Abstract
Purpose
Prolactin-releasing peptide (PrRP) is a neuropeptide that suppresses food intake and increases body temperature when delivered to the forebrain ventricularly or parenchymally. However, PrRP’s receptor GPR10 is widely distributed throughout the brain with particularly high levels found in the dorsomedial hindbrain. Thus, we hypothesized that hindbrain-directed PrRP administration would affect energy balance and motivated feeding behavior.
Methods
To address this hypothesis, a range of behavioral and physiologic variables were measured in Sprague-Dawley rats that received PrRP delivered to the fourth ventricle (4V) or the nucleus of the solitary tract (NTS) at the level of the area postrema (AP).
Results
4V PrRP delivery decreased chow intake and body weight, in part, through decreasing meal size in ad libitum maintained rats tested at dark onset. PrRP inhibited feeding when delivered to the nucleus tractus solitarius (NTS), but not to more ventral hindbrain structures. In addition, 4V as well as direct NTS administration of PrRP increased core temperature. By contrast, 4V PrRP did not reduce ad libitum intake of highly palatable food or the motivation to work for or seek palatable foods.
Conclusions
The dorsomedial hindbrain and NTS/AP, in particular, are sites of action in PrRP/GPR10-mediated control of chow intake, core temperature, and body weight.
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References
Alhadeff AL, Grill HJ (2014) Hindbrain nucleus tractus solitarius glucagon-like peptide-1 receptor signaling reduces appetitive and motivational aspects of feeding. Am J Physiol Regul Integr Comp Physiol 19104:465–470. https://doi.org/10.1152/ajpregu.00179.2014
Alhadeff AL, Mergler BD, Zimmer DJ, Turner CA, Reiner DJ, Schmidt HD, Grill HJ, Hayes MR (2017) Endogenous glucagon-like peptide-1 receptor signaling in the nucleus tractus solitarius is required for food intake control. Neuropsychopharmacology 42:1471–1479. https://doi.org/10.1038/npp.2016.246
Bechtold DA, Luckman SM (2006) Prolactin-releasing peptide mediates cholecystokinin-induced satiety in mice. Endocrinology 147:4723–4729. https://doi.org/10.1210/en.2006-0753
Bjursell M, Lennerås M, Göransson M, Elmgren A, Bohlooly-Y M (2007) GPR10 deficiency in mice results in altered energy expenditure and obesity. Biochem Biophys Res Commun 363:633–638. https://doi.org/10.1016/j.bbrc.2007.09.016
Chen CT, Dun SL, Dun NJ, Chang JK (1999) Prolactin-releasing peptide-immunoreactivity in A1 and A2 noradrenergic neurons of the rat medulla. Brain Res 822:276–279. https://doi.org/10.1016/S0006-8993(99)01153-1
Choi DL, Davis JF, Magrisso IJ, Fitzgerald ME, Lipton JW, Benoit SC (2012) Orexin signaling in the paraventricular thalamic nucleus modulates mesolimbic dopamine and hedonic feeding in the rat. Neuroscience 210:243–248. https://doi.org/10.1016/j.neuroscience.2012.02.036
Cummings DE, Overduin J (2007) Gastrointestinal regulation of food intake. J Clin Invest 117:13–23. https://doi.org/10.1172/JCI30227
Davis JF, Choi DL, Schurdak JD, Fitzgerald MF, Clegg DJ, Lipton JW, Figlewicz DP, Benoit SC (2011) Leptin regulates energy balance and motivation through action at distinct neural circuits. BPS 69:668–674. https://doi.org/10.1016/j.biopsych.2010.08.028
Dodd GT, Luckman SM (2013) Physiological roles of GPR10 and PrRP signaling. Front Endocrinol (Lausanne) 4:1–9. https://doi.org/10.3389/fendo.2013.00020
Dodd GT, Worth AA, Nunn N, Korpal AK, Bechtold DA, Allison MB, Myers MG Jr, Statnick MA, Luckman SM (2014) The Thermogenic effect of Leptin is dependent on a distinct population of prolactin-releasing peptide neurons in the dorsomedial hypothalamus. Cell Metab 20:639–649. https://doi.org/10.1016/j.cmet.2014.07.022
Ellacott KLJ, Donald EL, Clarkson P, Morten J, Masters D, Brennand J, Luckman SM (2005) Characterization of a naturally-occurring polymorphism in the UHR-1 gene encoding the putative rat prolactin-releasing peptide receptor. Peptides 26:675–681. https://doi.org/10.1016/j.peptides.2004.11.020
Ellacott KLJ, Lawrence CB, Pritchard LE, Luckman SM (2003) Repeated administration of the anorectic factor prolactin-releasing peptide leads to tolerance to its effects on energy homeostasis. Am J Physiol Regul Integr Comp Physiol 285:R1005–R1010. https://doi.org/10.1152/ajpregu.00237.2003
Ellacott KLJ, Lawrence CB, Rothwell NJ, Luckman SM (2002) PRL-releasing peptide interacts with leptin to reduce food intake and body weight. Endocrinology 143:368–374. https://doi.org/10.1210/en.143.2.368
Engström M, Brandt A, Wurster S, Savola JM, Panula P (2003) Prolactin releasing peptide has high affinity and efficacy at neuropeptide FF2 receptors. J Pharmacol Exp Ther 305:825–832. https://doi.org/10.1124/jpet.102.047118
Fujii R, Fukusumi S, Hosoya M, Kawamata Y, Habata Y, Hinuma S, Sekiguchi M, Kitada C, Kurokawa T, Nishimura O, Onda H, Sumino Y, Fujino M (1999) Tissue distribution of prolactin-releasing peptide (PrRP) and its receptor. Regul Pept 83:1–10. https://doi.org/10.1016/S0167-0115(99)00028-2
Grill HJ (2006) Distributed neural control of energy balance: contributions from hindbrain and hypothalamus. Obesity (Silver Spring) 14(Suppl 5):216S–221S. https://doi.org/10.1038/oby.2006.312
Grill HJ, Hayes MR (2012) Hindbrain neurons as an essential hub in the neuroanatomically distributed control of energy balance. Cell Metab 16:296–309. https://doi.org/10.1016/j.cmet.2012.06.015
Gu W, Geddes BJ, Zhang C, Foley KP, Stricker-Krongrad A (2004) The prolactin-releasing peptide receptor (GPR10) regulates body weight homeostasis in mice. J Mol Neurosci 22:93–103. https://doi.org/10.1385/JMN:22:1-2:93
Hayes MR, Bradley L, Grill HJ (2009) Endogenous hindbrain glucagon-like peptide-1 receptor activation contributes to the control of food intake by mediating gastric satiation signaling. Endocrinology 150:2654–2659. https://doi.org/10.1210/en.2008-1479
Hayes MR, Leichner TM, Zhao S, Lee GS, Chowansky A, Zimmer D, de Jonghe BC, Kanoski SE, Grill HJ, Bence KK (2011) Intracellular signals mediating the food intake-suppressive effects of hindbrain glucagon-like peptide-1 receptor activation. Cell Metab 13:320–330. https://doi.org/10.1016/j.cmet.2011.02.001
Hinuma S, Habata Y, Fujii R, Kawamata Y, Hosoya M, Fukusumi S, Kitada C, Masuo Y, Asano T, Matsumoto H, Sekiguchi M, Kurokawa T, Nishimura O, Onda H, Fujino M (1998) A prolactin-releasing peptide in the brain. Nature 393:272–276. https://doi.org/10.1038/30515
Horiuchi J, Saigusa T, Sugiyama N, Kanba S, Nishida Y, Sato Y, Hinuma S, Arita J (2002) Effects of prolactin-releasing peptide microinjection into the ventrolateral medulla on arterial pressure and sympathetic activity in rats. Brain Res 958:201–209. https://doi.org/10.1016/S0006-8993(02)03718-6
Huo L, Gamber KM, Grill HJ, Bjørbæk C (2008) Divergent leptin signaling in proglucagon neurons of the nucleus of the solitary tract in mice and rats. Endocrinology 149:492–497. https://doi.org/10.1210/en.2007-0633
Ibata Y, Iijima N, Kataoka Y, Kakihara K (2000) Morphological survey of prolactin-releasing peptide and its receptor with special reference to their functional roles in the brain. Neurosci Res 38(3):223–230. https://doi.org/10.1016/S0168-0102(00)00182-6
Iijima N, Kataoka Y, Kakihara K, Bamba H, Tamada Y, Hayashi S, Matsuda T, Tanaka M, Honjyo H, Hosoya M, Hinuma S, Ibata Y (1999) Cytochemical study of prolactin-releasing peptide (PrRP) in the rat brain. Neuroreport 10:1713–1716. https://doi.org/10.1097/00001756-199906030-00016
Kanoski SE, Alhadeff AL, Fortin SM, Gilbert JR, Grill HJ (2014) Leptin signaling in the medial nucleus tractus solitarius reduces food seeking and willingness to work for food. Neuropsychopharmacology 39:605–613. https://doi.org/10.1038/npp.2013.235
Kanoski SE, Fortin SM, Ricks KM, Grill HJ (2013) Ghrelin signaling in the ventral hippocampus stimulates learned and motivational aspects of feeding via PI3K-Akt signaling. Biol Psychiatry 73:915–923. https://doi.org/10.1016/j.biopsych.2012.07.002
Kanoski SE, Zhao S, Guarnieri DJ, DiLeone RJ, Yan J, de Jonghe BC, Bence KK, Hayes MR, Grill HJ (2012) Endogenous leptin receptor signaling in the medial nucleus tractus solitarius affects meal size and potentiates intestinal satiation signals. AJP Endocrinol Metab 303:E496–E503. https://doi.org/10.1152/ajpendo.00205.2012
Kataoka Y, Iijima N, Yano T, Kakihara K, Hayashi S, Hinuma S, Honjo H, Hayashi S, Tanaka M, Ibata Y (2001) Gonadal regulation of PrRP mRNA expression in the nucleus tractus solitarius and ventral and lateral reticular nuclei of the rat. Brain Res Mol Brain Res 87:42–47. https://doi.org/10.1016/S0169-328X(00)00280-1
Kreisler AD, Davis EA, Rinaman L (2014) Differential activation of chemically identified neurons in the caudal nucleus of the solitary tract in non-entrained rats after intake of satiating vs. non-satiating meals. Physiol Behav 136:47–54. https://doi.org/10.1016/j.physbeh.2014.01.015
Laurent P, Becker JAJ, Valverde O, Ledent C, de Kerchove d’Exaerde A, Schiffmann SN, Maldonado R, Vassart G, Parmentier M (2005) The prolactin-releasing peptide antagonizes the opioid system through its receptor GPR10. Nat Neurosci 8:1735–1741. https://doi.org/10.1038/nn1585
Lawrence CB, Celsi F, Brennand J, Luckman SM (2000) Alternative role for prolactin-releasing peptide in the regulation of food intake. Nat Neurosci 3:645–646. https://doi.org/10.1038/76597
Lawrence CB, Ellacott KLJ, Luckman SM (2002) PRL-releasing peptide reduces food intake and may mediate satiety signaling. Endocrinology 143:360–367. https://doi.org/10.1210/en.143.2.360
Lawrence CB, Liu Y-L, Stock MJ, Luckman SM (2004) Anorectic actions of prolactin-releasing peptide are mediated by corticotropin-releasing hormone receptors. Am J Physiol Regul Integr Comp Physiol 286:R101–R107. https://doi.org/10.1152/ajpregu.00402.2003
Lee Y, Yang SP, Soares MJ, Voogt JL (2000) Distribution of prolactin-releasing peptide mRNA in the rat brain. Brain Res Bull 51:171–176. https://doi.org/10.1016/S0361-9230(99)00212-9
Loewy AD, Wallach JH, McKellar S (1981) Efferent connections of the ventral medulla oblongata in the rat. Brain Res Rev 3:63–80. https://doi.org/10.1016/0165-0173(81)90012-6
Ma L, MacTavish D, Simonin F, Bourguignon JJ, Watanabe T, Jhamandas JH (2009) Prolactin-releasing peptide effects in the rat brain are mediated through the neuropeptide FF receptor. Eur J Neurosci 30:1585–1593. https://doi.org/10.1111/j.1460-9568.2009.06956.x
Maletínská L, Nagelová V, Tichá A et al (2015) Novel lipidized analogs of prolactin-releasing peptide have prolonged half-lives and exert anti-obesity effects after peripheral administration. Int J Obes:986–993. https://doi.org/10.1038/ijo.2015.28
Maniscalco JW, Kreisler AD, Rinaman L (2012) Satiation and stress-induced hypophagia: examining the role of hindbrain neurons expressing prolactin-releasing peptide or glucagon-like peptide 1. Front Neurosci 6:1–17. https://doi.org/10.3389/fnins.2012.00199
Maniscalco JW, Zheng H, Gordon PJ, Rinaman L (2015) Negative energy balance blocks neural and behavioral responses to acute stress by “silencing” central glucagon-like peptide 1 signaling in rats. J Neurosci 35:10701–10714. https://doi.org/10.1523/JNEUROSCI.3464-14.2015
Maruyama M, Matsumoto H, Fujiwara K, Kitada C, Hinuma S, Onda H, Fujino M, Inoue K (1999) Immunocytochemical localization of prolactin-releasing peptide in the rat brain. Endocrinology 140:2326–2333. https://doi.org/10.1210/endo.140.5.6685
Maruyama M, Matsumoto H, Fujiwara K, Noguchi J, Kitada C, Fujino M, Inoue K (2001) Prolactin-releasing peptide as a novel stress mediator in the central nervous system. Endocrinology 142:2032–2038. https://doi.org/10.1210/en.142.5.2032
Matsumoto H, Maruyama M, Noguchi J, Horikoshi Y, Fujiwara K, Kitada C, Hinuma S, Onda H, Nishimura O, Inoue K, Fujino M (2000) Stimulation of corticotropin-releasing hormone-mediated adrenocorticotropin secretion by central administration of prolactin-releasing peptide in rats. Neurosci Lett 285:234–238. https://doi.org/10.1016/S0304-3940(00)01077-6
Mera T, Fujihara H, Kawasaki M, Hashimoto H, Saito T, Shibata M, Saito J, Oka T, Tsuji S, Onaka T, Ueta Y (2006) Prolactin-releasing peptide is a potent mediator of stress responses through the hypothalamic paraventricular nucleus. Neuroscience 141:1069–1086. https://doi.org/10.1016/j.neuroscience.2006.04.023
Mikulášková B, Zemenová J, Pirník Z, Pražienková V, Bednárová L, Železná B, Maletínská L, Kuneš J (2015) Effect of palmitoylated prolactin-releasing peptide on food intake and neural activation after different routes of peripheral administration in rats. Peptides 75:109–117. https://doi.org/10.1016/j.peptides.2015.11.005
Moran TH, Dailey MJ (2011) Intestinal feedback signaling and satiety. Physiol Behav 105:77–81. https://doi.org/10.1016/j.physbeh.2011.02.005
Olszewski PK, Klockars A, Levine AS (2016) Oxytocin: a conditional anorexigen whose effects on appetite depend on the physiological, behavioural and social contexts. J Neuroendocrinol 28(4). https://doi.org/10.1111/jne.12376
Panula P, Aarnisalo AA, Wasowicz K (1996) Neuropeptide FF, a mammalian neuropeptide with multiple functions. Prog Neurobiol 48:461–487. https://doi.org/10.1016/0301-0082(96)00001-9
Rinaman L (2011) Hindbrain noradrenergic A2 neurons: diverse roles in autonomic, endocrine, cognitive, and behavioral functions. Am J Physiol Regul Integr Comp Physiol 300:R222–R235. https://doi.org/10.1152/ajpregu.00556.2010
Ritter RC, Slusser PG, Stone S (1981) Glucoreceptors controlling feeding and blood glucose: location in the hindbrain. Science 213:451–452. https://doi.org/10.1126/science.6264602
Roland BL, Sutton SW, Wilson SJ, Luo L, Pyati J, Huvar R, Erlander MG, Lovenberg TW (1999) Anatomical distribution of prolactin-releasing peptide and its receptor suggests additional functions in the central nervous system and periphery. Endocrinology 140:5736–5745. https://doi.org/10.1210/endo.140.12.7211
Samson WK, Keown C, Samson CK, Samson HW, Lane B, Baker JR, Taylor MM (2003) Prolactin-releasing peptide and its homolog RFRP-1 act in hypothalamus but not in anterior pituitary gland to stimulate stress hormone secretion. Endocrine 20:59–66. https://doi.org/10.1385/ENDO:20:1-2:59
Samson WK, Resch ZT, Murphy TC (2000) A novel action of the newly described prolactin-releasing peptides: cardiovascular regulation. Brain Res 858:19–25. https://doi.org/10.1016/S0006-8993(99)02451-8
Seal LJ, Small CJ, Dhillo WS, Stanley SA, Abbott CR, Ghatei MA, Bloom SR (2001) PRL-releasing peptide inhibits food intake in male rats via the dorsomedial hypothalamic nucleus and not the paraventricular hypothalamic nucleus. Endocrinology 142:4236–4243. https://doi.org/10.1210/en.142.10.4236
Skibicka KP, Grill HJ (2008) Energetic responses are triggered by caudal brainstem melanocortin receptor stimulation and mediated by local sympathetic effector circuits. Endocrinology 149:3605–3616. https://doi.org/10.1210/en.2007-1754
Smith GP (2000) The controls of eating: a shift from nutritional homeostasis to behavioral neuroscience. Nutrition 16(10):814-820. https://doi.org/10.1016/S0899-9007(00)00457-3
Stice E, Figlewicz DP, Gosnell BA, Levine AS, Pratt WE (2013) The contribution of brain reward circuits to the obesity epidemic. Neurosci Biobehav Rev 37:2047–2058. https://doi.org/10.1016/j.neubiorev.2012.12.001
Takayanagi Y, Matsumoto H, Nakata M, Mera T, Fukusumi S, Hinuma S, Ueta Y, Yada T, Leng G, Onaka T (2008) Endogenous prolactin-releasing peptide regulates food intake in rodents. J Clin Invest 118:4014–4024. https://doi.org/10.1172/JCI34682
Takayanagi Y, Onaka T (2010) Roles of prolactin-releasing peptide and RFamide related peptides in the control of stress and food intake. FEBS J 277:4998–5005. https://doi.org/10.1111/j.1742-4658.2010.07932.x
Thompson RH, Canteras NS, Swanson LW (1996) Organization of projections from the dorsomedial nucleus of the hypothalamus: a PHA-L study in the rat. J Comp Neurol 376:143–173. https://doi.org/10.1002/(SICI)1096-9861(19961202)376:1<143::AID-CNE9>3.0.CO;2-3
Watanabe T, Mikio S, Yuki Y, et al (2005) Mutated G-protein-coupled receptor GPR10 is responsible for the hyperphagia/dyslipidaemia/obesity locus of Dmo1 in the OLETF rat. Clin Exp Pharmacol Physiol 32(5-6):355–366. https://doi.org/10.1111/j.1440-1681.2005.04196.x
Yamada T, Mochiduki A, Sugimoto Y et al (2009) Prolactin-releasing peptide regulates the cardiovascular system via corticotrophin-releasing hormone. J Neuroendocrinol 21:586–593. https://doi.org/10.1111/j.1365-2826.2009.01875.x
Zheng H (2005) Brain stem melanocortinergic modulation of meal size and identification of hypothalamic POMC projections. AJP Regul Integr Comp Physiol 289:R247–R258. https://doi.org/10.1152/ajpregu.00869.2004
Acknowledgements
We thank Zhi Yi Ong, Hallie Wald, and Amber Alhadeff for their assistance with experiments.
Funding
This study was funded by NIH R01 DK21397 (HJG) and T32 DK007314 (XSD).
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All procedures conformed to and received approval from the institutional standards of the University of Pennsylvania Animal Care and Use Committee.
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Davis, X.S., Grill, H.J. The hindbrain is a site of energy balance action for prolactin-releasing peptide: feeding and thermic effects from GPR10 stimulation of the nucleus tractus solitarius/area postrema. Psychopharmacology 235, 2287–2301 (2018). https://doi.org/10.1007/s00213-018-4925-5
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DOI: https://doi.org/10.1007/s00213-018-4925-5