Hypothalamic Nesfatin-1 Stimulates Sympathetic Nerve Activity via Hypothalamic ERK Signaling

Abstract

Nesfatin-1 acts on the hypothalamus and regulates the autonomic nervous system. However, the hypothalamic mechanisms of nesfatin-1 on the autonomic nervous system are not well understood. In this study, we found that intracerebroventricular (ICV) administration of nesfatin-1 increased the extracellular signal-regulated kinase (ERK) activity in rats. Furthermore, the activity of sympathetic nerves, in the kidneys, liver, and white adipose tissue (WAT), and blood pressure was stimulated by the ICV injection of nesfatin-1, and these effects were abolished owing to pharmacological inhibition of ERK. Renal sympathoexcitatory and hypertensive effects were also observed with nesfatin-1 microinjection into the paraventricular hypothalamic nucleus (PVN). Moreover, nesfatin-1 increased the number of phospho (p)-ERK1/2-positive neurons in the PVN and coexpression of the protein in neurons expressing corticotropin-releasing hormone (CRH). Pharmacological blockade of CRH signaling inhibited renal sympathetic and hypertensive responses to nesfatin-1. Finally, sympathetic stimulation of WAT and increased p-ERK1/2 levels in response to nesfatin-1 were preserved in obese animals such as rats that were fed a high-fat diet and leptin receptor-deficient Zucker fatty rats. These findings indicate that nesfatin-1 regulates the autonomic nervous system through ERK signaling in PVN-CRH neurons to maintain cardiovascular function and that the antiobesity effect of nesfatin-1 is mediated by hypothalamic ERK-dependent sympathoexcitation in obese animals.Nesfatin-1 is an 82-amino acid neuropeptide produced in the hypothalamus that acts on the brain to suppress appetite (1-6), increase energy expenditure (7), and induce cardiovascular changes, leading to body weight reduction (1), blood pressure (BP) elevation (8-10), and increased insulin sensitivity (11) in animals. Intracerebroventricular (ICV) administration of nesfatin-1 reduces food intake and body weight gain and elevates BP, heart rate (HR) (8), and peripheral glucose uptake (11). Thus, central nesfatin-1 may regulate the function of peripheral organs through neural activity to maintain homeostasis and regulate a number of physiological processes.Regarding the neural mechanism of physiological regulation by nesfatin-1, our previous study demonstrated that sympathetic nervous supply to the kidneys in anesthetized rats could be stimulated by the ICV injection of nesfatin-1 (10), suggesting that the sympathetic nervous system mediates the action of nesfatin-1. Recently, it has been reported that increased sympathetic stimulation of white adipose tissue (WAT) and the liver resulted in lipolysis (12) and glucogenesis (13), respectively, with the intracerebral administration of leptin, a feeding regulator and sympathetic activator. Thus, central nesfatin-1 may modulate sympathetic nerve outflow to WAT and the liver and regulate lipid and glucose metabolism; however, there are no studies reporting the effect of ICV nesfatin-1 on the neural activity of sympathetic nerves to WAT and the live...

Nesfatin-1 protects dopaminergic neurons against MPP+/MPTP-induced neurotoxicity through the C-Raf–ERK1/2-dependent anti-apoptotic pathway

“…It has also been reported that nesfatin-1 can stimulate the phosphorylation of AMP-dependent protein kinase (AMPK), Akt kinase (Akt) and target of rapamycin complex (TORC) 2, resulting in an increase in Fos immunoreactivity in the hypothalamic nuclei that mediate glucose homeostasis58. In accordance with our results, nesfatin-1 has also been reported to stimulate sympathetic nerve activity via hypothalamic ERK signaling59 and increased cAMP response element (CRE) reporter activity in a mouse neuroblastoma cells60. Further studies are required to determine which CRE-regulated genes are involved in the protective effects of nesfatin-1 on dopaminergic neurons.…”

Paraventricular NUCB2/Nesfatin-1 Supports Oxytocin and Vasopressin Neurons to Control Feeding Behavior and Fluid Balance in Male Mice

“…Beyond these early studies that reported the effect of exogenous nesfatin-1 on BP, our results have revealed the endogenous NUCB2/nesfatin-1 in PVN as a regulator of preload of circulation through modulating PVN AVP. Alternatively, a recent study has reported that nesfatin-1 regulates the sympathetic nervous system through ERK signaling in PVN-CRH neurons to maintain cardiovascular function (33). In this line, we previously reported that NUCB2/nesfatin-1 is colocalized with CRH as well as oxytocin and AVP in PVN neurons (12).…”

Nesfatin-1: functions and physiology of a novel regulatory peptide

“…Accordingly, no increase 232:1 in cyclic adenosine monophosphate (cAMP) formation was observed (Ishida et al 2012). Nevertheless, CREB phosphorylation was increased in a neuroblastoma cell line (Ishida et al 2012), however, not in vivo (Tanida et al 2015). The activation of protein kinase A (PKA) appears to differ across tissues and might indicate a tissue-specific recruitment of G-protein subunits (Brailoiu et al 2007, Nakata et al 2011, Ishida et al 2012.…”

“…These findings, albeit unequivocal with regard to the type of G-proteins involved, suggest the existence of one or more 7-transmembrane receptor(s). Furthermore, mitogen-activated protein kinases (MAPK) (extracellular signal-regulated kinase (ERK1/2)) (Ishida et al 2012, Angelone et al 2013, Tanida et al 2015 is activated by nesfatin-1; 5′ AMP-activated protein kinase (AMPK) and phosphatidylinositol-3-kinases (PI3K), however, do not appear to be involved (Tanida et al 2015).…”

“…For example, it was shown that that i.c.v. administration of nesfatin-1 increases mean arterial pressure (MAP) , Tanida & Mori 2011, Tanida et al 2015; heart rate was also found to be increased (Tanida et al 2015); ERK phosphorylation CRF neurons of the PVN is involved in these effects (Tanida et al 2015). Until now, it is not clear whether central nervous nesfatin-1 activates cardiac sympathetic innervation, but it was shown that it increases renal sympathetic nerve activity (Tanida & Mori 2011, Tanida et al 2015, known to be involved in blood pressure regulation through the renin-angiotensin system (Nakamura & Johns 1995).…”