Physiology

Ovarian estradiol supports sexual behavior but not energy homeostasis in female marmoset monkeys

Abstract

Objective

In adult female rodents, ovarian estradiol (E2) regulates body weight, adiposity, energy balance, physical activity, glucose-insulin homeodynamics, and lipid metabolism, while protecting against diet-induced obesity. The same E2 actions are presumed to occur in primates, but confirmatory studies have been lacking.

Methods

We investigated the consequences of ovariectomy (OVX) and E2 replacement in female marmoset monkeys on major metabolic and morphometric endpoints. Sexual behavior and uterine diameters were assessed as positive controls for E2 treatment efficacy. Metabolic parameters were measured 1 mo prior to OVX, and 3 and 6 mo thereafter. During OVX, animals received empty or E2-containing silastic s.c. implants. To test the interaction between E2 and diet, both treatment groups were assigned to either a higher fat diet (HFD) or a low-fat diet (LFD).

Results

As anticipated, OVX animals exhibited diminished frequency (p = 0.04) of sexually receptive behavior and increased rejection behavior (p = 0.04) toward their male partners compared with E2-treated OVX females. OVX also decreased (p = 0.01) uterine diameter. There were no treatment effects on total caloric intake. There were no significant effects of OVX, E2 treatment, or diet on body weight, body composition, energy expenditure, physical activity, fasting glucose, or glucose tolerance. Regardless of E2 treatment, serum triglycerides were higher (p = 0.05) in HFD than LFD females. Postmortem qPCR analysis of hypothalamic tissues revealed higher mRNA expression (p < 0.001) for PGR in E2-treated monkeys versus OVX controls regardless of diet, but no differences between groups in other selected metabolic genes. In contrast, regardless of E2 treatment, there was a decreased mRNA expression of PGC1α (PPARGC1A), HTR1A, and HTR5A in HFD compared with LFD females.

Conclusions

Our findings, overall, document a greatly diminished role for ovarian E2 in the metabolic physiology of a female primate, and encourage consideration that primates, including humans, evolved metabolic control systems regulated by extra-ovarian E2 or are generally less subject to E2 regulation.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. 1.

    Wade GN, Gray JM. Gonadal effects on food intake and adiposity: a metabolic hypothesis. Physiol Behav. 1979;22:583–93.

  2. 2.

    Riant E, Waget A, Cogo H, Arnal JF, Burcelin R, Gourdy P. Estrogens protect against high-fat diet-induced insulin resistance and glucose intolerance in mice. Endocrinology. 2009;150:2109–17.

  3. 3.

    Yonezawa R, Wada T, Matsumoto N, Morita M, Sawakawa K, Ishii Y, et al. Central versus peripheral impact of estradiol on the impaired glucose metabolism in ovariectomized mice on a high-fat diet. Am J Physiol Endocrinol Metab. 2012;303:E445–56.

  4. 4.

    Hong J, Stubbins RE, Smith RR, Harvey AE, Nunez NP. Differential susceptibility to obesity between male, female and ovariectomized female mice. Nutr J. 2009;8:11.

  5. 5.

    Ludgero-Correia A Jr, Aguila MB, Mandarim-de-Lacerda CA, Faria TS. Effects of high-fat diet on plasma lipids, adiposity, and inflammatory markers in ovariectomized C57BL/6 mice. Nutrition. 2012;28:316–23.

  6. 6.

    Heine PA, Taylor JA, Iwamoto GA, Lubahn DB, Cooke PS. Increased adipose tissue in male and female estrogen receptor-alpha knockout mice. Proc Natl Acad Sci USA. 2000;97:12729–34.

  7. 7.

    Bryzgalova G, Gao H, Ahren B, Zierath JR, Galuska D, Steiler TL, et al. Evidence that oestrogen receptor-alpha plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver. Diabetologia. 2006;49:588–97.

  8. 8.

    Ogawa S, Chan J, Gustafsson JA, Korach KS, Pfaff DW. Estrogen increases locomotor activity in mice through estrogen receptor alpha: specificity for the type of activity. Endocrinology. 2003;144:230–9.

  9. 9.

    Xu Y, Nedungadi TP, Zhu L, Sobhani N, Irani BG, Davis KE, et al. Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction. Cell Metab. 2011;14:453–65.

  10. 10.

    Park CJ, Zhao Z, Glidewell-Kenney C, Lazic M, Chambon P, Krust A, et al. Genetic rescue of nonclassical ERalpha signaling normalizes energy balance in obese Eralpha-null mutant mice. J Clin Invest. 2011;121:604–12.

  11. 11.

    Musatov S, Chen W, Pfaff DW, Mobbs CV, Yang XJ, Clegg DJ, et al. Silencing of estrogen receptor alpha in the ventromedial nucleus of hypothalamus leads to metabolic syndrome. Proc Natl Acad Sci USA. 2007;104:2501–6.

  12. 12.

    Saito K, He Y, Yang Y, Zhu L, Wang C, Xu P, et al. PI3K in the ventromedial hypothalamic nucleus mediates estrogenic actions on energy expenditure in female mice. Sci Rep. 2016;6:23459.

  13. 13.

    Titolo D, Cai F, Belsham DD. Coordinate regulation of neuropeptide Y and agouti-related peptide gene expression by estrogen depends on the ratio of estrogen receptor (ER) alpha to ERbeta in clonal hypothalamic neurons. Mol Endocrinol. 2006;20:2080–92.

  14. 14.

    Lam DD, Garfield AS, Marston OJ, Shaw J, Heisler LK. Brain serotonin system in the coordination of food intake and body weight. Pharmacol Biochem Behav. 2010;97:84–91.

  15. 15.

    Bethea CL, Reddy AP, Flowers M, Shapiro RA, Colman RJ, Abbott DH, et al. High fat diet decreases beneficial effects of estrogen on serotonin-related gene expression in marmosets. Prog Neuropsychopharmacol Biol Psychiatry. 2015;58:71–80.

  16. 16.

    Clegg D, Hevener AL, Moreau KL, Morselli E, Criollo A, Van Pelt RE, et al. Sex hormones and cardiometabolic health: role of estrogen and estrogen receptors. Endocrinology. 2017;158:1095–105.

  17. 17.

    Al-Safi ZA, Polotsky AJ. Obesity and menopause. Best Pract Res Clin Obstet Gynaecol. 2015;29:548–53.

  18. 18.

    Davis SR, Castelo-Branco C, Chedraui P, Lumsden MA, Nappi RE, Shah D, et al. Understanding weight gain at menopause. Climacteric. 2012;15:419–29.

  19. 19.

    Ley CJ, Lees B, Stevenson JC. Sex- and menopause-associated changes in body-fat distribution. Am J Clin Nutr. 1992;55:950–4.

  20. 20.

    Genazzani AR, Gambacciani M. Effect of climacteric transition and hormone replacement therapy on body weight and body fat distribution. Gynecol Endocrinol. 2006;22:145–50.

  21. 21.

    Lovejoy JC, Champagne CM, de Jonge L, Xie H, Smith SR. Increased visceral fat and decreased energy expenditure during the menopausal transition. Int J Obes (Lond). 2008;32:949–58.

  22. 22.

    Wegorzewska IN, Walters K, Weiser MJ, Cruthirds DF, Ewell E, Larco DO, et al. Postovariectomy weight gain in female rats is reversed by estrogen receptor alpha agonist, propylpyrazoletriol. Am J Obstet Gynecol. 2008;199:67 e1–5.

  23. 23.

    Gambacciani M, Ciaponi M, Cappagli B, Genazzani AR. Effects of low-dose continuous combined conjugated estrogens and medroxyprogesterone acetate on menopausal symptoms, body weight, bone density, and metabolism in postmenopausal women. Am J Obstet Gynecol. 2001;185:1180–5.

  24. 24.

    Lahmann PH, Lissner L, Gullberg B, Berglund G. Sociodemographic factors associated with long-term weight gain, current body fatness and central adiposity in Swedish women. Int J Obes Relat Metab Disord. 2000;24:685–94.

  25. 25.

    Salpeter SR, Walsh JM, Ormiston TM, Greyber E, Buckley NS, Salpeter EE. Meta-analysis: effect of hormone-replacement therapy on components of the metabolic syndrome in postmenopausal women. Diabetes Obes Metab. 2006;8:538–54.

  26. 26.

    Chmouliovsky L, Habicht F, James RW, Lehmann T, Campana A, Golay A. Beneficial effect of hormone replacement therapy on weight loss in obese menopausal women. Maturitas. 1999;32:147–53.

  27. 27.

    dos Reis CM, de Melo NR, Meirelles ES, Vezozzo DP, Halpern A. Body composition, visceral fat distribution and fat oxidation in postmenopausal women using oral or transdermal oestrogen. Maturitas. 2003;46:59–68.

  28. 28.

    O’Sullivan AJ, Hoffman DM, Ho KK. Estrogen, lipid oxidation, and body fat. N Engl J Med. 1995;333:669–70.

  29. 29.

    Duncan AC, Lyall H, Roberts RN, Petrie JR, Perera MJ, Monaghan S, et al. The effect of estradiol and a combined estradiol/progestagen preparation on insulin sensitivity in healthy postmenopausal women. J Clin Endocrinol Metab. 1999;84:2402–7.

  30. 30.

    Mattiasson I, Rendell M, Tornquist C, Jeppsson S, Hulthen UL. Effects of estrogen replacement therapy on abdominal fat compartments as related to glucose and lipid metabolism in early postmenopausal women. Horm Metab Res. 2002;34:583–8.

  31. 31.

    Sites CK, L’Hommedieu GD, Toth MJ, Brochu M, Cooper BC, Fairhurst PA. The effect of hormone replacement therapy on body composition, body fat distribution, and insulin sensitivity in menopausal women: a randomized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab. 2005;90:2701–7.

  32. 32.

    Sullivan EL, Daniels AJ, Koegler FH, Cameron JL. Evidence in female rhesus monkeys (Macaca mulatta) that nighttime caloric intake is not associated with weight gain. Obes Res. 2005;13:2072–80.

  33. 33.

    Sandoval-Guzman T, Stalcup ST, Krajewski SJ, Voytko ML, Rance NE. Effects of ovariectomy on the neuroendocrine axes regulating reproduction and energy balance in young cynomolgus macaques. J Neuroendocrinol. 2004;16:146–53.

  34. 34.

    Wagner JD, Clarkson TB, St Clair RW, Schwenke DC, Shively CA, Adams MR. Estrogen and progesterone replacement therapy reduces low density lipoprotein accumulation in the coronary arteries of surgically postmenopausal cynomolgus monkeys. J Clin Invest. 1991;88:1995–2002.

  35. 35.

    Sullivan EL, Shearin J, Koegler FH, Cameron JL. Selective estrogen receptor modulator promotes weight loss in ovariectomized female rhesus monkeys (Macaca mulatta) by decreasing food intake and increasing activity. Am J Physiol Endocrinol Metab. 2012;302:E759–67.

  36. 36.

    Cefalu WT, Wagner JD, Bell-Farrow AD, Wang ZQ, Adams MR, Toffolo G, et al. The effects of hormonal replacement therapy on insulin sensitivity in surgically postmenopausal cynomolgus monkeys (Macaca fascicularis). Am J Obstet Gynecol. 1994;171:440–5.

  37. 37.

    Tardif SD, Power ML, Ross CN, Rutherford JN, Layne-Colon DG, Paulik MA. Characterization of obese phenotypes in a small nonhuman primate, the common marmoset (Callithrix jacchus). Obesity (Silver Spring). 2009;17:1499–505.

  38. 38.

    Wachtman LM, Kramer JA, Miller AD, Hachey AM, Curran EH, Mansfield KG. Differential contribution of dietary fat and monosaccharide to metabolic syndrome in the common marmoset (Callithrix jacchus). Obes (Silver Spring). 2011;19:1145–56.

  39. 39.

    Abbott DH, Barnett DK, Colman RJ, Yamamoto ME, Schultz-Darken NJ. Aspects of common marmoset basic biology and life history important for biomedical research. Comp Med. 2003;53:339–50.

  40. 40.

    Lemos DR, Downs JL, Raitiere MN, Urbanski HF. Photoperiodic modulation of adrenal gland function in the rhesus macaque: effect on 24-h plasma cortisol and dehydroepiandrosterone sulfate rhythms and adrenal gland gene expression. J Endocrinol. 2009;201:275–85.

  41. 41.

    Schneider JE. Guest editor’s introduction: energy homeostasis in context. Horm Behav. 2014;66:1–6.

  42. 42.

    Kendrick KM, Dixson AF. Effects of oestradiol 17B, progesterone and testosterone upon proceptivity and receptivity in ovariectomized common marmosets (Callithrix jacchus). Physiol Behav. 1985;34:123–8.

  43. 43.

    Kraynak M, Flowers MT, Shapiro RA, Kapoor A, Levine JE, Abbott DH. Extraovarian gonadotropin negative feedback revealed by aromatase inhibition in female marmoset monkeys. Am J Physiol Endocrinol Metab. 2017;313:E507–E14.

  44. 44.

    Gacad MA, Chen H, Arbelle JE, LeBon T, Adams JS. Functional characterization and purification of an intracellular vitamin D-binding protein in vitamin D-resistant new world primate cells. Amino acid sequence homology with proteins in the hsp-70 family. J Biol Chem. 1997;272:8433–40.

  45. 45.

    Chen H, Hewison M, Hu B, Sharma M, Sun Z, Adams JS. An Hsp27-related, dominant-negative-acting intracellular estradiol-binding protein. J Biol Chem. 2004;279:29944–51.

  46. 46.

    Abbott DH, Saltzman W, Schultz-Darken NJ, Tannenbaum PL. Adaptations to subordinate status in female marmoset monkeys. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol. 1998;119:261–74.

  47. 47.

    Chery I, Zahariev A, Simon C, Blanc S. Analytical aspects of measuring (2)H/(1)H and (18)O/(16)O ratios in urine from doubly labelled water studies by high-temperature conversion elemental analyser-isotope-ratio mass spectrometry. Rapid Commun Mass Spectrom. 2015;29:562–72.

  48. 48.

    Schoeller DA, Leitch CA, Brown C. Doubly labeled water method: in vivo oxygen and hydrogen isotope fractionation. Am J Physiol. 1986;251(6 Pt 2):R1137–43.

  49. 49.

    Ye J, Coulouris G, Zaretskaya I, Cutcutache I, Rozen S, Madden TL. Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction. BMC Bioinforma. 2012;13:134.

  50. 50.

    Tardif SD, Richter CB. Competition for a desired food in family groups of the common marmoset (Callithrix jacchus) and the cotton-top tamarin (Saguinus oedipus). Lab Anim Sci. 1981;31:52–5.

  51. 51.

    Brand JS, van der Schouw YT, Onland-Moret NC, Sharp SJ, Ong KK, Khaw KT, et al. Age at menopause, reproductive life span, and type 2 diabetes risk: results from the EPIC-InterAct study. Diabetes Care. 2013;36:1012–9.

  52. 52.

    Witte MM, Resuehr D, Chandler AR, Mehle AK, Overton JM. Female mice and rats exhibit species-specific metabolic and behavioral responses to ovariectomy. Gen Comp Endocrinol. 2010;166:520–8.

  53. 53.

    Liang H, Ward WF. PGC-1alpha: a key regulator of energy metabolism. Adv Physiol Educ. 2006;30:145–51.

  54. 54.

    Morselli E, Fuente-Martin E, Finan B, Kim M, Frank A, Garcia-Caceres C, et al. Hypothalamic PGC-1alpha protects against high-fat diet exposure by regulating ERalpha. Cell Rep. 2014;9:633–45.

  55. 55.

    Garfield AS, Heisler LK. Pharmacological targeting of the serotonergic system for the treatment of obesity. J Physiol. 2009;587:49–60.

  56. 56.

    Sa SI, Fonseca BM. Dynamics of progesterone and estrogen receptor alpha in the ventromedial hypothalamus. J Endocrinol. 2017;233:197–207.

  57. 57.

    Bethea CL, Mueller K, Reddy AP, Kohama SG, Urbanski HF. Effects of obesogenic diet and estradiol on dorsal raphe gene expression in old female macaques. PLOS ONE. 2017;12:e0178788.

  58. 58.

    Abbott DH, Hodges JK, George LM. Social status controls LH secretion and ovulation in female marmoset monkeys (Callithrix jacchus). J Endocrinol. 1988;117:329–39.

  59. 59.

    Masarachia PJ, Pennypacker BL, Pickarski M, Scott KR, Wesolowski GA, Smith SY, et al. Odanacatib reduces bone turnover and increases bone mass in the lumbar spine of skeletally mature ovariectomized rhesus monkeys. J Bone Miner Res. 2012;27:509–23.

  60. 60.

    Saltzman W, Digby LJ, Abbott DH. Reproductive skew in female common marmosets: what can proximate mechanisms tell us about ultimate causes? Proc Biol Sci. 2009;276:389–99.

  61. 61.

    DiSilvestro D, Petrosino J, Aldoori A, Melgar-Bermudez E, Wells A, Ziouzenkova O. Enzymatic intracrine regulation of white adipose tissue. Horm Mol Biol Clin Investig. 2014;19:39–55.

  62. 62.

    Guerriero KA, Keen KL, Millar RP, Terasawa E. Developmental changes in GnRH release in response to kisspeptin agonist and antagonist in female rhesus monkeys (Macaca mulatta): implication for the mechanism of puberty. Endocrinology. 2012;153:825–36.

  63. 63.

    Blaustein JD, Gentry RT, Roy EJ, Wade GN. Effects of ovariectomy and estradiol on body weight and food intake in gold thioglucose-treated mice. Physiol Behav. 1976;17:1027–30.

  64. 64.

    Odermatt A. The Western-style diet: a major risk factor for impaired kidney function and chronic kidney disease. Am J Physiol Ren Physiol. 2011;301:F919–31.

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Jon E. Levine.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kraynak, M., Colman, R.J., Flowers, M.T. et al. Ovarian estradiol supports sexual behavior but not energy homeostasis in female marmoset monkeys. Int J Obes 43, 1034–1045 (2019). https://doi.org/10.1038/s41366-018-0156-4

Download citation