Activation of the ARCPOMC→MeA Projection Reduces Food Intake

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 ARC POMC →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 ARC POMC →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 ARC POMC →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 ARC POMC →MeA neural circuit would play a role in regulating short-term food intake.

Disruption of CRTC1 and CRTC2 in Sim1 cells strongly increases high-fat diet intake in female mice but has a modest impact on male mice

“…Both CRTC1 and CRTC2 are also expressed in the same brain region [ 11 ]. Although PVH is a major brain region that regulates appetite in the brain [ 12 , 25 ], recent evidence has revealed that MeA is also involved in the regulation of appetite [ 39 ]. Therefore, it is possible that the loss of CRTCs in MeA might cause hyperphagia and obesity in Sim1-CRTCDKO mice.…”

Extrahypothalamic Control of Energy Balance and Its Connection with Reproduction: Roles of the Amygdala

“…These pharmacological data argue in favor of a role of direct α-MSH effects in the amygdala to modulate feeding. This contention has been recently documented by elegant studies from Kwon and Jo, showing by a combination of molecular tracing and optogenetic experiments, that a circuit originating from ARC POMC neurons projects to neurons in the medial amygdala (MeA), which express not only MC4R, but also estrogen receptors, whose activation reduces food intake, in a MC4R-dependent manner [30]. In the same vein, we present herein our previously unpublished evidence in the rat for the presence of α-MSH immunoreactive fibers surrounding/in close contact with another neuronal population in the amygdala, namely Kiss1 neurons (Figure 1).…”

The melanocortin pathway and energy homeostasis: From discovery to obesity therapy

“…This shows that α-MSH signalling through the MC4R axis is at least partly responsible for some of these endocrine effects. In general, anorectic actions of melanocortin signalling at MC4R are considered to occur through neurons in the PVN [ 43 , 44 , 45 ], but neurons in other areas as the amygdala, DMH, and MPO [ 46 ] also contribute to the effects of melanocortins on appetite [ 44 , 45 , 47 , 48 , 49 ]. MC4R expressed on sympathetic preganglionic cholinergic neurons mediate actions on energy expenditure and glucose homeostasis by increasing sympathetic nervous system activity [ 50 ].…”

“…Agouti and AgRP possess five C-terminal disulphide bonds, creating a similar cysteine knot conformation [ 20 , 133 , 134 ]. While in humans both are synthesised as 132 amino acid precursors, the active form of agouti is agouti [ [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] ], [ [51] , [52] , [53] , [54] , [55] , [56] , [57] , [58] , [59] , [60] , [61] , [62] , [63] , [64] , [65] , [66] , [67] , [68] , [69] , [70] ], [ [71] , [72] , [73] , [74] , [75] , [76] , [77] , [78] , [79] , [80] , [81] , [82] , [83] , [84] , [85] , [86] , [87] , ...…”