Changes in body composition and mRNA expression of ghrelin and lipoprotein lipase in rats treated with leuprolide acetate, a GnRH agonist

Olvera‑Sandoval,Carlos; Betanzos‑Cabrera,Gabriel; Casillas‑Peñuelas,Rafael; Quintanar,J.   Luis

doi:10.3892/etm.2017.5352

Changes in body composition and mRNA expression of ghrelin and lipoprotein lipase in rats treated with leuprolide acetate, a GnRH agonist

Authors:
- Carlos Olvera‑Sandoval
- Gabriel Betanzos‑Cabrera
- Rafael Casillas‑Peñuelas
- J. Luis Quintanar
View Affiliations

Affiliations: Neurophysiology Laboratory, Department of Physiology and Pharmacology, Basic Science Center, Universidad Autónoma de Aguascalientes, Ciudad Universitaria Aguascalientes, Ags 20131, México, Nutrigenomics Laboratory, Academic Area of Nutrition, Health Sciences Institute, Universidad Autónoma del Estado de Hidalgo, Pachuca de Soto, Hgo 42039, México, Department of Food Technology, Universidad Autónoma de Aguascalientes, Ciudad Universitaria Aguascalientes, Ags 20131, México
Published online on: October 23, 2017 https://doi.org/10.3892/etm.2017.5352
Pages: 592-598

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Leuprolide acetate (LA), a gonadotropin-releasing hormone (GnRH) agonist, was identified to cause changes in body weight in experimental and clinical trials; however, to date, the effect of LA on the body composition has not been properly assessed. The aim of the present study was to evaluate the long‑term effect of LA administration on body composition and the mRNA expression of ghrelin and lipoprotein lipase (LPL) in rats. Ovariectomized (OVX), ovariectomized and LA‑treated (OVX+LA), non‑ovariectomized (CTRL) and non‑ovariectomized but LA‑treated (LA) rats were used. LA treatment was performed by intramuscular injection at 5 µg/kg every 72 h over 120 days. Analysis of body composition and mRNA expression of ghrelin and lipoprotein lipase were performed. The results indicated significant changes in body composition after treatment; in the OVX, LA, OVX+LA and CTRL group, the body weight was increased by 216.1, 183.7, 175.4 and 150.1%, respectively, compared with baseline. The fat mass in the LA group was 14% higher than that in the CTRL group, while that in the OVX group was 19% higher than that in the OVX+LA, and the fat‑free mass was similar between the LA and CTRL as well as the OVX and OVX+LA groups. Following 120 days of treatment, the mRNA expression of ghrelin and LPL in the LA group was ~20% higher than that in the CTRL group, while that in the OVX+LA was downregulated in comparison with that in the OVX group. The results of the present study confirmed changes in body composition and mRNA expression of ghrelin and LPL caused by long‑term administration of LA. LA may contribute to regulate food consumption and exert control over adipogenesis.

View Figures

View References

1	Quintanar JL and Salinas E: Neurotrophic effects of GnRH on neurite outgrowth and neurofilament protein expression in cultured cerebral cortical neurons of rat embryos. Neurochem Res. 33:1051–1056. 2007. View Article : Google Scholar : PubMed/NCBI
2	Prange-Kiel J, Jarry H, Schoen M, Kohlmann P, Lohse C, Zhou L and Rune GM: Gonadotropin-releasing hormone regulates spine density via its regulatory role in hippocampal estrogen synthesis. J Cell Biol. 180:417–426. 2008. View Article : Google Scholar : PubMed/NCBI
3	Conn PM and Crowley WF Jr: Gonadotropin-releasing hormone and its analogs. Annu Rev Med. 45:391–405. 1994. View Article : Google Scholar : PubMed/NCBI
4	Periti P, Mazzei T and Mini E: Clinical pharmacokinetics of depot leuprorelin. Clin Pharmacokinet. 41:485–504. 2002. View Article : Google Scholar : PubMed/NCBI
5	Sennello LT, Finley RA, Chu SY, Jagst C, Max D, Rollins DE and Tolman KG: Single-dose pharmacokinetics of leuprolide in humans following intravenous and subcutaneous administration. J Pharm Sci. 75:158–60. 1986. View Article : Google Scholar : PubMed/NCBI
6	Lønning PE and Lien EA: Pharmacokinetics of anti-endocrine agents. Cancer Surv. 17:343–370. 1993.PubMed/NCBI
7	Wilson AC, Meethal SV, Bowen RL and Atwood CS: Leuprolide acetate: A drug of diverse clinical applications. Expert Opin Investig Drugs. 16:1851–1863. 2007. View Article : Google Scholar : PubMed/NCBI
8	Guzmán-Soto I, Salinas E, Hernández-Jasso I and Quintanar JL: Leuprolide Acetate, a GnRH Agonist, improves experimental autoimmune encephalomyelitis: A possible therapy for multiple sclerosis. Neurochem Res. 37:2190–2197. 2012. View Article : Google Scholar : PubMed/NCBI
9	Calderón-Vallejo D and Quintanar JL: Gonadotropin-releasing hormone treatment improves locomotor activity, urinary function and neurofilament protein expression after spinal cord injury in ovariectomized rats. Neurosci Lett. 515:187–190. 2012. View Article : Google Scholar : PubMed/NCBI
10	Díaz Galindo C, Gómez-González B, Salinas E, Calderón-Vallejo D, Hernández-Jasso I, Bautista E and Quintanar JL: Leuprolide acetate induces structural and functional recovery of injured spinal cord in rats. Neural Regen Res. 10:1819–1824. 2015. View Article : Google Scholar : PubMed/NCBI
11	Gevers EF, Wit JM and Robinson IC: Effects of long-term gonadotropin-releasing hormone analog treatment on growth, growth hormone (GH) Secretion, GH Receptors, and GH-binding protein in the rat. Pediatr Res. 43:111–120. 1998. View Article : Google Scholar : PubMed/NCBI
12	Müller TD, Nogueiras R, Andermann ML, Andrews ZB, Anker SD, Argente J, Batterham RL, Benoit SC, Bowers CY, Broglio F, et al: Ghrelin. Mol Metab. 4:437–460. 2015. View Article : Google Scholar : PubMed/NCBI
13	Wang H and Eckel RH: Lipoprotein lipase: From gene to obesity. Am J Physiol Endocrinol Metab. 297:E271–E288. 2009. View Article : Google Scholar : PubMed/NCBI
14	Novelli EL, Diniz YS, Galhardi CM, Ebaid GM, Rodrigues HG, Mani F, Fernandes AA, Cicogna AC and Filho JL Novelli: Anthropometrical parameters and markers of obesity in rats. Lab Anim. 41:111–119. 2007. View Article : Google Scholar : PubMed/NCBI
15	Hohl R, de Oliveira RB, Vaz de Macedo D and Brenzikofer R: Apparatus for measuring rat body volume: A methodological proposition. J Appl Physiol (1985). 102:1229–1234. 2007. View Article : Google Scholar : PubMed/NCBI
16	Muscaritoli M, Gleason JR, Meguid MM and Lukaski HC: Densitometry-based equations for estimating body composition in Fischer rats. Nutrition. 9:439–445. 1993.PubMed/NCBI
17	Bligh EG and Dyer WJ: A rapid method of total lipid extraction and purification. Can J Biochem Physiol. 37:911–917. 1959. View Article : Google Scholar : PubMed/NCBI
18	Lee SJ, Yang EM, Seo JY and Kim CJ: Effects of gonadotropin-releasing hormone agonist therapy on body mass index and height in girls with central precocious puberty. Chonnam Med J. 48:27–31. 2012. View Article : Google Scholar : PubMed/NCBI
19	Neely EK, Lee PA, Bloch CA, Larsen L, Yang D, Mattia-Goldberg C and Chwalis K: Leuprolide acetate 1-month depot for central precocious puberty: Hormonal suppression and recovery. Int J Pediatr Endocrinol. 2010:3986392010. View Article : Google Scholar : PubMed/NCBI
20	Basaria S, Lieb J II, Tang AM, DeWeese T, Carducci M, Eisenberger M and Dobs AS: Long-term effects of androgen deprivation therapy in prostate cancer patients. Clin Endocrinol (Oxf). 56:779–786. 2002. View Article : Google Scholar : PubMed/NCBI
21	Smith MR: Changes in fat and lean body mass during androgen-deprivation therapy for prostate cancer. Urology. 63:742–745. 2004. View Article : Google Scholar : PubMed/NCBI
22	Herbert CA and Trigg TE: Applications of GnRH in the control and management of fertility in female animals. Anim Reprod Sci. 88:141–153. 2005. View Article : Google Scholar : PubMed/NCBI
23	Lessey BA: Medical management of endometriosis and infertility. Fertil Steril. 73:1089–1096. 2000. View Article : Google Scholar : PubMed/NCBI
24	Wei A, Fascetti AJ, Kim K and Ramsey JJ: Post-castration variations in weight gain in a cohort of young adult male cats. J Nutr Sci. 3:e372014.PubMed/NCBI
25	Nguyen PG, Dumon HJ, Siliart BS, Martin LJ, Sergheraert R and Biourge VC: Effects of dietary fat and energy on body weight and composition after gonadectomy in cats. Am J Vet Res. 65:1708–1713. 2004. View Article : Google Scholar : PubMed/NCBI
26	Jiang JM, Sacco SM and Ward WE: Ovariectomy-induced hyperphagia does not modulate bone mineral density or bone strength in rats. J Nutr. 138:2106–2110. 2008. View Article : Google Scholar : PubMed/NCBI
27	Stoch SA, Parker RA, Chen L, Bubley G, Ko YJ, Vincelette A and Greenspan SL: Bone loss in men with prostate cancer treated with gonadotropin-releasing hormone agonists. J Clin Endocrinol Metab. 86:2787–2791. 2001. View Article : Google Scholar : PubMed/NCBI
28	Meldrum DR, Chang RJ, Lu J, Vale W, Rivier J and Judd HL: ‘Medical oophorectomy’ using a long-acting gnrh agonist-a possible new approach to the treatment of endometriosis. J Clin Endocrinol Metab. 54:1081–1083. 1982. View Article : Google Scholar : PubMed/NCBI
29	Ohtsuka S, Terakawa N, Shimizu I, Sakata M, Mizutani T, Miyake A, Tanizawa O and Aono T: Studies on GnRH agonist suppression of estrogen production in patients with endometriosis. Endocrinol Jpn. 36:611–619. 1989. View Article : Google Scholar : PubMed/NCBI
30	Shimizu H, Ohtani K, Kato Y, Tanaka Y and Mori M: Withdrawal of [corrected] estrogen increases hypothalamic neuropeptide Y (NPY) mRNA expression in ovariectomized obese rat. Neurosci Lett. 204:81–84. 1996. View Article : Google Scholar : PubMed/NCBI
31	Ainslie DA, Morris MJ, Wittert G, Turnbull H, Proietto J and Thorburn AW: Estrogen deficiency causes central leptin insensitivity and increased hypothalamic neuropeptide Y. Int J Obes Relat Metab Disord. 25:1680–1688. 2001. View Article : Google Scholar : PubMed/NCBI
32	Litwak SA, Wilson JL, Chen W, Garcia-Rudaz C, Khaksari M, Cowley MA and Enriori PJ: Estradiol prevents fat accumulation and overcomes leptin resistance in female high-fat diet mice. Endocrinology. 155:4447–4460. 2014. View Article : Google Scholar : PubMed/NCBI
33	Matysková R, Zelezná B, Maixnerová J, Koutová D, Haluzík M and Maletínská L: Estradiol supplementation helps overcome central leptin resistance of ovariectomized mice on a high fat diet. Horm Metab Res. 42:182–186. 2010. View Article : Google Scholar : PubMed/NCBI
34	Yamasaki H, Douchi T, Yamamoto S, Oki T, Kuwahata R and Nagata Y: Body fat distribution and body composition during GnRH agonist therapy. Obstet Gynecol. 97:338–342. 2001. View Article : Google Scholar : PubMed/NCBI
35	Boxer RS, Kenny AM, Dowsett R and Taxel P: The effect of 6 months of androgen deprivation therapy on muscle and fat mass in older men with localized prostate cancer. Aging Male. 8:207–212. 2005. View Article : Google Scholar : PubMed/NCBI
36	Park HK, Lee HS, Ko JH, Hwang IT, Lim JS and Hwang JS: The effect of gonadotrophin-releasing hormone agonist treatment over 3 years on bone mineral density and body composition in girls with central precocious puberty. Clin Endocrinol (Oxf). 77:743–748. 2012. View Article : Google Scholar : PubMed/NCBI
37	Kim EY: Long-term effects of gonadotropin-releasing hormone analogs in girls with central precocious puberty. Korean J Pediatr. 58:1–7. 2015. View Article : Google Scholar : PubMed/NCBI
38	Theander-Carrillo C, Wiedmer P, Cettour-Rose P, Nogueiras R, Perez-Tilve D, Pfluger P, Castaneda TR, Muzzin P, Schürmann A, Szanto I, et al: Ghrelin action in the brain controls adipocyte metabolism. J Clin Invest. 116:1983–1993. 2006. View Article : Google Scholar : PubMed/NCBI
39	Pedersen SB, Børglum JD, Møller-Pedersen T and Richelsen B: Effects of in vivo estrogen treatment on adipose tissue metabolism and nuclear estrogen receptor binding in isolated rat adipocytes. Mol Cell Endocrinol. 85:13–19. 1992. View Article : Google Scholar : PubMed/NCBI
40	Homma H, Kurachi H, Nishio Y, Takeda T, Yamamoto T, Adachi K, Morishige K, Ohmichi M, Matsuzawa Y and Murata Y: Estrogen suppresses transcription of lipoprotein lipase gene. Existence of A unique estrogen response element on the lipoprotein lipase promoter. J Biol Chem. 275:11404–11411. 2009. View Article : Google Scholar
41	Pedersen SB, Børglum JD, Eriksen EF and Richelsen B: Nuclear estradiol binding in rat adipocytes. Regional variations and regulatory influences of hormones. Biochim Biophys Acta. 1093:80–86. 1991. View Article : Google Scholar : PubMed/NCBI
42	Skinner DC, Albertson AJ, Navratil A, Smith A, Mignot M, Talbott H and Scanlan-Blake N: GnRH effects outside the hypothalamo-pituitary-reproductive axis. J Neuroendocrinol. 21:282–292. 2009. View Article : Google Scholar : PubMed/NCBI