Glial cells of the nucleus tractus solitarius as partners of the dorsal hindbrain regulation of energy balance: A proposal for a working hypothesis

Leptin receptor (LepRb) signaling in the hindbrain is required for energy balance control. Yet the specific hindbrain neurons and the behavioral processes mediating energy balance control by hindbrain leptin signaling are unknown. Studies here employ genetic [adeno-associated virally mediated RNA interference (AAV-RNAi)] and pharmacological methodologies to specify the neurons and the mechanisms through which hindbrain LepRb signaling contributes to the control of food intake. Results show that AAV-RNAi-mediated LepRb knockdown targeting a region encompassing the mNTS and area postrema (AP) (mNTS/AP LepRbKD) increases overall cumulative food intake by increasing the size of spontaneous meals. Other results show that pharmacological hindbrain leptin delivery and RNAi-mediated mNTS/AP LepRb knockdown increased and decreased the intake-suppressive effects of intraduodenal nutrient infusion, respectively. These meal size and intestinally derived signal amplification effects are likely mediated by LepRb signaling in the mNTS and not the AP, since 4th icv and mNTS parenchymal leptin (0.5 μg) administration reduced food intake, whereas this dose did not influence food intake when injected into the AP. Overall, these findings deepen the understanding of the distributed neuronal systems and behavioral mechanisms that mediate the effects of leptin receptor signaling on the control of food intake.

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Glial Modulation of Energy Balance: The Dorsal Vagal Complex Is No Exception

International Journal of Molecular Sciences ◽

10.3390/ijms23020960 ◽

2022 ◽

Vol 23 (2) ◽

pp. 960

Author(s):

Jean-Denis Troadec ◽

Stéphanie Gaigé ◽

Manon Barbot ◽

Bruno Lebrun ◽

Rym Barbouche ◽

...

Keyword(s):

Energy Balance ◽

Food Intake ◽

Glial Cells ◽

Present Review ◽

Dorsal Vagal Complex ◽

Central Regulation ◽

The World ◽

Nutritional Imbalance ◽

Nutritional Balance

The avoidance of being overweight or obese is a daily challenge for a growing number of people. The growing proportion of people suffering from a nutritional imbalance in many parts of the world exemplifies this challenge and emphasizes the need for a better understanding of the mechanisms that regulate nutritional balance. Until recently, research on the central regulation of food intake primarily focused on neuronal signaling, with little attention paid to the role of glial cells. Over the last few decades, our understanding of glial cells has changed dramatically. These cells are increasingly regarded as important neuronal partners, contributing not just to cerebral homeostasis, but also to cerebral signaling. Our understanding of the central regulation of energy balance is part of this (r)evolution. Evidence is accumulating that glial cells play a dynamic role in the modulation of energy balance. In the present review, we summarize recent data indicating that the multifaceted glial compartment of the brainstem dorsal vagal complex (DVC) should be considered in research aimed at identifying feeding-related processes operating at this level.

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Faculty Opinions recommendation of Endogenous leptin signaling in the caudal nucleus tractus solitarius and area postrema is required for energy balance regulation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1555993.1738054 ◽

2010 ◽

Author(s):

Julian Mercer

Keyword(s):

Energy Balance ◽

Nucleus Tractus Solitarius ◽

Area Postrema ◽

Leptin Signaling

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Faculty Opinions recommendation of Endogenous leptin signaling in the caudal nucleus tractus solitarius and area postrema is required for energy balance regulation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1555993.1047095 ◽

2010 ◽

Author(s):

Lora Heisler ◽

Al Garfield

Keyword(s):

Energy Balance ◽

Nucleus Tractus Solitarius ◽

Area Postrema ◽

Leptin Signaling

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Endogenous Leptin Signaling in the Caudal Nucleus Tractus Solitarius and Area Postrema Is Required for Energy Balance Regulation

Cell Metabolism ◽

10.1016/j.cmet.2016.02.009 ◽

2016 ◽

Vol 23 (4) ◽

pp. 744 ◽

Cited By ~ 6

Author(s):

Matthew R. Hayes ◽

Karolina P. Skibicka ◽

Theresa M. Leichner ◽

Douglas J. Guarnieri ◽

Ralph J. DiLeone ◽

...

Keyword(s):

Energy Balance ◽

Nucleus Tractus Solitarius ◽

Area Postrema ◽

Leptin Signaling

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Dorsal Hindbrain 5′-Adenosine Monophosphate-Activated Protein Kinase as an Intracellular Mediator of Energy Balance

Endocrinology ◽

10.1210/en.2008-1319 ◽

2008 ◽

Vol 150 (5) ◽

pp. 2175-2182 ◽

Cited By ~ 63

Author(s):

Matthew R. Hayes ◽

Karolina P. Skibicka ◽

Kendra K. Bence ◽

Harvey J. Grill

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Energy Balance ◽

Protein Kinase ◽

Food Intake ◽

Nucleus Tractus Solitarius ◽

Balance Control ◽

Whole Body ◽

Compound C ◽

Ampk Activity

The fuel-sensing enzyme AMP-activated protein kinase (AMPK) has been implicated in central nervous system control of energy balance. Hypothalamic AMPK activity is increased by food deprivation, and this elevation is inhibited by refeeding or by leptin treatment. The contribution of extrahypothalamic AMPK activity in energy balance control has not been addressed. Here, we investigate the effects of physiological state on the AMPK activity in hindbrain nucleus tractus solitarius (NTS) neurons because treatments that reduce energy availability in these neurons trigger behavioral, endocrine, and autonomic responses to restore energy balance. Food-deprived rats showed significantly increased AMPK activity in both NTS- and hypothalamus-enriched lysates compared with those that were ad libitum fed. Pharmacological inhibition of AMPK activity in medial NTS neurons, by intraparenchymal injection of compound C, suppressed food intake and body weight gain compared with vehicle. Fourth ventricle (4th icv) compound C delivery increased heart rate and spontaneous activity in free-moving rats. Suppression of AMPK activity has been implicated in leptin’s anorectic action in the hypothalamus. Given the role of leptin signaling in food intake inhibition within the medial NTS, we also examined whether stimulation of hindbrain AMPK by 4th icv administration of 5-aminoimidazole-4-carboxamide-riboside (AICAR), an AMP-mimicking promoter of AMPK activity, could attenuate the inhibition of food intake by 4th icv leptin. The intake-suppressive effects of leptin (at 2 and 4 h) were completely reversed by AICAR. We conclude that 1) hindbrain AMPK activity contributes to energy balance control through regulation of food intake and energy expenditure, 2) leptin’s intake-reducing effects in the NTS are meditated by AMPK, and 3) central nervous system AMPK controls whole-body homeostasis at anatomically distributed sites across the neuraxis.

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The hindbrain is a site of energy balance action for prolactin-releasing peptide: feeding and thermic effects from GPR10 stimulation of the nucleus tractus solitarius/area postrema

Psychopharmacology ◽

10.1007/s00213-018-4925-5 ◽

2018 ◽

Vol 235 (8) ◽

pp. 2287-2301 ◽

Cited By ~ 4

Author(s):

X. S. Davis ◽

H. J. Grill

Keyword(s):

Energy Balance ◽

Nucleus Tractus Solitarius ◽

Area Postrema ◽

A Site ◽

Prolactin Releasing Peptide ◽

Stimulation Of

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Blockade of Glial Connexin 43 Hemichannels Reduces Food Intake

Cells ◽

10.3390/cells9112387 ◽

2020 ◽

Vol 9 (11) ◽

pp. 2387

Author(s):

Florent Guillebaud ◽

Manon Barbot ◽

Rym Barbouche ◽

Jean-Michel Brézun ◽

Kevin Poirot ◽

...

Keyword(s):

Energy Balance ◽

Food Intake ◽

Glial Cells ◽

Connexin 43 ◽

Network Activity ◽

Early Gene ◽

Major Public Health Problem ◽

The Metabolic Syndrome ◽

Neuronal Network Activity ◽

Obesity And Diabetes

The metabolic syndrome, which comprises obesity and diabetes, is a major public health problem and the awareness of energy homeostasis control remains an important worldwide issue. The energy balance is finely regulated by the central nervous system (CNS), notably through neuronal networks, located in the hypothalamus and the dorsal vagal complex (DVC), which integrate nutritional, humoral and nervous information from the periphery. The glial cells’ contribution to these processes emerged few year ago. However, its underlying mechanism remains unclear. Glial connexin 43 hemichannels (Cx43 HCs) enable direct exchange with the extracellular space and can regulate neuronal network activity. In the present study, we sought to determine the possible involvement of glial Cx43 HCs in energy balance regulation. We here show that Cx43 is strongly expressed in the hypothalamus and DVC and is associated with glial cells. Remarkably, we observed a close apposition of Cx43 with synaptic elements in both the hypothalamus and DVC. Moreover, the expression of hypothalamic Cx43 mRNA and protein is modulated in response to fasting and diet-induced obesity. Functionally, we found that Cx43 HCs are largely open in the arcuate nucleus (ARC) from acute mice hypothalamic slices under basal condition, and significantly inhibited by TAT-GAP19, a mimetic peptide that specifically blocks Cx43 HCs activity. Moreover, intracerebroventricular (i.c.v.) TAT-GAP19 injection strongly decreased food intake, without further alteration of glycaemia, energy expenditures or locomotor activity. Using the immediate early gene c-Fos expression, we found that i.c.v. TAT-GAP19 injection induced neuronal activation in hypothalamic and brainstem nuclei dedicated to food intake regulation. Altogether, these results suggest a tonic delivery of orexigenic molecules associated with glial Cx43 HCs activity and a possible modulation of this tonus during fasting and obesity.

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