Decoding obesity in the brainstem

Abstract

Neurons in the brainstem are the input for a neural circuit that integrates nutrient signals to control feeding behavior.

Keywords: feeding behavior; mouse; neuornal circuits; neuropeptides; neuroscience.

Figure 1.. A neural circuit in the brainstem integrates signals from peripheral tissues to control feeding behavior and energy balance.

The lower brainstem (light blue) receives input (green arrow) from peripheral tissues such as the gut, and also sends output (red arrow) to these tissues. Now, in experiments on mice, D’Agostino et al. have characterized a neuronal pathway that starts with neurons that express CCK in the nucleus of the solitary tract (NTS), which is part of the lower brainstem. Genetically engineering the CCK^NTS neurons so that a chemical called CNO can activate them showed that activating the neurons signals satiety and strongly decreases eating in mice. This leads to significant weight loss in the mice. The CCK^NTS neurons send signals to a part of the hypothalamus (green) called the paraventricular nucleus (PVH). Specifically, the ends of the CCK^NTS neurons form connections with neurons expressing melanocortin 4 receptors (MC4R^PVH) in the PVH; the MC4R^PVH neurons are thought to regulate appetite. Using light to activate the endings of the CCK^NTS neurons that contact the PVH (via an optogenetics approach) also promoted satiety and a positive emotional state (or positive valence) in behavior tests. This strongly suggests that the connections between the CCK^NTS neurons and the PVH are important. Inhibiting the CCK-A receptors (CCK-A-R^PVH) with a chemical called devazepide meant that the chemogenetic and optogenetic activation of CCK^NTS neurons no longer inhibited food intake. This figure was created with help from Billie Marcheva.