Appetite controlled by a cholecystokinin nucleus of the solitary tract to hypothalamus neurocircuit

Giuseppe D'Agostino; David J. Lyons; Claudia Cristiano; Luke K. Burke; Joseph C. Madara; John N. Campbell; Ana Paula Garcia; Benjamin B. Land; Bradford B. Lowell; Ralph J. Dileone; Lora K. Heisler

doi:10.7554/eLife.12225

Appetite controlled by a cholecystokinin nucleus of the solitary tract to hypothalamus neurocircuit

Giuseppe D'Agostino^* (Corresponding Author), David J. Lyons, Claudia Cristiano, Luke K. Burke, Joseph C. Madara, John N. Campbell, Ana Paula Garcia, Benjamin B. Land, Bradford B. Lowell, Ralph J. Dileone, Lora K. Heisler^* (Corresponding Author)

^*Corresponding author for this work

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Abstract

The nucleus of the solitary tract (NTS) is a key gateway for meal-related signals entering the brain from the periphery. However, the chemical mediators crucial to this process have not been fully elucidated. We reveal that a subset of NTS neurons containing cholecystokinin (CCKNTS) is responsive to nutritional state and that their activation reduces appetite and body weight in mice. Cell-specific anterograde tracing revealed that CCKNTS neurons provide a distinctive innervation of the paraventricular nucleus of the hypothalamus (PVH), with fibers and varicosities in close apposition to a subset of melanocortin-4 receptor (MC4RPVH) cells, which are also responsive to CCK. Optogenetic activation of CCKNTS axon terminals within the PVH reveal the satiating function of CCKNTS neurons to be mediated by a CCKNTS→PVH pathway that also encodes positive valence. These data identify the functional significance of CCKNTS neurons and reveal a sufficient and discrete NTS to hypothalamic circuit controlling appetite.

Original language	English
Article number	12225
Number of pages	15
Journal	eLife
Volume	5
DOIs	https://doi.org/10.7554/eLife.12225
Publication status	Published - 14 Mar 2016

Bibliographical note

ACKNOWLEDGMENTS
Authors wish to thank members of staff of the Medical Research Facility (University of Aberdeen) for assisting with mouse care and husbandry and Raffaella Chianese for assisting with mouse genotyping. This work was supported by the Wellcome Trust (LKH; WT098012), Biotechnology and Biological Sciences Research Council (LKH and GD’A; BB/K001418/1), Wellcome Trust and the University of Aberdeen (GD’A; 105625/Z/14/Z), NIDDK (BBLo; R01 DK075632, P30 DK046200, P30 DK 057521) and American Heart Association (JNC; 14POST20100011). Single-cell qPCR experiment was supported in part by the Molecular Medicine Core facility at Beth Israel Deaconess Medical Center.

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10.7554/eLife.12225Licence: CC BY

Appetite controlled by a cholecystokinin nucleus of the solitary tract to hypothalamus neurocircuit
© 2016, D'Agostino et al This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. http://creativecommons.org/licenses/by/4.0/
Final published version, 2.4 MBLicence: CC BY

Lora Heisler
- School of Medicine, Medical Sciences & Nutrition, Aberdeen Cardiovascular and Diabetes Centre
- School of Medicine, Medical Sciences & Nutrition, The Rowett Institute of Nutrition and Health - Chair in Human Nutrition
Person: Academic

Cite this

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title = "Appetite controlled by a cholecystokinin nucleus of the solitary tract to hypothalamus neurocircuit",

abstract = "The nucleus of the solitary tract (NTS) is a key gateway for meal-related signals entering the brain from the periphery. However, the chemical mediators crucial to this process have not been fully elucidated. We reveal that a subset of NTS neurons containing cholecystokinin (CCKNTS) is responsive to nutritional state and that their activation reduces appetite and body weight in mice. Cell-specific anterograde tracing revealed that CCKNTS neurons provide a distinctive innervation of the paraventricular nucleus of the hypothalamus (PVH), with fibers and varicosities in close apposition to a subset of melanocortin-4 receptor (MC4RPVH) cells, which are also responsive to CCK. Optogenetic activation of CCKNTS axon terminals within the PVH reveal the satiating function of CCKNTS neurons to be mediated by a CCKNTS→PVH pathway that also encodes positive valence. These data identify the functional significance of CCKNTS neurons and reveal a sufficient and discrete NTS to hypothalamic circuit controlling appetite.",

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note = "ACKNOWLEDGMENTS Authors wish to thank members of staff of the Medical Research Facility (University of Aberdeen) for assisting with mouse care and husbandry and Raffaella Chianese for assisting with mouse genotyping. This work was supported by the Wellcome Trust (LKH; WT098012), Biotechnology and Biological Sciences Research Council (LKH and GD{\textquoteright}A; BB/K001418/1), Wellcome Trust and the University of Aberdeen (GD{\textquoteright}A; 105625/Z/14/Z), NIDDK (BBLo; R01 DK075632, P30 DK046200, P30 DK 057521) and American Heart Association (JNC; 14POST20100011). Single-cell qPCR experiment was supported in part by the Molecular Medicine Core facility at Beth Israel Deaconess Medical Center. ",

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AU - Garcia, Ana Paula

AU - Land, Benjamin B.

AU - Lowell, Bradford B.

AU - Dileone, Ralph J.

AU - Heisler, Lora K.

N1 - ACKNOWLEDGMENTS Authors wish to thank members of staff of the Medical Research Facility (University of Aberdeen) for assisting with mouse care and husbandry and Raffaella Chianese for assisting with mouse genotyping. This work was supported by the Wellcome Trust (LKH; WT098012), Biotechnology and Biological Sciences Research Council (LKH and GD’A; BB/K001418/1), Wellcome Trust and the University of Aberdeen (GD’A; 105625/Z/14/Z), NIDDK (BBLo; R01 DK075632, P30 DK046200, P30 DK 057521) and American Heart Association (JNC; 14POST20100011). Single-cell qPCR experiment was supported in part by the Molecular Medicine Core facility at Beth Israel Deaconess Medical Center.

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AB - The nucleus of the solitary tract (NTS) is a key gateway for meal-related signals entering the brain from the periphery. However, the chemical mediators crucial to this process have not been fully elucidated. We reveal that a subset of NTS neurons containing cholecystokinin (CCKNTS) is responsive to nutritional state and that their activation reduces appetite and body weight in mice. Cell-specific anterograde tracing revealed that CCKNTS neurons provide a distinctive innervation of the paraventricular nucleus of the hypothalamus (PVH), with fibers and varicosities in close apposition to a subset of melanocortin-4 receptor (MC4RPVH) cells, which are also responsive to CCK. Optogenetic activation of CCKNTS axon terminals within the PVH reveal the satiating function of CCKNTS neurons to be mediated by a CCKNTS→PVH pathway that also encodes positive valence. These data identify the functional significance of CCKNTS neurons and reveal a sufficient and discrete NTS to hypothalamic circuit controlling appetite.

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Appetite controlled by a cholecystokinin nucleus of the solitary tract to hypothalamus neurocircuit

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