ABSTRACT
ß-Hydroxybutyric acid (BHBA) has recently been shown to regulate hormone synthesis and secretion in the hypothalamus. However, little is known about the effects of BHBA-mediated hormone regulation or the detailed mechanisms by which BHBA regulates growth hormone-releasing hormone (GHRH) synthesis and secretion. In the present study, we examined the expression of the BHBA receptor GPR109A in primary hypothalamic cell cultures. We hypothesised that BHBA regulates GHRH via GPR109A and its downstream signals. Initial in vivo studies conducted in rats demonstrated that GHRH mRNA expression in the hypothalamus was strongly inversely correlated with BHBA levels in the cerebrospinal fluid during postnatal development (r = -0.89, P < 0.01). Furthermore, i.c.v. administration of BHBA acutely decreased GHRH mRNA expression in rats. Further in vitro studies revealed a decrease in GHRH synthesis and secretion in primary hypothalamic cells after treatment with BHBA; this effect was inhibited when hypothalamic cells were pretreated with pertussis toxin (PTX). BHBA had no effect on GHRH synthesis and secretion in GT1-7 cells, which do not exhibit cell surface expression of GPR109A. Furthermore, BHBA acutely decreased the transcription of the homeobox gene for Gsh-1 in the hypothalamus in both in vivo and in vitro, and this effect was also inhibited by PTX in vitro. In primary hypothalamic cells, BHBA activated the extracellular signal-regulated kinase (ERK)1/2, p38 and c-Jun N-terminal kinase mitogen-activated protein kinase (MAPK) kinases, as shown by western blot analysis. Moreover, inhibition of ERK1/2 with U0126 attenuated the BHBA-mediated reduction in Gsh-1 expression and GHRH synthesis and secretion. These results strongly suggest that BHBA directly regulates GHRH synthesis and secretion via the GPR109A/ERK1/2 MAPK pathway, and also that Gsh-1 is essential for this function.
Subject(s)
3-Hydroxybutyric Acid/physiology , Growth Hormone-Releasing Hormone/biosynthesis , Growth Hormone-Releasing Hormone/metabolism , Hypothalamus/metabolism , Receptors, G-Protein-Coupled/biosynthesis , Receptors, Nicotinic/biosynthesis , Signal Transduction , 3-Hydroxybutyric Acid/antagonists & inhibitors , 3-Hydroxybutyric Acid/cerebrospinal fluid , 3-Hydroxybutyric Acid/pharmacology , Animals , Butadienes/pharmacology , Cells, Cultured , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Homeodomain Proteins/biosynthesis , Humans , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Mitogen-Activated Protein Kinase 3/antagonists & inhibitors , Nitriles/pharmacology , Pertussis Toxin/pharmacology , Primary Cell Culture , Rats , Signal Transduction/drug effectsABSTRACT
Novel behaviors arising from the coupling between the built-in surface electric field, piezoelectricity, electron-hole pairs and external light beam were observed in GaN nanorods. An increase in the optical excitation density resulted in a blueshift in the photoluminescence spectra and a redshift in the frequency of the GaN A(1)(LO) phonon. The underlying mechanism was attributed to the screening of the built-in surface electric field by photoexcited carriers and, through the converse piezoelectric effect, a reduction in the internal strain. The existence of the built-in surface electric field in GaN nanorods was confirmed by scanning Kelvin probe microscopy. Our results firmly establish the existence of the photoelastic effect in GaN nanorods. In addition to underpinning the principle for applications in nanophotonic devices, this discovery also draws attention to the novel effects arising from the inherent large surface-to-volume ratio of nanostructures, which is possibly applicable to many other nanomaterials.
