Elsevier

Molecular Metabolism

Volume 6, Issue 10, October 2017, Pages 1092-1102
Molecular Metabolism

Original Article
Lorcaserin improves glycemic control via a melanocortin neurocircuit

https://doi.org/10.1016/j.molmet.2017.07.004Get rights and content
Under a Creative Commons license
open access

Highlights

  • Obesity medication lorcaserin directly improves glycemic control without altering energy balance or body weight.

  • Unlike current frontline type 2 diabetes medications, lorcaserin acts within the brain to improve glycemic control.

  • Brain Pro-opiomelanocortin (POMC) peptides are a neurochemical mediator of lorcaserin's glucoregulatory effects.

  • Lorcaserin increases insulin sensitivity, reduces hepatic glucose production and increases glucose disposal.

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, 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.

Keywords

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

Cited by (0)

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Current address: Cardiovascular and Metabolic Disease, MedImmune, Granta Park, CB21 6GH Cambridge, UK.