Journal Article

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

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

2016

Overview

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. Obesity primarily results from eating more food than the body requires, the energy from which is then stored as fat. In recent years obesity has become increasingly common, with the resulting health problems presenting one of the major healthcare challenges of the twenty-first century. New ways to tackle the obesity epidemic are therefore required to improve human health on a global scale. To regulate how much food is eaten, the gut sends chemical messengers to the brain about how much food has been consumed. These messengers activate particular cells in the brain that signal to other brain regions to trigger a decision about whether we’ve had enough food to eat. This raises a question: if we can artificially activate these cells, can we ‘trick’ the brain into thinking that food has been consumed? A brain region called the nucleus of the solitary tract (NTS) is known to play a key role in receiving signals from the gut about meals. By studying mice, D’Agostino et al. found that cells in the NTS that make a brain hormone called cholecystokinin (CCK) are particularly activated by food. Further experiments then used a technique called optogenetics to activate these cells in mice that had free access to different types of food. This activation significantly reduced how hungry the mice were, causing them to eat less food and lose weight. D’Agostino et al. also showed that CCK cells relay the signal about food intake to a brain region called the hypothalamus. Overall, D’Agostino et al. have found a way to trick the brain into thinking that food has been eaten when it actually hasn’t, and for this reason mice eat less without feeling hungry and lose weight. The next step is to try and find a way to activate the CCK cells in obese humans who have health complications associated with excess body weight.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Amino acids / Animals / Appetite / Apposition / Body weight / Brain / Brain Mapping / Cholecystokinin / Cholecystokinin - metabolism / Cytokinins / feeding behavior / Food / Glucose / Health aspects / Hypothalamus / Innervation / Melanocortin / Mice / Neural circuitry / Neural Pathways - anatomy & histology / neuronal circuits / Neurons / neuropeptides / Neuroscience / Nutrients / Optogenetics / Paraventricular Hypothalamic Nucleus - physiology / Paraventricular nucleus / Peptides / Presynapse / Rodents / Short Report / Solitary Nucleus - physiology / Solitary tract nucleus / Sucrose