Arginine vasopressin:Direct and indirect action on metabolism

From its identification and isolation in 1954, arginine vasopressin (AVP) has attracted attention, not only for its peripheral functions such as vasoconstriction and reabsorption of water from kidney, but also for its central effects. As there is now considerable evidence that AVP plays a crucial role in feeding behavior and energy balance, it has become a promising therapeutic target for treating obesity or other obesity-related metabolic disorders. However, the underlying mechanisms for AVP regulation of these central processes still remain largely unknown. In this review, we will provide a brief overview of the current knowledge concerning how AVP controls energy balance and feeding behavior, focusing on physiological aspects including the relationship between AVP, circadian rhythmicity, and glucocorticoids

Effect of dietary salt intake on epithelial Na\u3csup\u3e+\u3c/sup\u3e channels (ENaC) in vasopressin magnocellular neurosecretory neurons in the rat supraoptic nucleus

© 2017 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society Key points: A growing body of evidence suggests that epithelial Na+ channels (ENaCs) in the brain play a significant role in the regulation of blood pressure; however, the brain structures that mediate the effect are not well understood. Because vasopressin (VP) neurons play a pivotal role in coordinating neuroendocrine and autonomic responses to maintain cardiovascular homeostasis, a basic understanding of the regulation and activity of ENaC in VP neurons is of great interest. We show that high dietary salt intake caused an increase in the expression and activity of ENaC which resulted in the steady state depolarization of VP neurons. The results help us understand one of the mechanisms underlying how dietary salt intake affects the activity of VP neurons via ENaC activity. Abstract: All three epithelial Na+ channel (ENaC) subunits (α, β and γ) are located in vasopressin (VP) magnocellular neurons in the hypothalamic supraoptic (SON) and paraventricular nuclei. Our previous study demonstrated that ENaC mediates a Na+ leak current that affects the steady state membrane potential in VP neurons. In the present study, we evaluated the effect of dietary salt intake on ENaC regulation and activity in VP neurons. High dietary salt intake for 7 days caused an increase in expression of β- and γENaC subunits in the SON and the translocation of αENaC immunoreactivity towards the plasma membrane. Patch clamp experiments on hypothalamic slices showed that the mean amplitude of the putative ENaC currents was significantly greater in VP neurons from animals that were fed a high salt diet compared with controls. The enhanced ENaC current contributed to the more depolarized basal membrane potential observed in VP neurons in the high salt diet group. These findings indicate that high dietary NaCl intake enhances the expression and activity of ENaCs, which augments synaptic drive by depolarizing the basal membrane potential close to the action potential threshold during hormonal demand. However, ENaCs appear to have only a minor role in the regulation of the firing activity of VP neurons in the absence of synaptic inputs as neither the mean intraburst frequency, burst duration, nor interspike interval variability of phasic bursting activity was affected. Moreover, ENaC activity did not affect the initiation, sustention, or termination of the phasic bursting generated in an intrinsic manner without synaptic inputs

Physiology of spontaneous [Ca2+]i oscillations in the isolated vasopressin and oxytocin neurones of the rat supraoptic nucleus

AbstractThe magnocellular vasopressin (AVP) and oxytocin (OT) neurones exhibit specific electrophysiological behaviour, synthesise AVP and OT peptides and secrete them into the neurohypophysial system in response to various physiological stimulations. The activity of these neurones is regulated by the very same peptides released either somato-dendritically or when applied to supraoptic nucleus (SON) preparations in vitro. The AVP and OT, secreted somato-dendritically (i.e. in the SON proper) act through specific autoreceptors, induce distinct Ca2+ signals and regulate cellular events. Here, we demonstrate that about 70% of freshly isolated individual SON neurones from the adult non-transgenic or transgenic rats bearing AVP (AVP-eGFP) or OT (OT-mRFP1) markers, produce distinct spontaneous [Ca2+]i oscillations. In the neurones identified (through specific fluorescence), about 80% of AVP neurones and about 60% of OT neurones exhibited these oscillations. Exposure to AVP triggered [Ca2+]i oscillations in silent AVP neurones, or modified the oscillatory pattern in spontaneously active cells. Hyper- and hypo-osmotic stimuli (325 or 275 mOsmol/l) respectively intensified or inhibited spontaneous [Ca2+]i dynamics. In rats dehydrated for 3 or 5days almost 90% of neurones displayed spontaneous [Ca2+]i oscillations. More than 80% of OT-mRFP1 neurones from 3 to 6-day-lactating rats were oscillatory vs. about 44% (OT-mRFP1 neurones) in virgins. Together, these results unveil for the first time that both AVP and OT neurones maintain, via Ca2+ signals, their remarkable intrinsic in vivo physiological properties in an isolated condition

GABA is excitatory in adult vasopressinergic neuroendocrine cells

Neuronal excitability in the adult brain is controlled by a balance between synaptic excitation and inhibition mediated by glutamate and GABA, respectively. While generally inhibitory in the adult brain, GABAA receptor activation is excitatory under certain conditions in which the GABA reversal potential is shifted positive due to intracellular Cl-accumulation, such as during early postnatal development and brain injury. However, the conditions under which GABA is excitatory are generally either transitory or pathological. Here, we reveal GABAergic synaptic inputs to be uniformly excitatory in vasopressin (VP)-secreting magnocellular neurons in the adult hypothalamus under normal conditions. The GABA reversal potential (EGABA) was positive to resting potential and spike threshold in VP neurons, but not in oxytocin (OT)-secreting neurons. The VP neurons lacked expression of the K+-Cl-cotransporter 2 (KCC2), the predominant Cl- exporter in the adult brain. The EGABA was unaffected by inhibition of KCC2 in VP neurons, but was shifted positive in OT neurons, which express KCC2. Alternatively, inhibition of the Na+-K+-Cl-cotransporter 1 (NKCC1), aCl-importer expressed in most cell types mainly during postnatal development, caused a negative shift in EGABA in VP neurons, but had no effect on GABA currents in OT neurons. GABAA receptor blockade caused a decrease in the firing rate of VP neurons, but an increase in firing in OT neurons. Our findings demonstrate that GABA is excitatory in adultVPneurons, suggesting that the classical excitation/inhibition paradigm of synaptic glutamate and GABA control of neuronal excitability does not apply to VP neurons. © 2012 the authors

Colonic Delivery of α-Linolenic Acid by an Advanced Nutrient Delivery System Prolongs Glucagon-Like Peptide-1 Secretion and Inhibits Food Intake in Mice

ScopeNutrients stimulate the secretion of glucagon-like peptide-1 (GLP-1), an incretin hormone, secreted from enteroendocrine L-cells which decreases food intake. Thus, GLP-1 analogs are approved for the treatment of obesity, yet cost and side effects limit their use. L-cells are mainly localized in the distal ileum and colon, which hinders the utilization of nutrients targeting GLP-1 secretion. This study proposes a controlled delivery system for nutrients, inducing a prolonged endogenous GLP-1 release which results in a decrease food intake.Methods and Resultsα-Linolenic acid (αLA) was loaded into thermally hydrocarbonized porous silicon (THCPSi) particles. In vitro characterization and in vivo effects of αLA loaded particles on GLP-1 secretion and food intake were studied in mice. A total of 40.4 ± 3.2% of loaded αLA is released from particles into biorelevant buffer over 24 h, and αLA loaded THCPSi significantly increased in vitro GLP-1 secretion. Single-dose orally given αLA loaded mesoporous particles increased plasma active GLP-1 levels at 3 and 4 h and significantly reduced the area under the curve of 24 h food intake in mice.ConclusionsαLA loaded THCPSi particles could be used to endogenously stimulate sustain gastrointestinal hormone release and reduce food intake.</p

The Effects of Apelin on the Electrical Activity of Hypothalamic Magnocellular Vasopressin and Oxytocin Neurons and Somatodendritic Peptide Release

Apelin, a novel peptide originally isolated from bovine stomach tissue extracts, is widely but selectively distributed throughout the nervous system. Vasopressin and oxytocin are synthesised in the magnocellular neurons of the hypothalamic supraoptic (SON) and paraventricular nuclei (PVN), which are apelin-rich regions in the central nervous system. We made extracellular electrophysiological recordings from the transpharyngeally exposed SON of urethane-anaesthetised rats to assess the role of apelin in the control of the firing activity of identified magnocellular vasopressin and oxytocin neurons in vivo. Apelin-13 administration onto SON neurons via microdialysis revealed cell-specific responses; apelin-13 increased the firing rates of vasopressin cells, but had no effect on the firing rate of oxytocin neurons. A direct excitatory effect of apelin-13 on vasopressin cell activity is also supported by our in vitro studies showing depolarisation of membrane potential and increase in action potential firing. To assess the effects of apelin-13 on somato/dendritic peptide release we used in vitro release studies from SON explants in combination with highly sensitive and specific radioimmunoassays. Apelin-13 decrease basal (by 78%, p<0.05, n=6) and potassium-stimulated (by 57%, p<0.05, n=6) vasopressin release but had no effect on somato/dendritic oxytocin release. Taken together, our data suggest a local autocrine feedback action of apelin on magnocellular vasopressin neurons. Furthermore, these data show a marked dissociation between axonal and dendritic vasopressin release with a decrease in somato/dendritic release but an increase in electrical activity at the cell bodies, indicating that release from these two compartments can be regulated wholly independently