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

Abstract

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.

Inactivation of the Constitutively Active Ghrelin Receptor Attenuates Limbic Seizure Activity in Rodents

“…The ghrelin mimetic capromorelin and the presumed GHSR antagonist A778193 (found in this study to be a GHSR inverse agonist) were generously provided by Dr. Luc Ver Donck and Dr. Dieder Moechars. The ghrelin fragments (1-5) amide, (1-7), (1-9), (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11), (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), and (23-28) were supplied by Phoenix Pharmaceuticals (Karlsruhe, Germany). All other chemicals were analytical reagent grade or better and were supplied by Merck (Darmstadt, Germany).…”

“…Individual sampling times were set at 20 minutes each. Each experiment started with the collection of intrahippocampal basal samples (1)(2)(3)(4)(5)(6) in which the perfusion fluid was composed of only modified Ringer's solution. Consecutively, ghrelin, capromorelin, A778193, [D-Arg 1 ,D-Phe 5 , D-Trp 7,9 ,Leu 11 ]substance P, or ghrelin (1-5) amide were dissolved in modified Ringer's solution and perfused through the hippocampal microdialysis probe from the 7th collection period onward.…”

“…Cells were subcultured at 70 to 80 % confluency and re-suspended in 96-well plates at 60,000 cells per well. Concentrations of A778193 were added in quadruplicate to the cells and incubated for 90 minutes at 37°C in air/CO 2 (1-7), (1-9), (1-11), (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), and (23)(24)(25)(26)(27)(28) were tested next to the GHSR agonist capromorelin. A sigmoidal dose response curve was fitted using GraphPad Prism software, GraphPad Software, (La Jolla, USA), yielding a pEC 50 and curve maximum.…”

“…This 28 amino-acid bioactive peptide displays several important biological effects, including an influence on pituitary hormone secretion, appetite, metabolism, gastrointestinal function, and memory [2][3][4]. Ghrelin is best known as the endogenous ligand of the growth hormone secretagogue receptor (GHSR).…”

“…Centrally, ghrelin has the capability of altering neuronal activity in various brain regions. Being a gutderived hormone, the major emphasis of ghrelin research has been directed toward its orexigenic action via neuropeptide Y/agouti-related protein activation in the hypothalamus [3]. As for the hippocampus, peripheral ghrelin was shown to enter this brain region to bind to the GHSR, where it promoted spine synapse formation in the stratum radiatum of the CA1 subfield as well as facilitated long-term potentiation generation, which were paralleled by enhanced spatial learning and memory [2].…”