Endogenous Glucagon-like Peptide-1 Suppresses High-Fat Food Intake by Reducing Synaptic Drive onto Mesolimbic Dopamine Neurons.

Xue-Feng Wang,Zhiping P Pang,Jing-Jing Liu,Julia Xia,Vincent Mirabella,Ji Liu

doi:10.1016/j.celrep.2015.06.062

Xue-Feng Wang, Zhiping P Pang + Show 4 more

Open Access

https://doi.org/10.1016/j.celrep.2015.06.062

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Abstract

Glucagon-like peptide-1 (GLP-1) and its analogs act as appetite suppressants and have been proven to be clinically efficacious in reducing body weight in obese individuals. Central GLP-1 is expressed in a small population of brainstem cells located in the nucleus tractus solitarius (NTS), which project to a wide range of brain areas. However, it remains unclear how endogenous GLP-1 released in the brain contributes to appetite regulation. Using chemogenetic tools, we discovered that central GLP-1 acts on the midbrain ventral tegmental area (VTA) and suppresses high-fat food intake. We used integrated pathway tracing and synaptic physiology to further demonstrate that activation of GLP-1 receptors specifically reduces the excitatory synaptic strength of dopamine (DA) neurons within the VTA that project to the nucleus accumbens (NAc) medial shell. These data suggest that GLP-1 released from NTS neurons can reduce highly palatable food intake by suppressing mesolimbic DA signaling.

Highlights

The central glucagon-like peptide-1 (GLP-1) system plays a crucial role in the control of food intake (Turton et al, 1996)
We employed chemogenetics to address whether the activation of nucleus tractus solitarius (NTS) GLP-1 neurons affects food intake by expressing designer receptors exclusively activated by designer drugs (DREADDs)
We found that tyrosine hydroxylase (TH)+ DA ventral tegmental area (VTA) neurons have more dendritic branchings, smaller N-methyl-D-aspartate (NMDA) receptor mediated excitatory postsynaptic currents (EPSCs) and a higher ratio of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor to NMDA receptor mediated EPSCs (i.e., AMPA/NMDA EPSC ratio) (Figure S5)

Summary

Introduction

The central glucagon-like peptide-1 (GLP-1) system plays a crucial role in the control of food intake (Turton et al, 1996). Central GLP-1 is mainly secreted by a small group of neurons located within the nucleus tractus solitarius (NTS) in the brainstem. GLP-1 expressing neurons project broadly to other brain regions including the hypothalamus, the ventral tegmental area (VTA) and the nucleus accumbens (NAc) (Gu et al, 2013). Expression of GLP-1Rs has been detected in many brain areas such as the VTA and NAc (Merchenthaler et al, 1999). It is still not fully understood how release of central GLP-1 within the brain regulates food intake

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