Role of NUCB2/Nesfatin-1 in the Hypothalamic Control of Energy Homeostasis

A. Stengel; Y. Taché

doi:10.1055/s-0033-1351324

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2013; 45(13): 975-979
DOI: 10.1055/s-0033-1351324

Review

Role of NUCB2/Nesfatin-1 in the Hypothalamic Control of Energy Homeostasis

A. Stengel

¹Charité Center for Internal Medicine and Dermatology, Division for General Internal and Psychosomatic Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany

,

Y. Taché

²Department of Medicine, CURE Digestive Diseases Research Center and Center for Neurobiology of Stress, Digestive Diseases Division UCLA, and VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA

› Author Affiliations

Abstract

Hunger and satiety are regulated in a complex fashion by a few food intake stimulatory (orexigenic) and a multitude of inhibitory (anorexigenic) factors produced in the periphery (mainly in the gastrointestinal tract) or directly in the brain. Within the brain, the hypothalamus plays a pivotal role as a production site of food intake regulatory factors. Importantly, this site integrates peripheral and central signaling factors to orchestrate food intake and in the long term body weight. Our knowledge on these regulatory pathways is not static but rather rapidly changing as new factors as well as up- and downstream signaling pathways of already known transmitters are uncovered. Hypothalamic nucleobindin2 (NUCB2), the precursor of nesfatin-1, was first described in 2006 and nesfatin-1 found to be a novel anorexigenic modulator of food intake and body weight. The initial report stimulated several groups to investigate the biological actions of nesfatin-1 and subsequent studies delineated the underlying brain mechanisms involved in its food reducing effect. Of interest was the demonstration that NUCB2 also exerts its anorexigenic action in the paraventricular nucleus of the hypothalamus and is regulated at this site by changes in metabolic status with a diurnal rhythm inversely related to that of feeding in rats. The present review describes the current state-of-knowledge on central nesfatin-1’s effects on food intake and body weight and highlights important missing links regarding cellular signaling mechanisms involved in nesfatin-1’s action.

Key words

body weight - food intake - hypothalamus - NUCB2 - nesfatin-1 - obesity - satiation

Full Text

References

References
1 Oh-I S, Shimizu H, Satoh T, Okada S, Adachi S, Inoue K, Eguchi H, Yamamoto M, Imaki T, Hashimoto K, Tsuchiya T, Monden T, Horiguchi K, Yamada M, Mori M. Identification of nesfatin-1 as a satiety molecule in the hypothalamus. Nature 2006; 443: 709-712
2 Mohan H, Unniappan S. Phylogenetic Aspects of Nucleobindin-2/Nesfatin-1. Curr Pharm Des 2013; [Epub ahead of print]
3 Tsuchiya T, Shimizu H, Yamada M, Osaki A, Oh IS, Ariyama Y, Takahashi H, Okada S, Hashimoto K, Satoh T, Kojima M, Mori M. Fasting Concentrations of Nesfatin-1 Are Negatively Correlated with Body Mass Index in Non-Obese Males. Clin Endocrinol (Oxf) 2010; 73: 484-490
4 Foo K, Brismar H, Broberger C. Distribution and neuropeptide coexistence of nucleobindin-2 mRNA/nesfatin-like immunoreactivity in the rat CNS. Neuroscience 2008; 156: 563-579
5 Stengel A, Goebel M, Yakubov I, Wang L, Witcher D, Coskun T, Taché Y, Sachs G, Lambrecht NW. Identification and characterization of nesfatin-1 immunoreactivity in endocrine cell types of the rat gastric oxyntic mucosa. Endocrinology 2009; 150: 232-238
6 Gonzalez R, Kerbel B, Chun A, Unniappan S. Molecular, cellular and physiological evidences for the anorexigenic actions of nesfatin-1 in goldfish. PLoS One 2010; 5: e15201
7 Brailoiu GC, Dun SL, Brailoiu E, Inan S, Yang J, Chang JK, Dun NJ. Nesfatin-1: distribution and interaction with a G protein-coupled receptor in the rat brain. Endocrinology 2007; 148: 5088-5094
8 Kohno D, Nakata M, Maejima Y, Shimizu H, Sedbazar U, Yoshida N, Dezaki K, Onaka T, Mori M, Yada T. Nesfatin-1 neurons in paraventricular and supraoptic nuclei of the rat hypothalamus coexpress oxytocin and vasopressin and are activated by refeeding. Endocrinology 2008; 149: 1295-1301
9 Goebel M, Stengel A, Wang L, Lambrecht NW, Taché Y. Nesfatin-1 immunoreactivity in rat brain and spinal cord autonomic nuclei. Neurosci Lett 2009; 452: 241-246
10 Goebel-Stengel M, Wang L, Stengel A, Taché Y. Localization of nesfatin-1 neurons in the mouse brain and functional implication. Brain Res 2011; 1396: 20-34
11 Bustos G, Abarca J, Campusano J, Bustos V, Noriega V, Aliaga E. Functional interactions between somatodendritic dopamine release, glutamate receptors and brain-derived neurotrophic factor expression in mesencephalic structures of the brain. Brain Res Brain Res Rev 2004; 47: 126-144
12 Landgraf R, Neumann ID. Vasopressin and oxytocin release within the brain: a dynamic concept of multiple and variable modes of neuropeptide communication. Front Neuroendocrinol 2004; 25: 150-176
13 Stengel A, Hofmann T, Goebel-Stengel M, Lembke V, Ahnis A, Elbelt U, Lambrecht NWG, Ordemann J, Klapp BF, Kobelt P. Ghrelin and NUCB2/nesfatin-1 are expressed in the same gastric cell and differentially correlated with body mass index in obese patients. Histochem Cell Biol 2013; 139: 909-918
14 Ishida E, Hashimoto K, Shimizu H, Okada S, Satoh T, Kato I, Yamada M, Mori M. Nesfatin-1 induces the phosphorylation levels of cAMP response element-binding protein for intracellular signaling in a neural cell line. PLoS One 2012; 7: e50918
15 Maejima Y, Sedbazar U, Suyama S, Kohno D, Onaka T, Takano E, Yoshida N, Koike M, Uchiyama Y, Fujiwara K, Yashiro T, Horvath TL, Dietrich MO, Tanaka S, Dezaki K, Oh IS, Hashimoto K, Shimizu H, Nakata M, Mori M, Yada T. Nesfatin-1-regulated oxytocinergic signaling in the paraventricular nucleus causes anorexia through a leptin-independent melanocortin pathway. Cell Metab 2009; 10: 355-365
16 Xia ZF, Fritze DM, Li JY, Chai B, Zhang C, Zhang W, Mulholland MW. Nesfatin-1 inhibits gastric acid secretion via a central vagal mechanism in rats. Am J Physiol Gastrointest Liver Physiol 2012; 303: G570-G577
17 Iwasaki Y, Nakabayashi H, Kakei M, Shimizu H, Mori M, Yada T. Nesfatin-1 evokes Ca2+ signaling in isolated vagal afferent neurons via Ca2+ influx through N-type channels. Biochem Biophys Res Commun 2009; 390: 958-962
18 Fort P, Salvert D, Hanriot L, Jego S, Shimizu H, Hashimoto K, Mori M, Luppi PH. The satiety molecule nesfatin-1 is co-expressed with melanin concentrating hormone in tuberal hypothalamic neurons of the rat. Neuroscience 2008; 155: 174-181
19 Inhoff T, Stengel A, Peter L, Goebel M, Taché Y, Bannert N, Wiedenmann B, Klapp BF, Mönnikes H, Kobelt P. Novel insight in distribution of nesfatin-1 and phospho-mTOR in the arcuate nucleus of the hypothalamus of rats. Peptides 2010; 31: 257-262
20 Inhoff T, Mönnikes H, Noetzel S, Stengel A, Goebel M, Dinh QT, Riedl A, Bannert N, Wisser AS, Wiedenmann B, Klapp BF, Taché Y, Kobelt P. Desacyl ghrelin inhibits the orexigenic effect of peripherally injected ghrelin in rats. Peptides 2008; 29: 2159-2168
21 Gaige S, Bonnet MS, Tardivel C, Pinton P, Trouslard J, Jean A, Guzylack L, Troadec JD, Dallaporta M. c-Fos immunoreactivity in the pig brain following deoxynivalenol intoxication: focus on NUCB2/nesfatin-1 expressing neurons. Neurotoxicology 2013; 34: 135-149
22 Okere B, Xu L, Roubos EW, Sonetti D, Kozicz T. Restraint stress alters the secretory activity of neurons co-expressing urocortin-1, cocaine- and amphetamine-regulated transcript peptide and nesfatin-1 in the mouse Edinger-Westphal nucleus. Brain Res 2010; 1317C: 92-99
23 Stengel A, Goebel M, Taché Y. Nesfatin-1: a novel inhibitory regulator of food intake and body weight. Obes Rev 2011; 12: 261-271
24 Goebel M, Stengel A, Wang L, Taché Y. Central nesfatin-1 reduces the nocturnal food intake in mice by reducing meal size and increasing inter-meal intervals. Peptides 2011; 32: 36-43
25 Stengel A, Goebel M, Wang L, Rivier J, Kobelt P, Mönnikes H, Lambrecht NW, Taché Y. Central nesfatin-1 reduces dark-phase food intake and gastric emptying in rats: differential role of corticotropin-releasing factor2 receptor. Endocrinology 2009; 150: 4911-4919
26 Yosten GL, Samson WK. The anorexigenic and hypertensive effects of nesfatin-1 are reversed by pretreatment with an oxytocin receptor antagonist. Am J Physiol Regul Integr Comp Physiol 2010; 298: R1642-R1647
27 Atsuchi K, Asakawa A, Ushikai M, Ataka K, Tsai M, Koyama K, Sato Y, Kato I, Fujimiya M, Inui A. Centrally administered nesfatin-1 inhibits feeding behaviour and gastroduodenal motility in mice. Neuroreport 2010; 21: 1008-1011
28 Konczol K, Pinter O, Ferenczi S, Varga J, Kovacs K, Palkovits M, Zelena D, Toth ZE. Nesfatin-1 exerts long-term effect on food intake and body temperature. Int J Obes (Lond) 2012; 36: 1514-1521
29 Kerbel B, Unniappan S. Nesfatin-1 suppresses energy intake, co-localises ghrelin in the brain and gut, and alters ghrelin, cholecystokinin and orexin mRNA expression in goldfish. J Neuroendocrinol 2012; 24: 366-377
30 Merali Z, Cayer C, Kent P, Anisman H. Nesfatin-1 increases anxiety- and fear-related behaviors in the rat. Psychopharmacology (Berl) 2008; 201: 115-123
31 Yosten GL, Samson WK. Nesfatin-1 exerts cardiovascular actions in brain: possible interaction with the central melanocortin system. Am J Physiol Regul Integr Comp Physiol 2009; 297: R330-R336
32 Chen X, Dong J, Jiang ZY. Nesfatin-1 influences the excitability of glucosensing neurons in the hypothalamic nuclei and inhibits the food intake. Regul Pept 2012; 177: 21-26
33 Stengel A, Goebel-Stengel M, Wang L, Kato I, Mori M, Taché Y. Nesfatin-1(30-59) but not the N- and C-terminal fragments, nesfatin-1(1-29) and nesfatin-1(60-82) injected intracerebroventricularly decreases dark phase food intake by increasing inter-meal intervals in mice. Peptides 2012; 35: 143-148
34 Sedbazar U, Maejima Y, Nakata M, Mori M, Yada T. Paraventricular NUCB2/nesfatin-1 rises in synchrony with feeding suppression during early light phase in rats. Biochem Biophys Res Commun 2013; 434: 434-438
35 Yosten GL, Redlinger L, Samson WK. Evidence for a role of endogenous nesfatin-1 in the control of water drinking. J Neuroendocrinol 2012; 24: 1078-1084
36 Garcia-Galiano D, Navarro VM, Roa J, Ruiz-Pino F, Sanchez-Garrido MA, Pineda R, Castellano JM, Romero M, Aguilar E, Gaytan F, Dieguez C, Pinilla L, Tena-Sempere M. The anorexigenic neuropeptide, nesfatin-1, is indispensable for normal puberty onset in the female rat. J Neurosci 2010; 30: 7783-7792
37 Miyata S, Yamada N, Kawada T. Possible involvement of hypothalamic nucleobindin-2 in hyperphagic feeding in Tsumura Suzuki obese diabetes mice. Biol Pharm Bull 2012; 35: 1784-1793
38 Ogiso K, Asakawa A, Amitani H, Nakahara T, Ushikai M, Haruta I, Koyama KI, Amitani M, Harada T, Yasuhara D, Inui A. Plasma nesfatin-1 concentrations in restricting-type anorexia nervosa. Peptides 2011; 32: 150-153
39 Ramanjaneya M, Chen J, Brown JE, Tripathi G, Hallschmid M, Patel S, Kern W, Hillhouse EW, Lehnert H, Tan BK, Randeva HS. Identification of nesfatin-1 in human and murine adipose tissue: a novel depot-specific adipokine with increased levels in obesity. Endocrinology 2010; 151: 3169-3180
40 Tan BK, Hallschmid M, Kern W, Lehnert H, Randeva HS. Decreased cerebrospinal fluid/plasma ratio of the novel satiety molecule, nesfatin-1/NUCB-2, in obese humans: evidence of nesfatin-1/NUCB-2 resistance and implications for obesity treatment. J Clin Endocrinol Metab 2011; 96: E669-E673
41 Abaci A, Catli G, Anik A, Kume T, Bober E. The relation of serum nesfatin-1 level with metabolic and clinical parameters in obese and healthy children. Pediatr Diabetes 2013; 14: 189-195
42 Kirchgessner AL, Sclafani A. PVN-hindbrain pahway involved in the hypothalamic hyperphagia-obesity syndrome. Physiol Behav 1988; 42: 517-528
43 Schwartz MW, Woods SC, Porte Jr D, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature 2000; 404: 661-671
44 Zorrilla EP, Taché Y, Koob GF. Nibbling at CRF receptor control of feeding and gastrocolonic motility. Trends Pharmacol Sci 2003; 24: 421-427
45 Tabarin A, Diz-Chaves Y, Consoli D, Monsaingeon M, Bale TL, Culler MD, Datta R, Drago F, Vale WW, Koob GF, Zorrilla EP, Contarino A. Role of the corticotropin-releasing factor receptor type 2 in the control of food intake in mice: a meal pattern analysis. Eur J Neurosci 2007; 26: 2303-2314
46 Price CJ, Hoyda TD, Samson WK, Ferguson AV. Nesfatin-1 influences the excitability of paraventricular nucleus neurones. J Neuroendocrinol 2008; 20: 245-250
47 Gotoh K, Masaki T, Chiba S, Ando H, Shimasaki T, Mitsutomi K, Fujiwara K, Katsuragi I, Kakuma T, Sakata T, Yoshimatsu H. Nesfatin-1, corticotropin-releasing hormone, thyrotropin-releasing hormone, and neuronal histamine interact in the hypothalamus to regulate feeding behavior. J Neurochem 2013; 124: 90-99
48 Konczol K, Bodnar I, Zelena D, Pinter O, Papp RS, Palkovits M, Nagy GM, Toth ZE. Nesfatin-1/NUCB2 may participate in the activation of the hypothalamic-pituitary-adrenal axis in rats. Neurochem Int 2010; 57: 189-197
49 Hashimoto K, Nishiyama M, Tanaka Y, Noguchi T, Asaba K, Hossein PN, Nishioka T, Makino S. Urocortins and corticotropin releasing factor type 2 receptors in the hypothalamus and the cardiovascular system. Peptides 2004; 25: 1711-1721
50 Nonogaki K, Ohba Y, Sumii M, Oka Y. Serotonin systems upregulate the expression of hypothalamic NUCB2 via 5-HT2C receptors and induce anorexia via a leptin-independent pathway in mice. Biochem Biophys Res Commun 2008; 372: 186-190
51 Price CJ, Samson WK, Ferguson AV. Nesfatin-1 inhibits NPY neurons in the arcuate nucleus. Brain Res 2008; 1230: 99-106