Inhibition of glycine transporter-1 in the dorsal vagal complex improves metabolic homeostasis in diabetes and obesity.

Jessica T Y Yue,Mona A Abraham,Paige V Bauer,Frank A Duca,Peili Wang,Tony K T Lam,Mary P Lapierre,Owen Chan,Beatrice M Filippi

doi:10.1038/ncomms13501

Abstract

Impaired glucose homeostasis and energy balance are integral to the pathophysiology of diabetes and obesity. Here we show that administration of a glycine transporter 1 (GlyT1) inhibitor, or molecular GlyT1 knockdown, in the dorsal vagal complex (DVC) suppresses glucose production, increases glucose tolerance and reduces food intake and body weight gain in healthy, obese and diabetic rats. These findings provide proof of concept that GlyT1 inhibition in the brain improves glucose and energy homeostasis. Considering the clinical safety and efficacy of GlyT1 inhibitors in raising glycine levels in clinical trials for schizophrenia, we propose that GlyT1 inhibitors have the potential to be repurposed as a treatment of both obesity and diabetes.

Highlights

Impaired glucose homeostasis and energy balance are integral to the pathophysiology of diabetes and obesity
We have shown that targeted inhibition of dorsal vagal complex (DVC) glycine transporter 1 (GlyT1) through either administration of a GlyT1 inhibitor or a chronic molecular knockdown improves glucose homeostasis and lowers body weight gain in diabetic and obese rodents
The neurocircuitry involved in food intake and body weight regulation by DVC GlytT1 inhibition remains unclear, the underlying neuronal relay is likely different than glucose production regulation (since glucose production is altered by DVC GlyT1 inhibition independent of changes in food intake and body weight (Figs 1e, 2f and 5d), as well as blood pressure and heart rate regulation (since DVC injection of glycine or glutamate induce changes in blood pressure and heart rate at a much faster rate[39,40] than changes in feeding induced by DVC glycine injection (Fig. 7b))

Summary

Introduction

Impaired glucose homeostasis and energy balance are integral to the pathophysiology of diabetes and obesity. We show that administration of a glycine transporter 1 (GlyT1) inhibitor, or molecular GlyT1 knockdown, in the dorsal vagal complex (DVC) suppresses glucose production, increases glucose tolerance and reduces food intake and body weight gain in healthy, obese and diabetic rats. These findings provide proof of concept that GlyT1 inhibition in the brain improves glucose and energy homeostasis. We demonstrate that direct inhibition of GlyT1 in the DVC confers metabolic benefits including improved glucose tolerance, lowered glucose production, reduced feeding and lowered body weight gain in diabetic and obese rodents. Inhibiting GlyT1 in the brain represents a potential novel therapeutic strategy to lower plasma glucose levels and body weight in diabetes and obesity

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Results

Conclusion