Lorcaserin improves glycemic control via a melanocortin neurocircuit

Luke K. Burke, Emmanuel Ogunnowo-Bada, Teodora Georgescu, Claudia Cristiano, Pablo Blanco 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

Research output: Contribution to journalArticle

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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 languageEnglish
Pages (from-to)1092-1102
Number of pages11
JournalMolecular Metabolism
Volume6
Issue number10
Early online date21 Jul 2017
DOIs
Publication statusPublished - Oct 2017

Fingerprint

Melanocortins
Type 2 Diabetes Mellitus
Receptor, Serotonin, 5-HT2C
Glucose
Pro-Opiomelanocortin
Weight Loss
Brain
Homeostasis
Body Weight
lorcaserin
Appetite Depressants
Serotonin Receptor Agonists
Peptides
Cholinergic Neurons
Glucose Clamp Technique
Genetic Models
Insulin Resistance
Serotonin
Therapeutics
Obesity

Keywords

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

Cite this

Lorcaserin improves glycemic control via a melanocortin neurocircuit. / Burke, Luke K.; Ogunnowo-Bada, Emmanuel; Georgescu, Teodora; Cristiano, Claudia; Martinez De Morentin, Pablo Blanco; 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.

In: Molecular Metabolism, Vol. 6, No. 10, 10.2017, p. 1092-1102.

Research output: Contribution to journalArticle

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
Burke LK, Ogunnowo-Bada E, Georgescu T, Cristiano C, Martinez De Morentin PB, Valencia-Torres L et al. Lorcaserin improves glycemic control via a melanocortin neurocircuit. Molecular Metabolism. 2017 Oct;6(10):1092-1102. https://doi.org/10.1016/j.molmet.2017.07.004
Burke, Luke K. ; Ogunnowo-Bada, Emmanuel ; Georgescu, Teodora ; Cristiano, Claudia ; Martinez De Morentin, Pablo Blanco ; 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. / Lorcaserin improves glycemic control via a melanocortin neurocircuit. In: Molecular Metabolism. 2017 ; Vol. 6, No. 10. pp. 1092-1102.
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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.",
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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.",
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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 Blanco

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

Y1 - 2017/10

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

VL - 6

SP - 1092

EP - 1102

JO - Molecular Metabolism

JF - Molecular Metabolism

SN - 2212-8778

IS - 10

ER -