Nesfatin-1 influences the excitability of neurons in the nucleus of the solitary tract and regulates cardiovascular function

Abstract

Nesfatin-1 has been identified as one of the most potent centrally acting anorexigenic peptides, and it has also been shown to play important roles in the control of cardiovascular function. In situ hybridization and immunohistochemical studies have revealed the expression of nesfatin-1 throughout the brain and, in particular, in the medullary autonomic gateway known as the nucleus of the solitary tract (NTS). The present study was thus undertaken to explore the cellular correlates and functional roles of nesfatin-1 actions in the medial NTS (mNTS). Using current-clamp electrophysiology recordings from mNTS neurons in slice preparation, we show that bathapplied nesfatin-1 directly influences the excitability of the majority of mNTS neurons by eliciting either depolarizing (42%, mean: 7.8 Ϯ 0.8 mV) or hyperpolarizing (21%, mean: Ϫ8. 2 Ϯ 1.0 mV) responses. These responses were observed in all electrophysiologically defined cell types in the NTS and were site specific and concentration dependent. Furthermore, post hoc single cell reverse transcriptase polymerase reaction revealed a depolarizing action of nesfatin-1 on NPY and nucleobindin-2-expressing mNTS neurons. We have also correlated these actions of nesfatin-1 on neuronal membrane potential with physiological outcomes, using in vivo microinjection techniques to demonstrate that nesfatin-1 microinjected into the mNTS induces significant increases in both blood pressure (mean AUC ϭ 3354.1 Ϯ 750.7 mmHg·s, n ϭ 6) and heart rate (mean AUC ϭ 164.8 Ϯ 78.5 beats, n ϭ 6) in rats. Our results provide critical insight into the circuitry and physiology involved in the profound effects of nesfatin-1 and highlight the NTS as a key structure mediating these autonomic actions. microinjection; platch clamp; peptides NESFATIN-1 has been identified as one of the most potent centrally acting anorexigenic peptides (17). An 82 amino acid cleavage product of the nucleobindin-2 (NUCB2) protein, nesfatin-1 acutely and chronically reduces feeding in rodents when injected either intracerebroventricularly or peripherally, and these effects are dependent on melanocortin and oxytocin signaling (16,17,22,29). Furthermore, treatment with nesfatin-1 neutralizing antibodies markedly increases food consumption and weight gain in animals, underscoring the critical physiological, tonic inhibitory control this peptide exerts over ingestive behaviors (17). In addition to its remarkable effects on food intake, nesfatin-1 has also been shown to play important roles in the control of cardiovascular function, water intake, blood glucose regulation, stress responses, and puberty onset (6,8,23,28).In line with its numerous functions, comprehensive immunohistochemical studies have revealed a widespread distribution of nesfatin-1 throughout the brain. Notably, the nesfatin-1 peptide is strongly expressed in regions involved in the control of energy homeostasis and autonomic function in both hypothalamic and medullary centres (5), including the autonomic gateway known as the nucleus of the solitary tract (...

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

“…Infected neurons were also identified at other sites within the hypothalamus and extrahypothalamic nuclei (24)(25)(26)(27). Nesfatin-1 administration into the nucleus of the solitary tract, a pseudorabies virus-positive area, elevated BP and HR (28), suggesting that an extrahypothalamic area may be responsible for central nesfatin-1 activity within the brain stem. Therefore, additional investigations are required to elucidate the role of the PVN and/or other nuclei in mediating the sympathetic nerve response evoked by nesfatin-1.…”

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

“…Nucb2 mRNA and NUCB2/nesfatin-1 protein expression was observed in this nucleus (Brailoiu et al 2007, Foo et al 2008 and both central nervous and peripheral administration of nesfatin-1 induce c-fos expression in its neurons (Maejima et al 2009, Shimizu et al 2009a. Local injection of nesfatin-1 into the median NTS increased both blood pressure and heart rate (Mimee et al 2012). In contrast, site-specific injection into the nucleus ambiguus, a key site for parasympathetic cardiac control (Mendelowitz 1999), induced bradycardia, although MAP was not affected (Brailoiu et al 2013).…”

“…Electrophysiological studies have identified the median NTS as a potential site through which nesfatin-1 exerts is cardiovascular actions (Mimee et al 2012). Nucb2 mRNA and NUCB2/nesfatin-1 protein expression was observed in this nucleus (Brailoiu et al 2007, Foo et al 2008 and both central nervous and peripheral administration of nesfatin-1 induce c-fos expression in its neurons (Maejima et al 2009, Shimizu et al 2009a.…”

Nesfatin Role as Possible New Anti Obesity Treatment

“…Several interactions have been described to underlie the central anorexic effect of nesfatin-1 (Shimizu et al, 2009c). It has also been shown to play important roles in the control of cardiovascular function (Mimee et al, 2012). In situ hybridization and immunohistochemical researches have evidentiated the expression of nesfatin-1 throughout the brain and, particularly, in the medullary autonomic gateway known as the nucleus of the solitary tract (NTS) (Mimee et al, 2012).…”

“…In situ hybridization and immunohistochemical researches have evidentiated the expression of nesfatin-1 throughout the brain and, particularly, in the medullary autonomic gateway known as the nucleus of the solitary tract (NTS) (Mimee et al, 2012). Mimee et al (2012) showed that provide critical insight into the circuitry and physiology involved in the profound effects of nesfatin-1 and highlight the NTS as a key structure mediating these autonomic actions.…”