Decrease in Hypothalamic Kiss1 and Kiss1r Expression: A Potential Mechanism for Fasting-induced Suppression of the HPG Axis in the Adult Male Rhesus Monkey (Macaca mulatta)

Abstract

Fasting suppresses functioning of the hypothalamic-pituitary-gonadal (HPG) axis by mechanisms that are incompletely understood. In 2003, hypothalamic kisspeptin-Kiss1r signaling was discovered to play a significant role in regulating the HPG axis. We have recently shown that in adult male macaques, short-term fasting attenuates the response of the HPG axis to an exogenous kisspeptin challenge. In the present study, we explored the mechanism underlying this attenuated response by examining the modulation of the hypothalamic expression of Kiss1 and Kiss1r under short-term fasting and normal feeding conditions in the adult male macaques. Hypothalamic mRNA was extracted from normal fed (n=3) and 48-h fasted (n=3) monkeys. Kiss1, Kiss1r, and GnRH1 mRNA were quantified by reverse transcription followed by real-time polymerase chain reaction. In addition, blood samples were collected for measurement of plasma concentrations of glucose, cortisol, leptin, and testosterone. In contrast to fed animals, plasma glucose, leptin, and testosterone levels decreased and cortisol levels increased in fasted animals. The hypothalamic expression of Kiss1 and Kiss1r mRNA was significantly lower (p<0.05) in fasted monkeys compared to fed monkeys while hypothalamic GnRH1 mRNA expression was comparable between the 2 groups. Thus, our results demonstrate that expression of hypothalamic Kiss1 and Kiss1r decrease after a short-term fasting in monkeys. This decrease may contribute to the suppression of the HPG axis during fasting conditions in primates. In addition, our finding of lower expression of Kiss1r in fasted monkeys provides an explanation for the attenuation in the HPG axis response to peripheral kisspeptin challenge during short-term fasting.

fasting - HPG axis - GnRH1 - Kiss1 - Kiss1r - testosterone - monkey

References

• 1 Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Le Poul E, Brezillon S, Tyldesley R, Suarez-Huerta N, Vandeput F, Blanpain C, Schiffmann SN, Vassart G, Parmentier M. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54.  J Biol Chem. 2001;  276 34631-34636
• 2 Ohtaki T, Shintani Y, Honda S, Matsumoto H, Hori A, Kanehashi K, Terao Y, Kumano S, Takatsu Y, Masuda Y, Ishibashi Y, Watanabe T, Asada M, Yamada T, Suenaga M, Kitada C, Usuki S, Kurokawa T, Onda H, Nishimura O, Fujino M. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor.  Nature. 2001;  411 613-617
• 3 Muir AI, Chamberlain L, Elshourbagy NA, Michalovich D, Moore DJ, Calamari A, Szekeres PG, Sarau HM, Chambers JK, Murdock P, Steplewski K, Shabon U, Miller JE, Middleton SE, Darker JG, Larminie CG, Wilson S, Bergsma DJ, Emson P, Faull R, Philpott KL, Harrison DC. AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1.  J Biol Chem. 2001;  276 28969-28975
• 4 Gottsch ML, Clifton DK, Steiner RA. From KISS1 to kisspeptins: An historical perspective and suggested nomenclature.  Peptides. 2009;  30 4-9
• 5 De Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54.  PNAS. 2003;  100 10972-10976
• 6 Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno Jr J, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG, Zahn D, Dixon J, Kaiser UB, Slaugenhaupt SA, Gusella JF, O’Rahilly S, Carlton MB, Crowley WF, Aparicio SA, Colledge WH. The GPR54 gene as a regulator of puberty.  N Engl J Med. 2003;  349 1614-1627
• 7 Wahab F, Tanzeela R, Shahab M. Study of the effect of peripheral kisspeptin administration on basal and glucose-induced insulin secretion under fed and fasting conditions in the adult male rhesus monkey (Macaca mulatta).  Horm Metab Res. 2010;  in press
• 8 Makri A, Pissimissis N, Lembessis P, Polychronakos C, Koutsilieris M. The kisspeptin (KiSS-1)/GPR54 system in cancer biology.  Cancer Treat Rev. 2008;  34 682-692
• 9 Hiden U, Bilban M, Knöfler M, Desoye G. Kisspeptins and the placenta: regulation of trophoblast invasion.  Rev Endocr Metab Disord. 2007;  8 31-39
• 10 Wahab F, Bano R, Jabeen S, Irfan S, Shahab M. Effect of peripheral kisspeptin administration on adiponectin, leptin, and resistin secretion under fed and fasting condition in the adult male rhesus monkey (Macaca mulatta).  Horm Metab Res. 2010;  42 570-574
• 11 Matsui H, Takatsu Y, Kumano S, Matsumoto H, Ohtaki T. Peripheral administration of metastin induces marked gonadotropin release and ovulation in the rat.  Biochem Biophys Res Commun. 2004;  320 383-388
• 12 Thompson EL, Patterson M, Murphy KG, Smith KL, Dhillo WS, Todd JF, Ghatei MA, Bloom SR. Central and peripheral administration of kisspeptin-10 stimulates the hypothalamic-pituitary-gonadal axis.  J Neuroendocrinol. 2004;  16 850-858
• 13 Gottsch ML, Cunningham MJ, Smith JT, Popa SM, Acohido BV, Crowley WF, Seminara S, Clifton DK, Steiner RA. A role for kisspeptins in the regulation of gonadotropin secretion in the mouse.  Endocrinology. 2004;  145 4073-4077
• 14 Navarro VM, Castellano JM, Fernandez-Fernandez R, Barreiro ML, Roa J, Sanchez-Criado JE, Aguilar E, Dieguez C, Pinilla L, Tena-Sempere M. Developmental and hormonally regulated messenger ribonucleic acid expression of KiSS-1 and its putative receptor, GPR54, in rat hypothalamus and potent luteinizing hormone-releasing activity of KiSS-1 peptide.  Endocrinology. 2004;  145 4565-4574
• 15 Shahab M, Mastronardi C, Seminara SB, Crowley WF, Ojeda SR, Plant TM. Increased hypothalamic GPR54 signaling: A potential mechanism for initiation of puberty in primates.  PNAS. 2005;  102 2129-2134
• 16 Dhillo WS, Chaudhri OB, Patterson M, Thompson EL, Murphy KG, Badman MK, McGowan BM, Amber V, Patel S, Ghatei MA, Bloom SR. Kisspeptin-54 stimulates the hypothalamic-pituitary-gonadal axis in human males.  The Journal of Clinical Endocrinology and Metabolism. 2005;  90 6609-6615
• 17 Navarro VM, Castellano JM, Fernandez-Fernandez R, Tovar S, Roa J, Mayen A, Nogueiras R, Vazquez MJ, Barreiro ML, Magni P, Aguilar E, Dieguez C, Pinilla L, Tena-Sempere M. Characterization of the potent luteinizing hormone-releasing activity of KiSS-1 peptide, the natural ligand of GPR54.  Endocrinology. 2005;  146 156-163
• 18 Messager S, Chatzidaki EE, Ma D, Hendrick AG, Zahn D, Dixon J, Thresher RR, Malinge I, Lomet D, Carlton MB, Colledge WH, Caraty A, Aparicio SA. Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54.  PNAS. 2005;  102 1761-1766
• 19 Irwig MS, Fraley GS, Smith JT, Acohido BV, Popa SM, Cunningham MJ, Gottsch ML, Clifton DK, Steiner RA. Kisspeptin activation of gonadotropin releasing hormone neurons and regulation of KiSS-1 mRNA in the male rat.  Neuroendocrinology. 2004;  80 264-272
• 20 Shibata M, Gibbs RB, Shahab M, Plant TM. GnRH neurons in the peripubertal male rhesus monkey (Macaca mulatta) express GPR54: Implication for the control of primate puberty. Program of the 87th Annual Meeting of the Endocrine Society, San Diego, CA, USA; (abstract) 2005: P1-P98
• 21 Smith JT, Cunningham MJ, Rissman EF, Clifton DK, Steiner RA. Regulation of Kiss1 gene expression in the brain of the female mouse.  Endocrinology. 2005;  146 3686-3692
• 22 Simonneaux V, Ansel L, Revel FG, Klosen P, Pévet P, Mikkelsen JD. Kisspeptin and the seasonal control of reproduction in hamsters.  Peptides. 2009;  30 146-153
• 23 Smith JT. Sex steroid control of hypothalamic Kiss1 expression in sheep and rodents: comparative aspects.  Peptides. 2009;  30 94-102
• 24 Clarke IJ, Smith JT, Caraty A, Goodman RL, Lehman MN. Kisspeptin and seasonality in sheep.  Peptides. 2009;  30 154-163
• 25 Castellano JM, Roa J, Luque RM, Dieguez C, Aguilar E, Pinilla L, Tena-Sempere M. KiSS-1/kisspeptins and the metabolic control of reproduction: physiologic roles and putative physiopathological implications.  Peptides. 2009;  30 139-145
• 26 Castellano JM, Navarro VM, Fernández-Fernández R, Nogueiras R, Tovar S, Roa J, Vazquez MJ, Vigo E, Casanueva FF, Aguilar E, Pinilla L, Dieguez C, Tena-Sempere M. Changes in Hypothalamic KiSS-1 System and Restoration of Pubertal Activation of the Reproductive Axis by Kisspeptin in Undernutrition.  Endocrinology. 2005;  146 3917-3925
• 27 Luque RM, Kineman RD, Tena-Sempere M. Regulation of hypothalamic expression of KiSS-1 and GPR54 genes by metabolic factors: Analyses using mouse models and a cell line.  Endocrinology. 2007;  148 4601-4611
• 28 Castellano JM, Navarro VM, Fernández-Fernández R, Roa J, Vigo E, Pineda R, Dieguez C, Aguilar E, Pinilla L, Tena-Sempere M. Expression of hypothalamic KiSS-1 system and rescue of defective gonadotropic responses by kisspeptin in streptozotocin-induced diabetic male rats.  Diabetes. 2006;  55 2602-2610
• 29 Yamada S, Uenoyama Y, Kinoshita M, Iwata K, Takase K, Matsui H, Adachi S, Inoue K, Maeda KI, Tsukamura H. Inhibition of metastin (kisspeptin-54)-GPR54 signaling in the arcuate nucleus-median eminence region during lactation in rats.  Endocrinology. 2007;  148 2226-2232
• 30 Wahab F, Aziz F, Irfan S, Waheed-uz Zaman, Shahab M. Short-term fasting attenuates the response of the HPG axis to kisspeptin challenge in the adult male rhesus monkey (Macaca mulatta).  Life Sci. 2008;  83 633-637
• 31 Shibata M, Friedman RL, Ramaswamy S, Plant TM. Evidence that down regulation of hypothalamic KiSS-1 expression is involved in the negative feedback action of testosterone to regulate luteinising hormone secretion in the adult male rhesus monkey (Macaca mulatta).  J Neuroendocrinol. 2007;  19 432-438
• 32 Rozen S, Skaletsky HJ. Primer3 on the WWW for general users and for biologist programmers. In: Krawetz S, Misener S (eds) Bioinformatics Methods and Protocols: Methods in Molecular Biology. Totowa, NJ: Humana Press; 2000: 365-386
• 33 Smith JT, Acohido BV, Clifton DK, Steiner RA. KiSS-1 neurones are direct targets for leptin in the ob/ob mouse.  J Neuroendocrinol. 2006;  18 298-303
• 34 Bergendahl M, Perheentupa A, Huhtaniemi I. Starvation-induced suppression of pituitary-testicular function in rats is reversed by pulsatile gonadotropin-releasing hormone substitution.  Biol Reprod. 1991;  44 413-419
• 35 Cameron JL, Nosbisch C. Suppression of pulsatile luteinizing hormone and testosterone secretion during short term food restriction in the adult male rhesus monkey (Macaca mulatta).  Endocrinology. 1991;  128 1532-1540
• 36 Aloi JA, Bergendahl M, Iranmanesh A, Veldhuis JD. Pulsatile intravenous gonadotropin-releasing hormone administration averts fasting-induced hypogonadotropism and hypoandrogenemia in healthy, normal weight men.  J Clin Endocrinol Metab. 1997;  82 1543-1548
• 37 Ebling FJ, Wood RI, Karsch FJ, Vannerson LA, Suttie JM, Bucholtz DC, Schall RE, Foster DL. Metabolic interfaces between growth and reproduction: III. Central mechanisms controlling pulsatile luteinizing hormone secretion in the nutritionally growth-limited female lamb.  Endocrinology. 1990;  126 2719-2727
• 38 I’Anson H, Terry SK, Lehman MN, Foster DL. Regional differences in the distribution of gonadotropin-releasing hormone cells between rapidly growing and growth-restricted prepubertal female sheep.  Endocrinology. 1997;  138 230-236
• 39 McShane TM, Petersen SL, McCrone S, Keisler DH. Influence of food restriction on neuropeptide-Y, proopiomelanocortin, and luteinizing hormone-releasing hormone gene expression in sheep hypothalami.  Biol Reprod. 1993;  49 831-839
• 40 Cameron JL. Regulation of reproductive hormone secretion in primates by short-term changes in nutrition.  Rev Reprod. 1996;  1 117-126
• 41 Kinsey-Jones JS, Li XF, Knox AM, Wilkinson ES, Zhu XL, Chaudhary AA, Milligan SR, Lightman SL, O’Byrne KT. Down-regulation of hypothalamic kisspeptin and its receptor, Kiss1r, mRNA expression is associated with stress-induced suppression of luteinising hormone secretion in the female rat.  J Neuroendocrinol. 2009;  21 20-29
• 42 Iwasa T, Matsuzaki T, Murakami M, Shimizu F, Kuwahara A, Yasui T, Irahara M. Decreased expression of kisspeptin mediates acute immune/inflammatory stress-induced suppression of gonadotropin secretion in female rat.  J Endocrinol Invest. 2008;  31 656-659
• 43 Forbes S, Li XF, Kinsey-Jones J, O’Byrne K. Effects of ghrelin on Kisspeptin mRNA expression in the hypothalamic medial preoptic area and pulsatile luteinising hormone secretion in the female rat.  Neurosci Lett. 2009;  460 143-147

Correspondence