Activation of the ARCPOMC→MeA Projection Reduces Food Intake.

Eunjin Kwon,Young-Hwan Jo

doi:10.3389/fncir.2020.595783

Abstract

Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC) plays an essential role in the control of food intake and energy expenditure. Melanocortin-4 receptors (MC4Rs) are expressed in key areas that are implicated in regulating energy homeostasis. Although the importance of MC4Rs in the paraventricular hypothalamus (PVH) has been well documented, the role of MC4Rs in the medial amygdala (MeA) on feeding remains controversial. In this study, we specifically examine the role of a novel ARCPOMC→MeA neural circuit in the regulation of short-term food intake. To map a local melanocortinergic neural circuit, we use monosynaptic anterograde as well as retrograde viral tracers and perform double immunohistochemistry to determine the identity of the neurons receiving synaptic input from POMC neurons in the ARC. To investigate the role of the ARCPOMC→MeA projection on feeding, we optogenetically stimulate channelrhodopsin-2 (ChR2)-expressing POMC fibers in the MeA. Anterograde viral tracing studies reveal that ARC POMC neurons send axonal projections to estrogen receptor-α (ER-α)- and MC4R-expressing neurons in the MeA. Retrograde viral tracing experiments show that the neurons projecting to the MeA is located mainly in the lateral part of the ARC. Optogenetic stimulation of the ARCPOMC→MeA pathway reduces short-term food intake. This anorectic effect is blocked by treatment with the MC4R antagonist SHU9119. In addition to the melanocortinergic local circuits within the hypothalamus, this extrahypothalamic ARCPOMC→MeA neural circuit would play a role in regulating short-term food intake.

Highlights

As the medial amygdala (MeA) receives dense α-melanocyte-stimulating hormone (α-MSH)-positive fibers (Jacobowitz and O’Donohue, 1978) and single-minded 1 (SIM1) neurons in the MeA express both estrogen receptor-α (ER-α) and Melanocortin-4 receptors (MC4Rs) (Balthasar et al, 2005; Xu et al, 2015), we examined the role of this ARCPOMC→MeA projection in the control of feeding
As it has been shown that the MeA exhibits dense α-MSH-positive fibers (Jacobowitz and O’Donohue, 1978), we first sought to determine if the MeA is innervated by arcuate nucleus of the hypothalamus (ARC) POMC neurons
Double immunostaining with an anti-adrenocorticotropic hormone (ACTH) antibody revealed that GFP-positive fibers in the MeA were co-labeled with ACTH (Figure 1C), consistent with early studies describing the presence of α-MSH and ACTH-positive fibers in the MeA (Jacobowitz and O’Donohue, 1978; Watson et al, 1978)

Summary

INTRODUCTION

Melanocortin-4 receptors (MC4Rs) play a critical role in regulating food intake and energy expenditure and in preventing obesity (Huszar et al, 1997; Balthasar et al, 2005; Rossi et al, 2011; Liu et al, 2013; Berglund et al, 2014; Shah et al, 2014). AgRP neurons send inhibitory input to NPY 1 receptor (NPY1R)-expressing neurons, and activation of NPY1R-expressing neurons in the MeA reduces food intake (Padilla et al, 2016). Both the MeA and the PVH would be downstream targets of the central melanocortin system. ER-α- and MC4R-expressing neurons in the MeA were innervated by ARC POMC neurons Optogenetic stimulation of this ARCPOMC→MeA projection reduced short-term food intake. The ARCPOMC→MeA pathway that we identified would be an important melanocortinergic circuit for regulating feeding

Ethics Statement

RESULTS

DISCUSSION

ETHICS STATEMENT