6 research outputs found
Endogenous kisspeptin tone is a critical excitatory component of spontaneous GnRH activity and the GnRH response to NPY and CART
BACKGROUND / AIMS : Kisspeptin is the major excitatory regulator
of gonadotropin-releasing hormone (GnRH) neurons and
is responsible for basal GnRH/LH release and the GnRH/LH
surge. Although it is widely assumed, based on mutations in
kisspeptin and Kiss1R, that kisspeptin acts to sustain basal
GnRH neuronal activity, there have been no studies to investigate
whether endogenous basal kisspeptin tone plays a direct
role in basal spontaneous GnRH neuronal excitability. It
is also of interest to examine possible interactions between
endogenous kisspeptin tone and other neuropeptides that
have direct effects on GnRH neurons, such as neuropeptide
Y (NPY) or cocaine- and amphetamine-regulated transcript
(CART), since the activity of all these neuropeptides changes
during states of negative energy balance. METHODS : Loose
cell-attached and whole-cell current patch-clamp recordings
were made from GnRH-GFP neurons in hypothalamic
slices from female and male rats. RESULTS : Kisspeptin activated
GnRH neurons in a concentration-dependent manner
with an EC 50 of 3.32 ± 0.02 n M . Surprisingly, a kisspeptin an-endogenous kisspeptin tone. Furthermore, inhibition of endogenous
kisspeptin tone blocked the direct activation of
GnRH cells that occurs in response to antagonism of NPY Y5
receptor or by CART. CONCLUSIONS : Our electrophysiology
studies suggest that basal endogenous kisspeptin tone is
not only essential for spontaneous GnRH neuronal firing, but
it is also required for the net excitatory effects of other neuropeptides,
such as CART or NPY antagonism, on GnRH neurons.
Therefore, endogenous kisspeptin tone could serve as
the linchpin in GnRH activation or inhibition.NIH grants HD014643, HD014643 (ARRA Supplement),OD011092.http://www.karger.com/Journal/Home/223855hb201
Proinflammatory Endothelial Activation Detected by Molecular Imaging in Obese Nonhuman Primates Coincides With Onset of Insulin Resistance and Progressively Increases With Duration of Insulin Resistance
general view, 196
Transthyretin RNA profiling in livers from transplanted patients affected by familial amyloidotic polyneuropathy, and identification of a dual transcription start point
β2-Adrenergic receptor desensitization in perirenal adipose tissue in fetuses and lambs with placental insufficiency-induced intrauterine growth restriction
Placental insufficiency-induced intrauterine growth restriction (IUGR) fetuses have chronic hypoxaemia and elevated plasma catecholamine concentrations. In this study, we determined whether adrenergic responsiveness becomes desensitized in the perirenal adipose tissue of IUGR fetuses and lambs by measuring adrenergic receptor (AR) mRNA and protein levels. We also tested the ability of adrenaline to mobilize non-esterified fatty acids (NEFAs) in young lambs. Perirenal adipose tissue was collected from IUGR and control fetuses at 133 days of gestational age (dGA) and lambs at 18 days of age (dA). β2-AR mRNA concentrations were 59% and 74% lower (P < 0.05) in IUGR fetuses and lambs compared to controls, respectively, which also resulted in lower protein levels (P < 0.05). No treatment differences were detected for α1A-, α1B-, α1D-, α2A-, α2B-, α2C-, β1- and β3-AR expression. mRNA concentrations were also determined for hormone sensitive lipase (HSL), perilipin (lipid droplet-associated protein), and two adipokines, leptin and adiponectin. Adiponectin and HSL were not different between treatments at either age. Compared to controls, perilipin and leptin mRNA concentrations were lower (P < 0.05) in IUGR fetuses but not in lambs. Because of the β2-AR results, we challenged a second cohort of lambs with exogenous adrenaline at 21 dA. The ability of adrenaline to mobilize NEFA was 55 ± 15% lower (P < 0.05) in IUGRs than controls. Collectively, our findings indicate that elevated catecholamine exposure in utero causes desensitization of adipose tissue by down-regulation of β2-AR, and this persists in lambs. This impairment in adrenergic stimulated lipolysis might partially explain early onset obesity in IUGR offspring