Enhanced AMPA Receptor Trafficking Mediates the Anorexigenic Effect of Endogenous Glucagon Like Peptide-1 in the Paraventricular Hypothalamus

Liu, Ji; Conde, Kristie; Zhang, Peng; Lilascharoen, Varoth; Lim, Byung Kook; Seeley, Randy J.; Zhu, Julius J.; Scott, Michael M.; Pang, Zhiping P.

doi:10.2139/ssrn.3155507

Cited by 36 publications

(95 citation statements)

References 67 publications

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“…Speculatively, as GLP‐1+ axonal varicosities in rats and YFP+ varicosities in transgenic PPG reporter mice are immunoreactive for vesicular glutamate transporter 2 (Trapp & Cork, ; Zheng et al, 2014), synaptic signaling between GLP‐1 neurons may be mediated by glutamate. Light‐evoked release of glutamate from PPG nerve terminals within the hypothalamic paraventricular nucleus has been demonstrated in mice (Liu et al, ); similarly, clonal intestinal L‐cells that secrete GLP‐1 express VGLUT2 and co‐release glutamate, hypothesized as important for intercellular signaling among intestinal L‐cells (Uehara et al, ). The relatively low density of GLP‐1+ fibers and terminals within the rat cNTS (see Figures and ) contrasts with the high density of GLP‐1+ terminals within the rat hypothalamus and limbic forebrain (Gu et al, ).…”

Section: Discussionmentioning

confidence: 98%

“…Glutamatergic and GLP‐1R signaling mechanisms interact in many brain regions (Gilman et al, ; Liu et al, ; Mietlicki‐Baase et al, , ), and GLP‐1R signaling may modify excitatory synaptic transmission via cellular mechanisms involved in long‐term synaptic plasticity (Liu et al, ). Speculatively, as GLP‐1+ axonal varicosities in rats and YFP+ varicosities in transgenic PPG reporter mice are immunoreactive for vesicular glutamate transporter 2 (Trapp & Cork, ; Zheng et al, 2014), synaptic signaling between GLP‐1 neurons may be mediated by glutamate.…”

Section: Discussionmentioning

confidence: 99%

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GLP‐1 neurons form a local synaptic circuit within the rodent nucleus of the solitary tract

Card

Johnson

Llewellyn‐Smith

et al. 2018

J of Comparative Neurology

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Glutamatergic neurons that express pre-proglucagon (PPG) and are immunopositive (+) for glucagon-like peptide-1 (i.e., GLP-1+ neurons) are located within the caudal nucleus of the solitary tract (cNTS) and medullary reticular formation in rats and mice. GLP-1 neurons give rise to an extensive central network in which GLP-1 receptor (R) signaling suppresses food intake, attenuates rewarding, increases avoidance, and stimulates stress responses, partly via. GLP-1R signaling within the cNTS. In mice, noradrenergic (A2) cNTS neurons express GLP-1R, whereas PPG neurons do not. In the present study, confocal microscopy in rats confirmed that prolactin-releasing peptide (PrRP)+ A2 neurons are closely apposed by GLP-1+ axonal varicosities. Surprisingly, GLP-1+ appositions were also observed on dendrites of PPG/GLP-1+ neurons in both species, and electron microscopy in rats revealed that GLP-1+ boutons form asymmetric synaptic contacts with GLP-1+ dendrites. However, RNAscope confirmed that rat GLP-1 neurons do not express GLP-1R mRNA. Similarly, Ca2+ imaging of somatic and dendritic responses in mouse ex vivo slices confirmed that PPG neurons do not respond directly to GLP-1, and a mouse cross breeding strategy revealed that fewer than 1% of PPG neurons co-express GLP-1R. Collectively, these data suggest that GLP-1R signaling pathways modulate the activity of PrRP+ A2 neurons, and also reveal a local “feed-forward” synaptic network among GLP-1 neurons that apparently does not utilize GLP-1R signaling. This local GLP-1 network may instead use glutamatergic signaling to facilitate dynamic and potentially selective recruitment of GLP-1 neural populations that shape behavioral and physiological responses to internal and external challenges.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

GLP‐1 neurons form a local synaptic circuit within the rodent nucleus of the solitary tract

Card

Johnson

Llewellyn‐Smith

et al. 2018

J of Comparative Neurology

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“…The specific neural circuit mediating the satiety effect induced by AMP-DNM still needs to be elucidated, but oral administration of AMP-DNM modulated POMC expression in the ARC and CRH expression in the PVN. In both these regions, GLP1r is expressed by neurons (30), and activation of these neurons is known to have anorexigenic effects (31)(32)(33). Besides the hypothalamic pathways, we also found increased C-Fos expression in the caudal part of the NTS and in the AP and a concomitant activation of PPG (precursor protein of GLP1) neurons in the NTS in the brainstem.…”

Section: Discussionmentioning

confidence: 53%

“…Thus, our data suggest that besides peripheral GLP1, the anorexigenic effect of AMP-DNM might also be mediated via the GLP1-producing neurons and their projections to different forebrain regions, including the PVN, DMH, and ARC (28). Indeed, optogenetic and chemogenetic activation of GLP1 neurons in the NTS reduces food intake and body weight gain through simulation of the GLP1r-expressing CRH neurons in the PVN (33,38). Collectively, it is plausible that AMP-DNM stimulates both gut and brainstem GLP1 synthesis and that brainstem-derived GLP1 further acts on the hypothalamic circuits to mediate satiety as induced by AMP-DNM.…”

Section: Discussionmentioning

confidence: 72%

The Iminosugar AMP-DNM Improves Satiety and Activates Brown Adipose Tissue Through GLP1

et al. 2019

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Obesity is taking on worldwide epidemic proportions, yet effective pharmacological agents with longterm efficacy remain unavailable. Previously, we designed the iminosugar N-adamantine-methyloxypentyldeoxynojirimycin (AMP-DNM), which potently improves glucose homeostasis by lowering excessive glycosphingolipids. Here we show that AMP-DNM promotes satiety and activates brown adipose tissue (BAT) in obese rodents. Moreover, we demonstrate that the mechanism mediating these favorable actions depends on oral, but not central, administration of AMP-DNM, which ultimately stimulates systemic glucagon-like peptide 1 (GLP1) secretion. We evidence an essential role of brain GLP1 receptors (GLP1r), as AMP-DNM fails to promote satiety and activate BAT in mice lacking the brain GLP1r as well as in mice treated intracerebroventricularly with GLP1r antagonist exendin-9. In conclusion, AMP-DNM markedly ameliorates metabolic abnormalities in obese rodents by restoring satiety and activating BAT through central GLP1r, while improving glucose homeostasis by mechanisms independent of central GLP1r.

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“…NTS GLP-1 neurons can be projected to the entire brain [4] . However, research on the GLP-1R signal has mainly focused on the hypothalamic nuclei and the NTS [5] . Current research shows that the ventral tegmental area (VTA) and nucleus accumbens GLP-1R in the midbrain can influence the feeding and reward system [6] , suggesting that GLP-1 plays an important physiological role in regulation of food intake and motivational behavior.…”

Section: Introductionmentioning

confidence: 99%

Study on the Effect of LHA on Feeding and its Mechanism

Zhongxiang¹,

Wang²,

Wang³

et al. 2018

ijSciences

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Objective: To study the effect of lateral hypothalamic area on feeding and its specific mechanism. Methods: Intraventricular catheterization was used in rats,GLP-1 receptor agonist Ex4 or GLP-1 receptor antagonist Ex9 were injected into the lateral hypothalamic area (LHA) of rats, and the effects of food intake, water intake, body weight, kaolin intake and high-carbonhydrate diet were observed. Results: Immunohistochemical experiments showed the presence of GLP-1 receptor LHA in rats; When GLP-1 receptor was excited, the 1h and 24 h food intake of rats decreased, and the body weight decreased , and there was no significant change in the kaolin intake in rats; When GLP-1 receptor was blocked, there was no significant change in 24h food intake but weight gain in rats; When GLP-1 receptor was excited, high-carbonhydrate diet significantly reduced but there was no significant change in water intake; When GLP-1 receptor was blocked, high-carbonhydrate diet significantly increased but there was no significant change in water intake. Conclusion: GLP-1 receptor can be involved in the regulation of feeding behavior, and the signal may be related to the hedonicproperties of food.

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Enhanced AMPA Receptor Trafficking Mediates the Anorexigenic Effect of Endogenous Glucagon Like Peptide-1 in the Paraventricular Hypothalamus

Cited by 36 publications

References 67 publications

GLP‐1 neurons form a local synaptic circuit within the rodent nucleus of the solitary tract

GLP‐1 neurons form a local synaptic circuit within the rodent nucleus of the solitary tract

The Iminosugar AMP-DNM Improves Satiety and Activates Brown Adipose Tissue Through GLP1

Study on the Effect of LHA on Feeding and its Mechanism

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