Ghrelin activates hypophysiotropic corticotropin-releasing factor neurons independently of the arcuate nucleus

Abstract

Previous work has established that the hormone ghrelin engages the hypothalamic-pituitary-adrenal neuroendocrine axis via activation of corticotropin-releasing factor (CRF) neurons of the hypothalamic paraventricular nucleus (PVN). The neuronal circuitry that mediates this effect of ghrelin is currently unknown. Here, we show that ghrelin-induced activation of PVN CRF neurons involved inhibition of γ-aminobutyric acid (GABA) inputs, likely via ghrelin binding sites that were localized at GABAergic terminals within the PVN. While ghrelin activated PVN CRF neurons in the presence of neuropeptide Y (NPY) receptor antagonists or in arcuate nucleus (ARC)-ablated mice, it failed to do it so in mice with ghrelin receptor expression limited to ARC agouti gene related protein (AgRP)/NPY neurons. These data support the notion that ghrelin activates PVN CRF neurons via inhibition of local GABAergic tone, in an ARC-independent manner. Furthermore, these data suggest that the neuronal circuits mediating ghrelin’s orexigenic action vs. its role as a stress signal are anatomically dissociated.

Is Ghrelin Synthesized in the Central Nervous System?

“…Electron microscopy analyses have shown that ghrelin-IR signal is present in dense-cored vesicles of axon terminals. However, it is known that GHSR-1a is located at presynaptic terminals [26,54], and that ghrelin/GHSR-1a complexes are progressively internalized after the binding of ghrelin and accumulated intracellularly for around three hours [114]. Thus, the source of the ghrelin detected in these studies remains unclear.…”

“…The ghrelin-induced activation of the hypothalamic–GH–insulin-like growth factor axis seems to involve the action of the hormone at both hypothalamic neurons and somatotroph pituitary cells [23,24,25]. In contrast, studies in mice indicate that ghrelin-induced activation of the hypothalamic–pituitary–adrenal axis mainly occurs at the hypothalamic level [26,27]. The ghrelin-induced activation of these neuroendocrine axes together to the direct or indirect action of ghrelin on other organs, such as the liver or the pancreas, promotes an increase of plasma glucose levels; however, the mechanisms by which ghrelin controls glucose homeostasis remain poorly understood.…”

Growth hormone secretagogue receptor signalling affects high‐fat intake independently of plasma levels of ghrelin andLEAP2, in a 4‐day binge eating model

“…PI‐G‐03), dissolved in phosphate‐buffered saline (PBS) (pH 7.4) and prepared fresh on experimental days. For s.c. injections, mice were injected with 60 pmol g ‐1 body weight (BW) of ghrelin, a dose that transiently increases plasma ghrelin levels resembling concentrations observed in mice under energy deficit conditions and elicits a robust increase in food intake . For i.c.v.…”

“…For i.c.v. injections, mice were injected with 300 pmol/mouse of ghrelin, which is a dose that induces maximal food intake response in our experimental conditions . Because we recently demonstrated that the N‐terminal sequence of LEAP2 confers full receptor binding and activity, a peptide containing the initial 14 residues of N‐terminal LEAP2 sequence (hereafter named LEAP2 1‐14 ) was employed as an analogue of full‐length LEAP2.…”

The Dichotomous Effect of Chronic Stress on Obesity

“…A recent study demonstrated that ghrelin modulation of PVH-CRF can be dissociated from ARC-NPY→PVH signaling while is mediated by growth hormone secretagogue receptors (GHSR) expressed on GABAergic terminal in the PVH [32]. Acyl-ghrelin plasma levels are lower in obesity and diabetes and elevated after several types of stress [31,33].…”