Estradiol Supplementation Helps Overcome Central Leptin Resistance of Ovariectomized Mice on a High Fat Diet

Abstract

Ovariectomized mice on a high fat diet represent a model of diet-induced obesity during estrogen deficiency. Here, we tested the hypothesis that sensitivity to centrally administered leptin in ovariectomized mice with diet-induced obesity could be restored by estrogen supplementation. Ovariectomized C57BL/6 female mice were fed either a standard or high fat diet until they were 27 weeks old. Ovariectomized mice on a high fat diet developed extreme obesity and hyperleptinemia and moderate hyperinsulinemia compared to those on a standard diet. For the last 4 weeks, 17β-estradiol-3-benzoate or its vehicle was administered subcutaneously in a 4-day cyclic regimen. Finally, leptin or saline was injected into the third ventricle, and food intake and body weight were measured for 36 h. In ovariectomized mice fed a standard diet, the decrease in food intake and body weight was significant and was pronounced in 17β-estradiol-3-benzoate-supplemented mice. The response to centrally injected leptin in ovariectomized mice on a high fat diet was insignificant, whereas in 17β-estradiol-3-benzoate-supplemented mice, the effect was significant, particularly with respect to body weight. We showed for the first time that central insensitivity to leptin in ovariectomized diet-induced obese mice was restored with 17β-estradiol-3-benzoate supplementation, which also attenuated most of the parameters of metabolic syndrome. Only circulating adiponectin, a peripheral insulin sensitivity marker, was lowered following 17β-estradiol-3-benzoate administration in both high fat and standard diet-fed ovariectomized mice, despite of decreased or unchanged glycemia, respectively.

Key words

leptin - estrogen deficiency - obesity - adipokines

References

• 1 Mayes JS, Watson GH. Direct effects of sex steroid hormones on adipose tissues and obesity.  Obes Rev. 2004;  5 197-216
• 2 Mistry AM, Swick AG, Romsos DR. Leptin rapidly lowers food intake and elevates metabolic rates in lean and ob/ob mice.  J Nutr. 1997;  127 2065-2072
• 3 Harris RBS, Mitchell TD, Yan X, Simpson JS, Redmann SM. Metabolic responses to leptin in obese db/db mice are strain dependent.  Am J Physiol Regul Integr Comp Physiol. 2001;  281 R115-R132
• 4 Morton GJ, Niswender KD, Rhodes CJ, Myers MG, Blevins JE, Baskin DG, Schwartz MW. Arcuate nucleus-specific leptin receptor gene therapy attenuates the obesity phenotype of Koletsky (fa/fa) rats.  Endocrinology. 2003;  144 2016-2024
• 5 Münzberg H, Flier JS, Bjorbaek C. Region-specific leptin resistance within the hypothalamus of diet-induced obese mice.  Endocrinology. 2004;  145 4880-4889
• 6 El-Haschimi K, Pierroz DD, Hileman SM, Bjorbaek C, Flier JS. Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity.  J Clin Invest. 2000;  105 1827-1832
• 7 Banks WA, Farrell CL. Impaired transport of leptin across the blood-brain barrier in obesity is acquired and reversible.  Am J Physiol. 2003;  285 E10-E15
• 8 Yu WH, Kimura M, Walczewska A, Karanth S, McCann SM. Role of leptin in hypothalamic-pituitary function.  Proc Natl Acad Sci USA. 1997;  94 1023-1028
• 9 Gonzalez LC, Pinilla L, Tena-Sempere M, Aguilar E. Leptin116-130 stimulates prolactin and luteinizing hormone secretion in fasted adult male rats.  Neuroendocrinology. 1999;  70 213-220
• 10 Asarian L, Geary N. Cyclic estradiol treatment normalizes body weight and restores physiological patterns of spontaneous feeding and sexual receptivity in ovariectomized rats.  Horm Behav. 2002;  42 461-471
• 11 Asarian L, Geary N. Modulation of appetite by gonadal steroid hormones.  Philos Trans R Soc Lond B Biol Sci. 2006;  361 1251-1263
• 12 Clegg DJ, Brown LM, Woods SC, Benoit SC. Gonadal hormones determine sensitivity to central leptin and insulin.  Diabetes. 2006;  55 978-987
• 13 Gao Q, Horvath TL. Cross-talk between estrogen and leptin signaling in the hypothalamus.  Am J Physiol Endocrinol Metab. 2008;  294 E817-E826
• 14 Matyšková R, Maletínská L, Maixnerová J, Pirník Z, Kiss A, Železná B. Comparison of the obesity phenotypes related to monosodium glutamate effect on arcuate nucleus and/or the high fat diet feeding in C57Bl/6 and NMRI mice.  Physiol Res. 2008;  57 727-734
• 15 Kopecký J, Hodný Z, Rossmeisl M, Syrový I, Kozak LP. Reduction of dietary obesity in aP2-Ucp transgenic mice: physiology and adipose tissue distribution.  Am J Physiol. 1996;  270 E768-E775
• 16 Geary N, Asarian L, Korach KS, Pfaff DW, Ogawa S. Deficits in E2-dependent control of feeding, weight gain, and cholecystokinin satiation in ER-α null mice.  Endocrinology. 2001;  142 4751-4757
• 17 Maletínská L, Maixnerová J, Matyšková R, Haugvicová R, loncová E, Elbert T, Slaninová J, Železná B. Cocaine- and amphetamine-regulated transcript (CART) peptide specific binding in pheochromocytoma cells PC12.  Eur J Pharmacol. 2007;  559 109-114
• 18 Lin S, Thomas TC, Storlien LH, Huang XF. Development of high fat diet-induced obesity and leptin resistance in C57Bl/6J mice.  Int J Obes. 2000;  24 639-646
• 19 West DB, Waguespack J, McCollister S. Dietary obesity in the mouse: interaction of strain with diet composition.  Am J Physiol. 1995;  268 R658-R665
• 20 Kimura M, Irahara M, Yasui T, Saito S, Tezuka M, Yamano S, Kamada M, Aono T. The obesity in bilateral ovariectomized rats is related to a decrease in the expression of leptin receptors in the brain.  Biochem Biophys Res Commun. 2002;  290 1349-1353
• 21 Paquette A, Chapados NA, Bergeron R, Lavoie JM. Fatty acid oxidation is decreased in the liver of ovariectomized rats.  Horm Metab Res. 2009;  41 511-515
• 22 Gao Q, Mezei G, Nie Y, Rao Y, Choi CS, Bechmann I, Leranth C, Toran-Allerand D, Priest CA, Roberts JL, Gao XB, Mobbs C, Shulman GI, Diano S, Horvath TL. Anorectic estrogen mimics leptin's effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals.  Nat Med. 2007;  13 89-94
• 23 Buettner R, Parhofer KG, Woenckhaus M, Wrede CE, Kunz-Schughart LA, Schölmerich J, Bollheimer LC. Defining high-fat-diet rat models: metabolic and molecular effects of different fat types.  J Mol Endocrinol. 2006;  36 485-501
• 24 Bryzgalova G, Lundholm L, Portwood N, Gustafsson J-A, Khan A, Efendic S, Dahlman-Wright K. Mechanism of antidiabetogenic and body weight-lowering effects of estrogen in high-fat diet-fed mice.  Am J Physiol Endocrinol Metab. 2008;  295 E904-E912
• 25 Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA. The hormone resistin links obesity to diabetes.  Nature. 2001;  409 307-312
• 26 Steppan CM, Lazar MA. Resistin and obesity-associated insulin resistance.  Trends in Endocrinol Metab. 2002;  13 18-23
• 27 Lay SL, Boucher J, Rey A, Castan-Laurell I, Krief S, Ferré P, Valet P, Dugail I. Decreased resistin expression in mice with different sensitivities to a high-fat diet.  Biochem Biophys Res Commun. 2001;  289 564-567
• 28 Juan CC, Au LC, Fang VS, Kang SF, Ko YH, Kuo SF, Hsu YP, Kwok CF, Ho LT. Suppressed gene expression of adipocyte resistin in an insulin-resistant rat model probably by elevated free fatty acids.  Biochem Biophys Res Commun. 2001;  289 1328-1333
• 29 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
• 30 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
• 31 Combs TP, Berg AH, Rajala MW, Klebanov S, Iyengar P, Jimenez-Chillaron JC, Patti ME, Klein SL, Weinstein RS. Sexual differentiation, pregnancy, calorie restriction, and aging affect the adipocyte-specific secretory protein adiponectin.  Diabetes. 2003;  52 268-276
• 32 Caja S, Puerta M. Control by reproduction-related hormones of resistin expression and plasma concentration.  Horm Metab Res. 2007;  39 501-506

Notice: The text was changed in accordance with the erratum by January 21th, 2010. In Table 1 of the original article the values for triglycerides (mg/dl) are incorrect. The correct values are: 58.2, 66.1, 70.7 and 68.8 mg/dl

Correspondence