UCP2 mediates ghrelin’s action on NPY/AgRP neurons by lowering free radicals

The gut-derived hormone ghrelin exerts its effect on the brain by regulating neuronal activity. Ghrelin-induced feeding behaviour is controlled by arcuate nucleus neurons that co-express neuropeptide Y and agouti-related protein (NPY/AgRP neurons). However, the intracellular mechanisms triggered by ghrelin to alter NPY/AgRP neuronal activity are poorly understood. Here we show that ghrelin initiates robust changes in hypothalamic mitochondrial respiration in mice that are dependent on uncoupling protein 2 (UCP2). Activation of this mitochondrial mechanism is critical for ghrelin-induced mitochondrial proliferation and electric activation of NPY/AgRP neurons, for ghrelin-triggered synaptic plasticity of pro-opiomelanocortin-expressing neurons, and for ghrelin-induced food intake. The UCP2-dependent action of ghrelin on NPY/AgRP neurons is driven by a hypothalamic fatty acid oxidation pathway involving AMPK, CPT1 and free radicals that are scavenged by UCP2. These results reveal a signalling modality connecting mitochondria-mediated effects of G-protein-coupled receptors on neuronal function and associated behaviour. The gut-derived hormone ghrelin stimulates food intake by regulating the neuropeptide Y/agouti-related protein (NPY/AgRP) neurons in the hypothalamic arcuate nucleus. How it does that was unclear, but studies in mice now show the ghrelin-induced increase in appetite is driven by burning fat in hypothalamic mitochondria, which produces free radicals that are scavenged by the mitochondrial protein UCP2 (uncoupling protein 2). This raises the possibility that free radicals are involved in regulating appetite control, and that interventions that interfere with free radicals may have an effect on eating and satiety. Ghrelin stimulates food uptake by bringing about changes in mitochondrial respiration and proliferation, which are essential for activation of NPY/AgRP neurons. The effects of ghrelin are dependent on the presence of UCP2.