Abstract
In the last few years, kisspeptin-KISS1R signaling has appeared as a major regulator of the reproductive function in several vertebrate species. However, KISS1 (encoding kisspeptin) and its putative receptor, KISS1R , are expressed in several other tissues. Adipose tissue, which secretes many peptides with diverse functions in normal physiology, expresses Kiss1 , which is modulated by gonadal steroids as well as by body nutritional status. Similarly, Kiss1r expression is also found in adipose tissue, but the local role of kisspeptin in adipocyte function is currently unknown. Therefore, in the present study the effects of exogenous human kisspeptin-10 (KP10) were studied on three important adipokines, namely, adiponectin, leptin, and resistin in a set of four chair-restraint habituated intact adult male rhesus monkeys under; 1) normal fed conditions, 2) 24-h fasting conditions, and 3) 48-h fasting conditions. Plasma resistin and leptin levels decreased (p<0.01), whereas adiponectin levels increased (p<0.05) in fasted monkeys. Kisspeptin administration significantly increased (p<0.05) mean plasma adiponectin levels under fed and 24-h fasting conditions as compared to pretreatment or vehicle-treatment levels. A stimulatory effect was also observed on the 48-h fasting stimulated plasma adiponectin levels, but it lacked statistical significance. In contrast, no effect of kisspeptin was observed on mean plasma leptin and resistin levels. Thus, the present study demonstrated a stimulatory effect of peripheral kisspeptin administration on the plasma adiponectin levels under fed and 24-h fasting conditions in the adult male rhesus monkey. These findings, therefore, assign a novel role to kisspeptin, a regulator of adipocyte function in higher primate.
Key words
fasting - kisspeptin - GPR54 - adiponectin - leptin - resistin - monkey
References
1
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.
Procd Natl Acad Sci U S A.
2003;
100
10972-10976
2
Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno Jr JS, 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 Jr WF, Aparicio SA, Colledge WH.
The GPR54 gene as a regulator of puberty.
N Engl J Med.
2003;
349
1614-1627
3
Navarro VM, Fernandez-Fernandez R, Castellano JM, Roa J, Mayen A, Barreiro ML, Gaytan F, Aguilar E, Pinilla L, Dieguez C, Tena-Sempere M.
Advanced vaginal opening and precocious activation of the reproductive axis by KiSS-1 peptide, the endogenous ligand of GPR54.
J Physiol.
2004;
561
379-386
4
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
5
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.
Procd Natl Acad Sci U S A.
2005;
102
2129-2134
6
Oakley AE, Clifton DK, Steiner RA.
Kisspeptin signaling in the brain.
Endocr Rev.
2009;
30
713-743
7
Teles MG, Bianco SD, Brito VN, Trarbach EB, Kuohung W, Xu S, Seminara SB, Mendonca BB, Kaiser UB, Latronico AC.
A GPR54-activating mutation in a patient with central precocious puberty.
N Engl J Med.
2008;
358
709-715
8
Funes S, Hedrick JA, Vassileva G, Markowitz L, Abbondanzo S, Golovko A, Yang S, Monsma FJ, Gustafson EL.
The KiSS-1 receptor GPR54 is essential for the development of the murine reproductive system.
Biochem Biophys Res Commun.
2003;
312
1357-1363
9
Lapatto R, Pallais JC, Zhang D, Chan YM, Mahan A, Cerrato F, Le WW, Hoffman GE, Seminara SB.
Kiss1-/- mice exhibit more variable hypogonadism than Gpr54-/- mice.
Endocrinology.
2007;
148
4927-4936
10
d’Anglemont de Tassigny X, Fagg LA, Dixon JP, Day K, Leitch HG, Hendrick AG, Zahn D, Franceschini I, Caraty A, Carlton MB, Aparicio SA, Colledge WH.
Hypogonadotropic hypogonadism in mice lacking a functional Kiss1 gene.
PNAS.
2007;
104
10714-10719
11
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.
J Clin Endocrinol Metab.
2005;
90
6609-6615
12
Ramaswamy S, Seminara SB, Pohl CR, DiPietro MJ, Crowley WF, Plant TM.
Effect of continuous intravenous administration of human metastin 45–54 on the neuroendocrine activity of the hypothalamic-pituitary-testicular axis in the adult male rhesus monkey (Macaca mulatta).
Endocrinology.
2007;
148
3364-3370
13
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
14
Castellano JM, Navarro VM, Fernandez-Fernandez 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
15
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
16
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
17
Wahab F, Aziz F, Irfan S, Zaman W, Shahab M.
Short-term fasting attenuates the response of the HPG axis to kisspeptin challenge in the adult male rhesus monkey (Macaca mulatta).
Life Sciences.
2008;
83
633-637
18
Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Le Poul E, Brézillon 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
19
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
20
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
21
Hauge-Evans AC, Richardson CC, Milne HM, Christie MR, Persaud SJ, Jones PM.
A role for kisspeptin in islet function.
Diabetologia.
2006;
49
2131-2135
22
Brown RE, Imran SA, Ur E, Wilkinson M.
KiSS-1 mRNA in adipose tissue is regulated by sex hormones and food intake.
Mol Cell Endocrinol.
2008;
281
64-72
23
Fischer-Posovszky P, Wabitsch M, Hochberg Z.
Endocrinology of adipose tissue – an update.
Horm Metab Res.
2007;
39
314-321
24
Ahima RS, Lazar MA.
Adipokines and the peripheral and neural control of energy balance.
Mol Endocrinol.
2008;
22
1023-1031
25
Lado-Abeal J, Hickox JR, Cheung TL, Veldhuis JD, Hardy DM, Norman RL.
Neuroendocrine consequences of fasting in adult male macaques: effects of recombinant rhesus macaque leptin infusion.
Neuroendocrinology.
2000;
71
196-208
26
Smith JT, Acohido BV, Clifton DK, Steiner RA.
KiSS-1 neurones are direct targets for leptin in the ob/ob mouse.
Journal of Neuroendocrinology.
2006;
18
298-303
27
Rodriguez-Pacheco F, Martinez-Fuentes AJ, Tovar S, Pinilla L, Tena-Sempere M, Dieguez C, Castaño JP, Malagon MM.
Regulation of pituitary cell function by adiponectin.
Endocrinology.
2007;
148
401-410
28
Caminos JE, Nogueiras R, Gaytán F, Pineda R, González CR, Barreiro ML, Castaño JP, Malagón MM, Pinilla L, Toppari J, Diéguez C, Tena-Sempere M.
Novel expression and direct effects of adiponectin in the rat testis.
Endocrinology.
2008;
149
3390-3402
29
Kadowaki T, Yamauchi T.
Adiponectin and adiponectin receptors.
Endocr Rev.
2005;
26
439-451
30
Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanafusa T, Matsuzawa Y.
Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients.
Arterioscler Thromb Vasc Biol.
2000;
20
1595-1599
31
Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y.
Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity.
Biochem Biophys Res Commun.
1999;
257
79-83
32
Guevara R, Valle A, Gianotti M, Roca P, Oliver J.
Gender-dependent differences in serum profiles of insulin and leptin in caloric restricted rats.
Horm Metab Res.
2008;
40
38-43
33
Rajala MW, Qi Y, Patel HR, Takahashi N, Banerjee R, Pajvani UB, Sinha MK, Gingerich RL, Scherer PE, Ahima RS.
Regulation of resistin expression and circulating levels in obesity, diabetes, and fasting.
Diabetes.
2004;
53
1671-1679
34
Horikoshi Y, Matsumoto H, Takatsu Y, Ohtaki T, Kitada C, Usuki S, Fujino M.
Dramatic elevation of plasma metastin concentrations in human pregnancy: Metastin as a novel placenta-derived hormone in humans.
Journal of Clinical Endocrinology and Metabolism.
2003;
88
914-919
35
Panidis D, Rousso D, Koliakos G, Kourtis A, Katsikis I, Farmakiotis D, Votsi E, Diamanti-Kandarakis E.
Plasma metastin levels are negatively correlated with insulin resistance and free androgens in women with polycystic ovary syndrome.
Fertility and Sterility.
2006;
85
1778-1883
36
de Vries L, Shtaif B, Phillip M, Gat-Yablonski G.
Kisspeptin serum levels in girls with central precocious puberty.
Clin Endocrinol (Oxf).
2009;
71
524-528
37
Qi Y, Takahashi N, Hileman SM, Patel HR, Berg AH, Pajvani UB, Scherer PE, Ahima RS.
Adiponectin acts in the brain to decrease body weight.
Nat Med.
2004;
10
524-529
38
Kos K, Harte AL, da Silva NF, Tonchev A, Chaldakov G, James S, Snead DR, Hoggart B, O’Hare JP, McTernan PG, Kumar S.
Adiponectin and resistin in human cerebrospinal fluid and expression of adiponectin receptors in the human hypothalamus.
J Clin Endocrinol Metab.
2007;
92
1129-1136
Correspondence
Dr. M. Shahab
Reproductive Neuroendocrinology
Laboratory
Department of Animal Sciences
Faculty of Biological Sciences
Quaid-i-Azam University
45320 Islamabad
Pakistan
Phone: +92/51/9064 30 14
Fax: +92/51/2601 176
Email: Shahab@qau.edu.pk