Effects of the β3 Adrenergic Receptor Agonist on Developmental Obesity in Oophorectomized Rats

Abstract

In this study, we evaluated the anti-obesity effects of selective β3 adrenergic receptor agonist (ARa) and/or a diet in oophorectomized (OVX) treatment in obese rats. Ten-week-old female Sprague-Dawley rats were divided into 4 groups: (1) OVX; (2) OVX treated with β3 ARa, BRL 35 135; (3) sham-operated controls (sham group); (4) sham-treated with β3 ARa (sham+ARa group). These four groups were divided into two groups, one on ad libitum diet, and the other on a diet of limited chow. The effects of β3 ARa on body weight, intraabdominal fat weight, adipocyte volume, serum lipid content, and serum leptin were measured after 4 weeks had been completed. On both the ad libitum and the limited diet, ARa significantly reduced the ratio of intraabdominal fat and body weight (IAF ratio) regardless whether in the OVX or sham group, although ARa had no influence on weight gain. On the ad libitum diet, the serum leptin was significantly increased after OVX, and significantly reduced after ARa administration. ARa significantly reduced the volume of intraabdominal adipocytes. We conclude that ARa reduces intraabdominal fat without reducing body weight in oophorectomized rats. The serum parameter affected differently to rats on the ad libitum diet and on the limited diet.

Estrogen - Diet - Lipolysis - Leptin - Adipocyte

References

• 1 Tarttelin M F, Gorski R A. The effects of ovarian steroids on food and water intake and body weight in the female rat.  Acta Endocrinol. 1973;  72 551-568
• 2 Roy E J, Wade G N. Role of food intake in estradiol-induced body weight changes in female rats.  Horm Behav. 1977;  8 265-274
• 3 Mook D G, Kenney N J, Roberts S, Nussbaum A I, Roider W I. Ovarian-adrenal interactions in regulating of body weight by female rats.  J Comp Physiol Psychol. 1972;  81 198-211
• 4 He G, Pedersen S B, Bruun J M, Richelsen B. Regulation of plasminogen activitor inhibitor-1 in human adipose tissue: interaction between cytokines, cortisol and estrogen.  Horm Metab Res. 2000;  32 515-520
• 5 McElroy J F, Wade G N. Short- and long-term effects of ovariectomy on food intake, body weight, carcass composition, and brown adipose tissue in rats.  Physiol Behav. 1987;  39 361-365
• 6 Minami T, Oomura Y, Nabekura J, Fukuda A. 17 beta-estradiol depolarization of hypothalamic neurons is mediated by cyclic AMP.  Brain Res. 1990;  519 301-307
• 7 Shimizu H, Bray G A. Effects of castration, estrogen replacement and estrus cycle on monoamine metabolism in the nucleus accumbens, measured by microdialysis.  Brain Res. 1993;  621 200-206
• 8 Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman J M. Positional cloning of the mouse obese gene and its human homologue.  Nature. 1994;  372 425-432
• 9 Halaas J L, Gajiwala K S, Maffei M, Cohen S L, Chait B T, Rabinowitz D, Lallone R L, Burley S K, Friedman J M. Weight-reducing effects of the plasma protein encoded by the obese gene.  Science. 1995;  269 543-546
• 10 Kolaczynski J W, Nyce M R, Considine R V, Boden G, Nolan J J, Henry R, Mudaliar S R, Olefsky J, Caro J F. Acute and chronic effects of insulin on leptin production in humans: Studies in vivo and in vitro.  Diabetes. 1996;  45 699-701
• 11 Wabitsch M, Jensen P B, Blum W F, Christoffersen C T, Englaro P, Heinze E, Rascher W, Teller W, Tornqvist H, Hauner H. Insulin and cortisol promote leptin production in cultured human fat cells.  Diabetes. 1996;  45 1435-1438
• 12 Havel P J, Kasim-Karakas S, Dubuc G R, Mueller W, Phinney S D. Gender differences in plasma leptin concentrations.  Nat Med. 1996;  2 949-950
• 13 Zimmet P, Hodge A, Nicolson M, Staten M, de Courten M, Moore J, Morawiecki A, Lubina J, Collier G, Alberti G, Dowse G. Serum leptin concentration, obesity, and insulin resistance in Western Samoans: Cross sectional study.  BMJ. 1996;  313 965-969
• 14 Hardie L, Trayhurn P, Abramovich D, Fowler P. Circulating leptin in women: a longitudinal study in the menstrual cycle and during pregnancy.  Clin Endocrinol. 1997;  47 101-106
• 15 Ghizzoni L, Barreca A, Mastorakos G, Furlini M, Vottero A, Ferrari B, Chrousos G P, Bernasconi S. Leptin inhibits steroid biosynthesis by human granulosa-lutein cells.  Horm Metab Res. 2001;  33 323-328
• 16 Shimizu H, Shimomura Y, Nakanishi Y, Futawatari T, Ohtani K, Sato N, Mori M. Estrogen increases in vivo leptin production in rats and human subjects.  J Endocrinol. 1997;  154 285-292
• 17 Arch J R, Ainsworth A T, Cawthorne M A, Piercy V, Sennitt M V, Thody V E, Wilson C, Wilson S. Atypical beta-adrenoceptor on brown adipocytes as target for anti-obesity drugs.  Nature. 1984;  309 163-165
• 18 Hollenga C, Zaagsma J. Direct evidence for the atypical nature of functional beta-adrenoceptors in rat adipocytes.  Br J Pharmacol. 1989;  98 1420-1424
• 19 Santti E, Huupponen R, Rouru J, Hanninen V, Pesonen U, Jhanwar-Uniyal M, Koulu M. Potentiation of the anti-obesity effect of the selective beta 3-adrenoceptor agonist BRL 35 135 in obese Zucker rats by exercise.  Br J Pharmacol. 1994;  113 1231-1236
• 20 Cawthorne M A, Sennitt M V, Arch J RS, Smith S A. BRL 35 135, a potent and selective atypical beta-adrenoceptor agonist.  Am J Clin Nutr. 1992;  55 252S-257S
• 21 Hashimoto K, Nagao Y, Ida K, Takeda M, Murakami N, Kato K, Mizota M. Improvement of metabolic disorders and visceral fat obesity by the beta 3-adrenoceptor agonist (R*,R*)-(+/-)-methyl-4-[2-[2-hydroxy-2-(3-chlorophenyl)ethylamino]propyl]-phenoxyacetate hydrobromide (BRL35135A) in genetically obese rodents.  Biochem Pharmacol. 1996;  52 1529-1535
• 22 Spayd R W, Bruschi B, Burdick B A, Dappen G M, Eikenberry J N, Esders T W, Figueras J, Goodhue C T, LaRossa D D, Nelson R W, Rand R N, Wu T W. Multilayer film elements for clinical analysis: Applications to representative chemical determinations.  Clin Chem. 1978;  24 1343-1350
• 23 Allain C C, Poon L S, Chan C S, Richmond W, Fu P C. Enzymatic determination of total serum cholesterol.  Clin Chem. 1974;  20 470-475
• 24 Shimizu S, Tani Y, Yamada H, Tabata M, Murachi T. Enzymatic determination of serum-free fatty acids: A colorimetric method.  Anal Biochem. 1980;  107 193-198
• 25 Berger J J, Barnard R J. Effect of diet on fat cell size and hormone-sensitive lipase activity.  J Appl Physiol. 1999;  87 227-232
• 26 Landau T, Zucker I. Estrogenic regulation of body weight in the female rat.  Horm Behav. 1976;  7 29-39
• 27 Ghorbani M, Himms-Hagen J. Treatment with CL 316,243, a beta 3-adrenoceptor agonist, reduces serum leptin in rats with diet- or aging-associated obesity, but not in Zucker rats with genetic (fa/fa) obesity.  Int J Obes Relat Metab Disord. 1998;  22 63-65
• 28 Berraondo B, Marti A, Duncan J S, Trayhurn P, Martinez J A. Up-regulation of muscle UCP2 gene expression by a new beta3-adrenoceptor agonist, trecadrine, in obese (cafeteria) rodents, but down-regulation in lean animals.  Int J Obes Relat Metab Disord. 2000;  24 156-163
• 29 Nicholls D G, Locke R M. Thermogenic mechanisms in brown fat.  Physiol Rev. 1984;  64 1-64
• 30 Pinilla L, Seoane L M, Gonzalez L, Carro E, Aguilar E, Casanueva F F, Dieguez C. Regulation of serum leptin levels by gonadal function in rats.  Eur J Endocrinol. 1999;  140 468-473
• 31 Vilà R, Adan C, Grasa M M, Masanes R M, Esteve M, Cabot C, Fernandez-Lopez J A, Remesar X, Alemany M. Effect of food deprivation on rat plasma estrone fatty acid esters.  Diabetes Obes Metab. 1999;  1 353-356