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, 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.

Combination of Lorcaserin and GLP-1/glucagon Coagonist Improves Metabolic Dysfunction in Diet Induced-obese Mice

“…However, the glycemic control was minimal in lorcaserin-treated mice despite weight loss. This is in contrast to a previous report [36]. The reasons could be manifold.…”

“…The pharmacodynamics profile of the coagonist used in the current study has already been described [13]. Since lorcaserin has an independent mechanism for reduction in body weight [36], we proposed that it may have an additive effect in reduction of body weight with a coagonist of GLP-1 and glucagon.…”

“…In the current study, we have observed that lorcaserin and the coagonist, as a monotherapy, can reduce body weight in diet-induced obese mice. The dose of coagonist and lorcaserin were selected based on reported literature [15,16,36]. We have also observed that a combination of the suboptimal doses of these two agents have additive effect on reduction of body weight, primarily the fat mass.…”

“…The reasons could be manifold. In the report [36], the body weight independent effect of lorcaserin was evaluated using a single dose treatment by intraperitoneal route, indicating the effect on supra-pharmacological doses. Further, the route of administration was injectable, deviating from the clinical route of administration of lorcaserin, which is oral.…”

Lorcaserin and metabolic disease: weight‐loss dependent and independent effects

“…With specific regard to lorcaserin, murine models of T2DM suggest lorcaserin improves glycaemic control in the absence of reduction in food intake or body weight. These improvements in glycaemic parameters require sufficient POMC activity and functional MC4‐receptor signalling, both of which contribute to lorcaserin‐mediated increased insulin sensitivity, reduction in hepatic glucose production and increased glucose disposal .…”