinez De Morentin, PB, Valencia-Torres, L, D'Agostino, G, Riches, C, Heeley, N, Ruan, Y, Rubinstein, M, Low, MJ, Myers, MG, Rochford, JJ, Evans, ML & Heisler, LK 2017, 'Lorcaserin improves glycemic control via a melanocortin neurocircuit', Molecular Metabolism, vol. 6, no. 10, pp. 1092-1102. https://doi.org/10.1016/j.molmet.2017.07.004

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title = "Lorcaserin improves glycemic control via a melanocortin neurocircuit",

abstract = "ObjectiveThe 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 that 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.MethodsMurine models of common and genetic T2D were utilized to probe the direct effect of lorcaserin on glycemic control.ResultsLorcaserin 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.ConclusionsThese data suggest that lorcaserin's action within the brain represents a mechanistically novel treatment for T2D: findings of significance to a prevalent global disease.",

keywords = "5-HT2c receptor, Type 2 diabetes, Hypothalamus, Lorcaserin, Pro-opiomelanocortin (POMC), Melanocortin4 receptor (Mc4r)",

author = "Burke, {Luke K.} and Emmanuel Ogunnowo-Bada and Teodora Georgescu and Claudia Cristiano and {Martinez De Morentin}, {Pablo B.} and Lourdes Valencia-Torres and Giuseppe D'Agostino and Christine Riches and Nicholas Heeley and Yue Ruan and Marcelo Rubinstein and Low, {Malcolm J.} and Myers, {Martin G.} and Rochford, {Justin J.} and Evans, {Mark L.} and Heisler, {Lora K.}",

note = "Authors wish to thank members of staff of the Medical Research Facility University of Aberdeen, Ms Raffaella Chianese, Ms Pat Bain, Dr Samuel Virtue and Dr Guenievre Roussel for technical assistance. Work was supported by the Wellcome Trust (LKH: WT098012, WT081713; LKH/LKB: 093566/Z/10/A; JJR/GD'A/PBMM: 100574/Z/12/Z), Diabetes UK (MLE: 13/0004680), Biotechnology and Biological Sciences Research Council (LKH: BB/K001418/1, BB/NO17838/1 and JJR: BB/K017772/1), the Medical Research Council (JJR: MR/L002620/1; LKH: MC/PC/15077; GD'A: MR/P009824/1), the Cambridge MRC Centre for Study of Obesity and Related Disorders (MRC-CORD) to LKH, MLE and LKB, European Commission (PBMM/LKH 660219-NeuroEE), Genomics/Transcriptomics Core Facilities, the Neuroscience Graduate Program, the National Institutes of Health (MJL: DK066604; MJL/MR: DK068400; MGM: DK056731) and the Marilyn H. Vincent Foundation to MGM.",

year = "2017",

month = oct,

day = "31",

doi = "10.1016/j.molmet.2017.07.004",

language = "English",

volume = "6",

pages = "1092--1102",

journal = "Molecular Metabolism",

issn = "2212-8778",

publisher = "Elsevier GmbH",

number = "10",

}

TY - JOUR

T1 - Lorcaserin improves glycemic control via a melanocortin neurocircuit

AU - Burke, Luke K.

AU - Ogunnowo-Bada, Emmanuel

AU - Georgescu, Teodora

AU - Cristiano, Claudia

AU - Martinez De Morentin, Pablo B.

AU - Valencia-Torres, Lourdes

AU - D'Agostino, Giuseppe

AU - Riches, Christine

AU - Heeley, Nicholas

AU - Ruan, Yue

AU - Rubinstein, Marcelo

AU - Low, Malcolm J.

AU - Myers, Martin G.

AU - Rochford, Justin J.

AU - Evans, Mark L.

AU - Heisler, Lora K.

N1 - Authors wish to thank members of staff of the Medical Research Facility University of Aberdeen, Ms Raffaella Chianese, Ms Pat Bain, Dr Samuel Virtue and Dr Guenievre Roussel for technical assistance. Work was supported by the Wellcome Trust (LKH: WT098012, WT081713; LKH/LKB: 093566/Z/10/A; JJR/GD'A/PBMM: 100574/Z/12/Z), Diabetes UK (MLE: 13/0004680), Biotechnology and Biological Sciences Research Council (LKH: BB/K001418/1, BB/NO17838/1 and JJR: BB/K017772/1), the Medical Research Council (JJR: MR/L002620/1; LKH: MC/PC/15077; GD'A: MR/P009824/1), the Cambridge MRC Centre for Study of Obesity and Related Disorders (MRC-CORD) to LKH, MLE and LKB, European Commission (PBMM/LKH 660219-NeuroEE), Genomics/Transcriptomics Core Facilities, the Neuroscience Graduate Program, the National Institutes of Health (MJL: DK066604; MJL/MR: DK068400; MGM: DK056731) and the Marilyn H. Vincent Foundation to MGM.

PY - 2017/10/31

Y1 - 2017/10/31

N2 - ObjectiveThe 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 that 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.MethodsMurine models of common and genetic T2D were utilized to probe the direct effect of lorcaserin on glycemic control.ResultsLorcaserin 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.ConclusionsThese data suggest that lorcaserin's action within the brain represents a mechanistically novel treatment for T2D: findings of significance to a prevalent global disease.

AB - ObjectiveThe 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 that 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.MethodsMurine models of common and genetic T2D were utilized to probe the direct effect of lorcaserin on glycemic control.ResultsLorcaserin 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.ConclusionsThese data suggest that lorcaserin's action within the brain represents a mechanistically novel treatment for T2D: findings of significance to a prevalent global disease.

KW - 5-HT2c receptor

KW - Type 2 diabetes

KW - Hypothalamus

KW - Lorcaserin

KW - Pro-opiomelanocortin (POMC)

KW - Melanocortin4 receptor (Mc4r)

U2 - 10.1016/j.molmet.2017.07.004

DO - 10.1016/j.molmet.2017.07.004

M3 - Article

SN - 2212-8778

VL - 6

SP - 1092

EP - 1102

JO - Molecular Metabolism

JF - Molecular Metabolism

IS - 10

ER -

Lorcaserin improves glycemic control via a melanocortin neurocircuit

Abstract

Bibliographical note

Keywords

UN SDGs

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Lora Heisler

Justin Rochford

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