Ghrelin Receptor Stimulation of the Lateral Parabrachial Nucleus in Rats Increases Food Intake but not Food Motivation

Although Agouti-related peptide (AgRP) neurons play a key role in the regulation of food intake, their contribution to the anorexia caused by proinflammatory insults has yet to be identified. Using a combination of neuroanatomical and pharmacogenetics experiments, this study sought to investigate the importance of AgRP neurons and downstream targets in the anorexia caused by the peripheral administration of a moderate dose of lipopolysaccharide (LPS) (100 μg/kg, ip). First, in the C57/Bl6 mouse, we demonstrated that LPS induced c-fos in select AgRP-innervated brain sites involved in feeding but not in any arcuate proopiomelanocortin neurons. Double immunohistochemistry further showed that LPS selectively induced c-Fos in a large subset of melanocortin 4 receptor-expressing neurons in the lateral parabrachial nucleus. Secondly, we used pharmacogenetics to stimulate the activity of AgRP neurons during the course of LPS-induced anorexia. In AgRP-Cre mice expressing the designer receptor hM3Dq-Gq only in AgRP neurons, the administration of the designer drug clozapine-N-oxide (CNO) induced robust food intake. Strikingly, CNO-mediated food intake was rapidly and completely blunted by the coadministration of LPS. Neuroanatomical experiments further indicated that LPS did not interfere with the ability of CNO to stimulate c-Fos in AgRP neurons. In summary, our findings combined together support the view that the stimulation of select AgRP-innervated brain sites and target neurons, rather than the inhibition of AgRP neurons themselves, is likely to contribute to the rapid suppression of food intake observed during acute bacterial endotoxemia.

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GLP-1 Receptor Stimulation of the Lateral Parabrachial Nucleus Reduces Food Intake: Neuroanatomical, Electrophysiological, and Behavioral Evidence

Endocrinology ◽

10.1210/en.2014-1248 ◽

2014 ◽

Vol 155 (11) ◽

pp. 4356-4367 ◽

Cited By ~ 46

Author(s):

Jennifer E. Richard ◽

Imre Farkas ◽

Fredrik Anesten ◽

Rozita H. Anderberg ◽

Suzanne L. Dickson ◽

...

Keyword(s):

Feeding Behavior ◽

Fluorescent Protein ◽

Yellow Fluorescent Protein ◽

Parabrachial Nucleus ◽

Lateral Parabrachial Nucleus ◽

Electrophysiological Studies ◽

Glucagon Like Peptide 1 ◽

Behavioral Evidence ◽

Stimulation Of

Abstract The parabrachial nucleus (PBN) is a key nucleus for the regulation of feeding behavior. Inhibitory inputs from the hypothalamus to the PBN play a crucial role in the normal maintenance of feeding behavior, because their loss leads to starvation. Viscerosensory stimuli result in neuronal activation of the PBN. However, the origin and neurochemical identity of the excitatory neuronal input to the PBN remain largely unexplored. Here, we hypothesize that hindbrain glucagon-like peptide 1 (GLP-1) neurons provide excitatory inputs to the PBN, activation of which may lead to a reduction in feeding behavior. Our data, obtained from mice expressing the yellow fluorescent protein in GLP-1-producing neurons, revealed that hindbrain GLP-1-producing neurons project to the lateral PBN (lPBN). Stimulation of lPBN GLP-1 receptors (GLP-1Rs) reduced the intake of chow and palatable food and decreased body weight in rats. It also activated lPBN neurons, reflected by an increase in the number of c-Fos-positive cells in this region. Further support for an excitatory role of GLP-1 in the PBN is provided by electrophysiological studies showing a remarkable increase in firing of lPBN neurons after Exendin-4 application. We show that within the PBN, GLP-1R activation increased gene expression of 2 energy balance regulating peptides, calcitonin gene-related peptide (CGRP) and IL-6. Moreover, nearly 70% of the lPBN GLP-1 fibers innervated lPBN CGRP neurons. Direct intra-lPBN CGRP application resulted in anorexia. Collectively, our molecular, anatomical, electrophysiological, pharmacological, and behavioral data provide evidence for a functional role of the GLP-1R for feeding control in the PBN.

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Rapid stimulation of sodium intake combining aldosterone into the 4th ventricle and the blockade of the lateral parabrachial nucleus

Neuroscience ◽

10.1016/j.neuroscience.2017.01.005 ◽

2017 ◽

Vol 346 ◽

pp. 94-101 ◽

Cited By ~ 1

Author(s):

S. Gasparini ◽

M.R. Melo ◽

G.F. Leite ◽

P.A. Nascimento ◽

G.M.F. Andrade-Franzé ◽

...

Keyword(s):

Sodium Intake ◽

Parabrachial Nucleus ◽

Lateral Parabrachial Nucleus ◽

Rapid Stimulation ◽

4Th Ventricle ◽

Stimulation Of

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Ghrelin in the lateral parabrachial nucleus influences the excitability of glucosensing neurons, increases food intake and body weight

Endocrine Connections ◽

10.1530/ec-20-0285 ◽

2020 ◽

Vol 9 (12) ◽

pp. 1168-1177

Author(s):

Caishun Zhang ◽

Junhua Yuan ◽

Qian Lin ◽

Manwen Li ◽

Liuxin Wang ◽

...

Keyword(s):

Body Weight ◽

Weight Gain ◽

Food Intake ◽

Firing Rate ◽

Body Weight Gain ◽

Parabrachial Nucleus ◽

Growth Hormone Secretagogue Receptor ◽

Growth Hormone Secretagogue ◽

Lateral Parabrachial Nucleus

Ghrelin plays a pivotal role in the regulation of food intake, body weight and energy metabolism. However, these effects of ghrelin in the lateral parabrachial nucleus (LPBN) are unexplored. C57BL/6J mice and GHSR−/− mice were implanted with cannula above the right LPBN and ghrelin was microinjected via the cannula to investigate effect of ghrelin in the LPBN. In vivo electrophysiological technique was used to record LPBN glucose-sensitive neurons to explore potential udnderlying mechanisms. Microinjection of ghrelin in LPBN significantly increased food intake in the first 3 h, while such effect was blocked by [D-Lys3]-GHRP-6 and abolished in GHSR−/− mice. LPBN ghrelin microinjection also significantly increased the firing rate of glucose-excited (GE) neurons and decreased the firing rate of glucose-inhibited (GI) neurons. Additionally, LPBN ghrelin microinjection also significantly increased c-fos expression. Chronic ghrelin administration in the LPBN resulted in significantly increased body weight gain. Meanwhile, no significant changes were observed in both mRNA and protein expression levels of UCP-1 in BAT. These results demonstrated that microinjection of ghrelin in LPBN could increase food intake through the interaction with growth hormone secretagogue receptor (GHSR) in C57BL/6J mice, and its chronic administration could also increase body weight gain. These effects might be associated with altered firing rate in the GE and GI neurons.

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Nesfatin-1 in the Lateral Parabrachial Nucleus Inhibits Food Intake, Modulates Excitability of Glucosensing Neurons, and Enhances UCP1 Expression in Brown Adipose Tissue

Frontiers in Physiology ◽

10.3389/fphys.2017.00235 ◽

2017 ◽

Vol 8 ◽

Cited By ~ 9

Author(s):

Jun-hua Yuan ◽

Xi Chen ◽

Jing Dong ◽

Di Zhang ◽

Kun Song ◽

...

Keyword(s):

Adipose Tissue ◽

Food Intake ◽

Brown Adipose Tissue ◽

Parabrachial Nucleus ◽

Lateral Parabrachial Nucleus ◽

Brown Adipose ◽

Ucp1 Expression

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Functional and Neurochemical Identification of Ghrelin Receptor (GHSR)-Expressing Cells of the Lateral Parabrachial Nucleus in Mice

Frontiers in Neuroscience ◽

10.3389/fnins.2021.633018 ◽

2021 ◽

Vol 15 ◽

Author(s):

Marie V. Le May ◽

Fiona Peris-Sampedro ◽

Iris Stoltenborg ◽

Erik Schéle ◽

Tina Bake ◽

...

Keyword(s):

Body Weight ◽

Weight Gain ◽

Food Intake ◽

Food Choice ◽

Viral Vector ◽

Sucrose Solution ◽

Parabrachial Nucleus ◽

Growth Hormone Secretagogue ◽

Lateral Parabrachial Nucleus ◽

Obesogenic Diet

The lateral parabrachial nucleus (lPBN), located in the pons, is a well-recognized anorexigenic center harboring, amongst others, the calcitonin gene-related peptide (CGRP)-expressing neurons that play a key role. The receptor for the orexigenic hormone ghrelin (the growth hormone secretagogue receptor, GHSR) is also abundantly expressed in the lPBN and ghrelin delivery to this site has recently been shown to increase food intake and alter food choice. Here we sought to explore whether GHSR-expressing cells in the lPBN (GHSRlPBN cells) contribute to feeding control, food choice and body weight gain in mice offered an obesogenic diet, involving studies in which GHSRlPBN cells were silenced. We also explored the neurochemical identity of GHSRlPBN cells. To silence GHSRlPBN cells, Ghsr-IRES-Cre male mice were bilaterally injected intra-lPBN with a Cre-dependent viral vector expressing tetanus toxin-light chain. Unlike control wild-type littermates that significantly increased in body weight on the obesogenic diet (i.e., high-fat high-sugar free choice diet comprising chow, lard and 9% sucrose solution), the heterozygous mice with silenced GHSRlPBN cells were resistant to diet-induced weight gain with significantly lower food intake and fat weight. The lean phenotype appeared to result from a decreased food intake compared to controls and caloric efficiency was unaltered. Additionally, silencing the GHSRlPBN cells altered food choice, significantly reducing palatable food consumption. RNAscope and immunohistochemical studies of the lPBN revealed considerable co-expression of GHSR with glutamate and pituitary adenylate cyclase-activating peptide (PACAP), and much less with neurotensin, substance P and CGRP. Thus, the GHSRlPBN cells are important for diet-induced weight gain and adiposity, as well as in the regulation of food intake and food choice. Most GHSRlPBN cells were found to be glutamatergic and the majority (76%) do not belong to the well-characterized anorexigenic CGRP cell population.

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Leptin receptor signaling in the lateral parabrachial nucleus contributes to the control of food intake

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00329.2014 ◽

2014 ◽

Vol 307 (11) ◽

pp. R1338-R1344 ◽

Cited By ~ 25

Author(s):

Amber L. Alhadeff ◽

Matthew R. Hayes ◽

Harvey J. Grill

Keyword(s):

Food Intake ◽

Neural Control ◽

Leptin Receptor ◽

Sensory Information ◽

Progressive Ratio ◽

Meal Size ◽

Parabrachial Nucleus ◽

Lateral Parabrachial Nucleus ◽

Site Of Action ◽

Integral Role

Pontine parabrachial nucleus (PBN) neurons integrate visceral, oral, and other sensory information, playing an integral role in the neural control of feeding. Current experiments probed whether lateral PBN (lPBN) leptin receptor (LepRb) signaling contributes to this function. Intra-lPBN leptin microinjection significantly reduced cumulative chow intake, average meal size, and body weight in rats, independent of effects on locomotor activity or gastric emptying. In contrast to the effects observed following LepRb activation in other nuclei, lPBN LepRb stimulation did not affect progressive ratio responding for sucrose reward or conditioned place preference for a palatable food. Collectively, results suggest that lPBN LepRb activation reduces food intake by modulating the neural processing of meal size/satiation signaling, and highlight the lPBN as a novel site of action for leptin-mediated food intake control.

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