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

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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.

No MeSH data available.


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Molecular inhibition of DVC GlyT1 regulates metabolic homeostasis in obese rats.(a) Experimental protocol for b–e. (b) Glucose infusion rates and (c) glucose production during clamps in 28-d HFD-fed rats with DVC lentivirus (LV) injection of GlyT1 shRNA (n=10) or a mismatch sequence (MM, n=9) as a control. (b,c: *P<0.001 versus 28d-HFD+MM determined by t-test.) (d) Body weights on the morning of clamp experiments in 28-d HFD-fed rats with DVC LV MM or GlyT1 shRNA. *P<0.04 determined by t-test. (e) Percentage body weight change on days 4 and 5 following DVC injection of LV-MM (white circles, n=9) or GlyT1 shRNA (black circles, n=9) in 28-d HFD-fed rats and of MM fed with regular chow (white squares, n=5). *P<0.05 compared with all other groups determined by ANOVA and Dunnett's posthoc test. Data are shown as the mean+s.e.m.
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f6: Molecular inhibition of DVC GlyT1 regulates metabolic homeostasis in obese rats.(a) Experimental protocol for b–e. (b) Glucose infusion rates and (c) glucose production during clamps in 28-d HFD-fed rats with DVC lentivirus (LV) injection of GlyT1 shRNA (n=10) or a mismatch sequence (MM, n=9) as a control. (b,c: *P<0.001 versus 28d-HFD+MM determined by t-test.) (d) Body weights on the morning of clamp experiments in 28-d HFD-fed rats with DVC LV MM or GlyT1 shRNA. *P<0.04 determined by t-test. (e) Percentage body weight change on days 4 and 5 following DVC injection of LV-MM (white circles, n=9) or GlyT1 shRNA (black circles, n=9) in 28-d HFD-fed rats and of MM fed with regular chow (white squares, n=5). *P<0.05 compared with all other groups determined by ANOVA and Dunnett's posthoc test. Data are shown as the mean+s.e.m.

Mentions: Given that acute inhibition of DVC GlyT1 improves glucose homeostasis in short-term (Fig. 3c) and long-term high-fat-fed rats, we postulated that chronic inhibition of GlyT1 in the DVC might confer a gluco-regulatory benefit during 28 days of HFD-induced obesity. We tested this hypothesis by subjecting 28-d HFD-fed rats to targeted knockdown of GlyT1 in the DVC (via DVC LV-GlyT1 shRNA injection on day 16 after HFD; Fig. 6a) to determine whether this chronic (from day 16 to day 29; Fig. 6a) intervention modulates glucose homeostasis. Indeed, chronic genetic inhibition of GlyT1 in the DVC robustly increases the glucose infusion rate (Fig. 6b) and suppresses glucose production (Fig. 6c) as compared with MM controls. This glucose-lowering effect occurs independent of changes in glucose uptake (Supplementary Fig. 6c)and plasma glucose levels (Supplementary Fig. 6d). Surprisingly, body weights on the morning of clamp experiments are markedly lower in 28-d HFD rats with chronic DVC GlyT1 inhibition (Fig. 6d). In fact, this lowering of body weight in 28-d HFD-induced obese rats is evident by day 4 post viral (LV-GlyT1 shRNA versus LV-MM) injection (Fig. 6e). However, it is unlikely that the gluco-regulatory improvement results from a decrease in body weight since chronic DVC GlyT1 inhibition lowers glucose production in healthy rats without affecting the body weight on the morning of the clamp studies (Fig. 2f, Supplementary Fig. 4c).


Inhibition of glycine transporter-1 in the dorsal vagal complex improves metabolic homeostasis in diabetes and obesity
Molecular inhibition of DVC GlyT1 regulates metabolic homeostasis in obese rats.(a) Experimental protocol for b–e. (b) Glucose infusion rates and (c) glucose production during clamps in 28-d HFD-fed rats with DVC lentivirus (LV) injection of GlyT1 shRNA (n=10) or a mismatch sequence (MM, n=9) as a control. (b,c: *P<0.001 versus 28d-HFD+MM determined by t-test.) (d) Body weights on the morning of clamp experiments in 28-d HFD-fed rats with DVC LV MM or GlyT1 shRNA. *P<0.04 determined by t-test. (e) Percentage body weight change on days 4 and 5 following DVC injection of LV-MM (white circles, n=9) or GlyT1 shRNA (black circles, n=9) in 28-d HFD-fed rats and of MM fed with regular chow (white squares, n=5). *P<0.05 compared with all other groups determined by ANOVA and Dunnett's posthoc test. Data are shown as the mean+s.e.m.
© Copyright Policy - open-access
Related In: Results  -  Collection

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f6: Molecular inhibition of DVC GlyT1 regulates metabolic homeostasis in obese rats.(a) Experimental protocol for b–e. (b) Glucose infusion rates and (c) glucose production during clamps in 28-d HFD-fed rats with DVC lentivirus (LV) injection of GlyT1 shRNA (n=10) or a mismatch sequence (MM, n=9) as a control. (b,c: *P<0.001 versus 28d-HFD+MM determined by t-test.) (d) Body weights on the morning of clamp experiments in 28-d HFD-fed rats with DVC LV MM or GlyT1 shRNA. *P<0.04 determined by t-test. (e) Percentage body weight change on days 4 and 5 following DVC injection of LV-MM (white circles, n=9) or GlyT1 shRNA (black circles, n=9) in 28-d HFD-fed rats and of MM fed with regular chow (white squares, n=5). *P<0.05 compared with all other groups determined by ANOVA and Dunnett's posthoc test. Data are shown as the mean+s.e.m.
Mentions: Given that acute inhibition of DVC GlyT1 improves glucose homeostasis in short-term (Fig. 3c) and long-term high-fat-fed rats, we postulated that chronic inhibition of GlyT1 in the DVC might confer a gluco-regulatory benefit during 28 days of HFD-induced obesity. We tested this hypothesis by subjecting 28-d HFD-fed rats to targeted knockdown of GlyT1 in the DVC (via DVC LV-GlyT1 shRNA injection on day 16 after HFD; Fig. 6a) to determine whether this chronic (from day 16 to day 29; Fig. 6a) intervention modulates glucose homeostasis. Indeed, chronic genetic inhibition of GlyT1 in the DVC robustly increases the glucose infusion rate (Fig. 6b) and suppresses glucose production (Fig. 6c) as compared with MM controls. This glucose-lowering effect occurs independent of changes in glucose uptake (Supplementary Fig. 6c)and plasma glucose levels (Supplementary Fig. 6d). Surprisingly, body weights on the morning of clamp experiments are markedly lower in 28-d HFD rats with chronic DVC GlyT1 inhibition (Fig. 6d). In fact, this lowering of body weight in 28-d HFD-induced obese rats is evident by day 4 post viral (LV-GlyT1 shRNA versus LV-MM) injection (Fig. 6e). However, it is unlikely that the gluco-regulatory improvement results from a decrease in body weight since chronic DVC GlyT1 inhibition lowers glucose production in healthy rats without affecting the body weight on the morning of the clamp studies (Fig. 2f, Supplementary Fig. 4c).

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus