Research ReportNesfatin-1 inhibits NPY neurons in the arcuate nucleus
Introduction
The arcuate nucleus of the hypothalamus is an integral component of the central control of feeding behavior. Here signals that indicate the metabolic state of the animal are received and processed following which the activity of either orexigenic NPY neurons or anorexigenic αMSH-containing neurons is increased (Abizaid et al., 2006, Schwartz et al., 2000, Zigman and Elmquist, 2003). Over the last decade several peptides have been identified as satiety signals, including one of the most recently described satiety peptides, nesfatin-1 (Oh-I et al., 2006). This peptide arises from cleavage of the calcium and DNA-binding protein nucleobindin-2 yielding an 82 amino acid product that, when injected intracerebroventricularly, reduces feeding. Moreover, inactivation of endogenous nesfatin-1 with a neutralizing antibody increases feeding, underscoring the potential importance of this peptide in the central control of appetite. Nesfatin-1 is expressed in many hypothalamic nuclei, including the arcuate where levels are affected by fasting/refeeding (Brailoiu et al., 2007). Furthermore, nucleobindin-2 recently was found to belong to the adipocyte proteome presenting the possibility that nesfatin-1 may also be a peripheral satiety signal (Adachi et al., 2007). While there is good information available on the activity and distribution of nesfatin-1 in the rat, so far there has been no receptor identified for this peptide. However, results showing that increases in intracellular calcium in cultured hypothalamic neurons are inhibited by pretreatment with pertussis toxin and by exposure to inhibitors of protein kinase A indicate the receptor is likely to belong to the family of G-protein coupled receptors (Brailoiu et al., 2007).
We previously have demonstrated that nesfatin-1 has effects on the excitability of neurons within the hypothalamic paraventricular nucleus (PVN) (Price et al., 2008b). Nesfatin-1 either excited or inhibited PVN neurons without much discrimination based on electrophysiological or molecular phenotypic criteria, thereby suggesting that nesfatin-1 broadly influences the output of the PVN. Owing to the importance of the arcuate nucleus in the regulation of feeding behavior and that the arcuate nucleus receives inputs from many brain structures, such as the PVN, nucleus of the solitary tract (NTS) and the raphe nuclei, that possess nesfatin-1 expressing neurons (Brailoiu et al., 2007, Ricardo and Koh, 1978) we now have performed electrophysiological recordings on neurons within the arcuate nucleus, examining how nesfatin-1 influences the excitability of these neurons.
Section snippets
Nesfatin-1 influences the excitability of the majority of neurons in the arcuate nucleus
The results presented here represent data from a total of 102 arcuate neurons from which whole cell recordings were obtained to assess nesfatin-1 effects on membrane potential. Cytoplasm was collected from 84 of these cells at the completion of recordings to permit later phenotypic identification (see NPY neurons below). Whole cell current clamp recordings demonstrated that bath application of 10 nM nesfatin-1 caused significant changes in membrane potential in a total of 65% of arcuate neurons
Discussion
The regulation of feeding behavior involves the integration of peripherally and centrally derived signals to establish the energy state of the animal. Nesfatin-1 may represent one of the more important centrally derived peptidergic signals involved in this process. This peptide inhibits feeding, while antibodies against native nesfatin-1 stimulate feeding (Oh et al., 2006). Immunohistochemical studies have found this peptide to be located in neuronal cell bodies in the arcuate nucleus as well
Slice preparation
All animal procedures conformed to the standards of the Canadian Council on Animal Care and were approved by the Queen's University Animal Care Committee. Male Sprague Dawley rats (Charles River, Quebec, Canada) aged postnatal day 21 to 27 (approximately 50–100 g) were used in the preparation of hypothalamic slices. Rats were quickly decapitated and the brain dissected out and placed into ice cold carbogenated slicing solution, consisting of (in mM): 87 NaCl, 2.5 KCl, 25 NaHCO3, 0.5 CaCl2, 7
Acknowledgments
We would like to thank Ms. Christie Hopf for technical assistance. This work was supported by funding from the NIH (grant HL66023 to W.K.S. and A.V.F.).
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