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
Affiliations
Giuseppe D'Agostino
Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, United Kingdom; Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
David J Lyons
Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, United Kingdom
Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, United Kingdom
Luke K Burke
Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
Joseph C Madara
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States
John N Campbell
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States
Ana Paula Garcia
Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
Benjamin B Land
Department of Psychiatry, Yale University School of Medicine, New Haven, United States
Bradford B Lowell
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States
Ralph J Dileone
Department of Psychiatry, Yale University School of Medicine, New Haven, United States
Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, United Kingdom; Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom
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 hypothalamus circuit controlling appetite.
