Estradiol Regulation of Brown Adipose Tissue Thermogenesis

Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1043)

Abstract

Physiologically, estrogens carry out a myriad of functions, the most essential being the regulation of the reproductive axis. Currently, it is also dogmatic that estrogens play an important role modulating energy balance and metabolism. In this sense, it is well known that low estrogens levels, occurring due to ovarian insufficiency, in conditions such as menopause or ovariectomy (OVX), are associated with increased food intake and decreased energy expenditure, leading to weight gain and obesity at long term. Concerning energy expenditure, the main effect of estradiol (E2) is on brown adipose tissue (BAT) thermogenesis. Thus, acting through a peripheral or a central action, E2 activates brown fat activity and increases body temperature, which is negatively associated with body weight. Centrally, the hypothalamic AMP-activated protein kinase (AMPK) mediates the E2 action on BAT thermogenesis. In this chapter, we will summarize E2 regulation of BAT thermogenesis and how this can influence energy balance and metabolism in general.

Keywords

Brown adipose tissue Energy expenditure Estradiol Hypothalamus Obesity 

Notes

Acknowledgments

The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement n° 281854 – the ObERStress European Research Council project (ML), Xunta de Galicia (ML: 2015-CP079 and 2016-PG068), Junta de Andalucía (MTS: P08-CVI-03788 and P12-FQM-01943), MINECO co-funded by the FEDER Program of EU (ML: SAF2015-71026-R and BFU2015-70454-REDT/Adipoplast; MTS: BFU2011-25021 and BFU2014-58571-P), and ISCIII (MTS: PIE2014-005). CIBER de Fisiopatología de la Obesidad y Nutrición is an initiative of ISCIII. IG-G is a recipient of a fellowship from MINECO (FPU12/01827).

References

  1. Allison, M. B., & Myers, M. G., Jr. (2014). 20 years of leptin: Connecting leptin signaling to biological function. The Journal of Endocrinology, 223(1), T25–T35.CrossRefPubMedCentralPubMedGoogle Scholar
  2. Anand, B. K., & Brobeck, J. R. (1951). Localization of a “feeding center” in the hypothalamus of the rat. Proceedings of the Society for Experimental Biology and Medicine, 77(2), 323–324.CrossRefPubMedGoogle Scholar
  3. Bartness, T. J., & Wade, G. N. (1984). Effects of interscapular brown adipose tissue denervation on body weight and energy metabolism in ovariectomized and estradiol-treated rats. Behavioral Neuroscience, 98(4), 674–685.CrossRefPubMedGoogle Scholar
  4. Beiroa, D., Imbernon, M., Gallego, R., Senra, A., Herranz, D., Villaroya, F., Serrano, M., Ferno, J., Salvador, J., Escalada, J., Dieguez, C., Lopez, M., Fruhbeck, G., & Nogueiras, R. (2014). GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK. Diabetes, 63(10), 3346–3358.CrossRefPubMedGoogle Scholar
  5. Bellefontaine, N., & Elias, C. F. (2014). Minireview: Metabolic control of the reproductive physiology: Insights from genetic mouse models. Hormones and Behavior, 66(1), 7–14.CrossRefPubMedCentralPubMedGoogle Scholar
  6. Beyer, C., & Gonzalez-Mariscal, G. (1986). Elevation in hypothalamic cyclic AMP as a common factor in the facilitation of lordosis in rodents: A working hypothesis. Annals of the New York Academy of Sciences, 474, 270–281.CrossRefPubMedGoogle Scholar
  7. Bianco, A. C., Sheng, X. Y., & Silva, J. E. (1988). Triiodothyronine amplifies norepinephrine stimulation of uncoupling protein gene transcription by a mechanism not requiring protein synthesis. The Journal of Biological Chemistry, 263(34), 18168–18175.PubMedGoogle Scholar
  8. Blaustein, J. D., & Wade, G. N. (1976). Ovarian influences on the meal patterns of female rats. Physiology & Behavior, 17(2), 201–208.CrossRefGoogle Scholar
  9. Boyer, P. D. (1997). The ATP synthase – a splendid molecular machine. Annual Review of Biochemistry, 66, 717–749.CrossRefPubMedGoogle Scholar
  10. Caminos, J. E., Nogueiras, R., Gallego, R., Bravo, S., Tovar, S., Garcia-Caballero, T., Casanueva, F. F., & Dieguez, C. (2005). Expression and regulation of adiponectin and receptor in human and rat placenta. Journal of Clinical Endocrinology and Metabolism, 90(7), 4276–4286.CrossRefPubMedGoogle Scholar
  11. Cani, P. D., Plovier, H., Van, H. M., Geurts, L., Delzenne, N. M., Druart, C., & Everard, A. (2016). Endocannabinoids – at the crossroads between the gut microbiota and host metabolism. Nature Reviews Endocrinology, 12(3), 133–143.CrossRefPubMedGoogle Scholar
  12. Cannon, B., & Nedergaard, J. (2004). Brown adipose tissue: Function and physiological significance. Physiological Reviews, 84(1), 277–359.CrossRefPubMedGoogle Scholar
  13. Cao, X., Xu, P., Oyola, M. G., Xia, Y., Yan, X., Saito, K., Zou, F., Wang, C., Yang, Y., Hinton, A., Jr., Yan, C., Ding, H., Zhu, L., Yu, L., Yang, B., Feng, Y., Clegg, D. J., Khan, S., DiMarchi, R., Mani, S. K., Tong, Q., & Xu, Y. (2014). Estrogens stimulate serotonin neurons to inhibit binge-like eating in mice. The Journal of Clinical Investigation, 124(10), 4351–4362.CrossRefPubMedCentralPubMedGoogle Scholar
  14. Carling, D., Mayer, F. V., Sanders, M. J., & Gamblin, S. J. (2011). AMP-activated protein kinase: Nature’s energy sensor. Nature Chemical Biology, 7(8), 512–518.CrossRefPubMedGoogle Scholar
  15. Carr, M. C. (2003). The emergence of the metabolic syndrome with menopause. Journal of Clinical Endocrinology and Metabolism, 88(6), 2404–2411.CrossRefPubMedGoogle Scholar
  16. Castillo, M., Hall, J. A., Correa-Medina, M., Ueta, C., Kang, H. W., Cohen, D. E., & Bianco, A. C. (2011). Disruption of thyroid hormone activation in type 2 deiodinase knockout mice causes obesity with glucose intolerance and liver steatosis only at thermoneutrality. Diabetes, 60(4), 1082–1089.CrossRefPubMedCentralPubMedGoogle Scholar
  17. Chevalier, C., Stojanovic, O., Colin, D. J., Suarez-Zamorano, N., Tarallo, V., Veyrat-Durebex, C., Rigo, D., Fabbiano, S., Stevanovic, A., Hagemann, S., Montet, X., Seimbille, Y., Zamboni, N., Hapfelmeier, S., & Trajkovski, M. (2015). Gut microbiota orchestrates energy homeostasis during cold. Cell, 163(6), 1360–1374.CrossRefPubMedGoogle Scholar
  18. Christoffolete, M. A., Linardi, C. C., De, J. L., Ebina, K. N., Carvalho, S. D., Ribeiro, M. O., Rabelo, R., Curcio, C., Martins, L., Kimura, E. T., & Bianco, A. C. (2004). Mice with targeted disruption of the Dio2 gene have cold-induced overexpression of the uncoupling protein 1 gene but fail to increase brown adipose tissue lipogenesis and adaptive thermogenesis. Diabetes, 53(3), 577–584.CrossRefPubMedGoogle Scholar
  19. Clemmensen, C., Muller, T. D., Finan, B., Tschop, M. H., & DiMarchi, R. (2016). Current and emerging treatment options in diabetes care. Handbook of Experimental Pharmacology, 233, 437–459.CrossRefPubMedGoogle Scholar
  20. Contreras, C., González, F., Ferno, J., Diéguez, C., Rahmouni, K., Nogueiras, R., & López, M. (2015). The brain and brown fat. Annals of Medicine, 47(2), 150–168.CrossRefPubMedGoogle Scholar
  21. Contreras, C., Nogueiras, R., Dieguez, C., Medina-Gomez, G., & Lopez, M. (2016). Hypothalamus and thermogenesis: Heating the BAT, browning the WAT. Molecular and Cellular Endocrinology, 438, 107–115.CrossRefPubMedGoogle Scholar
  22. Cooke, P. S., Heine, P. A., Taylor, J. A., & Lubahn, D. B. (2001). The role of estrogen and estrogen receptor-alpha in male adipose tissue. Molecular and Cellular Endocrinology, 178(1–2), 147–154.CrossRefPubMedGoogle Scholar
  23. Cornejo, M. P., Hentges, S. T., Maliqueo, M., Coirini, H., Becu-Villalobos, D., & Elias, C. F. (2016). Neuroendocrine regulation of metabolism. Journal of Neuroendocrinology, 28(7), 1–12.Google Scholar
  24. Correa, S. M., Newstrom, D. W., Warne, J. P., Flandin, P., Cheung, C. C., Lin-Moore, A. T., Pierce, A. A., Xu, A. W., Rubenstein, J. L., & Ingraham, H. A. (2015). An estrogen-responsive module in the ventromedial hypothalamus selectively drives sex-specific activity in females. Cell Reports, 10(1), 62–74.CrossRefPubMedGoogle Scholar
  25. Cypess, A. M., Lehman, S., Williams, G., Tal, I., Rodman, D., Goldfine, A. B., Kuo, F. C., Palmer, E. L., Tseng, Y. H., Doria, A., Kolodny, G. M., & Kahn, C. R. (2009). Identification and importance of brown adipose tissue in adult humans. The New England Journal of Medicine, 360(15), 1509–1517.CrossRefPubMedCentralPubMedGoogle Scholar
  26. Davis, K. E., Neinast, D., Sun, K., Skiles, M., Bills, D., Zehr, A., Zeve, D., Hahner, D., Cox, W., Gent, M., Xu, Y., Wang, V., Khan, A., & Clegg, D. J. (2013). The sexually dimorphic role of adipose and adipocyte estrogen receptors in modulating adipose tissue expansion, inflammation, and fibrosis. Molecular Metabolism, 2(3), 227–242.CrossRefPubMedCentralPubMedGoogle Scholar
  27. Davis, K. E., Carstens, E. J., Irani, B. G., Gent, L. M., Hahner, L. M., & Clegg, D. J. (2014). Sexually dimorphic role of G protein-coupled estrogen receptor (GPER) in modulating energy homeostasis. Hormones and Behavior, 66(1), 196–207.CrossRefPubMedCentralPubMedGoogle Scholar
  28. Dietrich, M. O., & Horvath, T. L. (2012a). A marriage made to last in drug design. Nature Medicine, 18(12), 1737–1738.CrossRefPubMedGoogle Scholar
  29. Dietrich, M. O., & Horvath, T. L. (2012b). Limitations in anti-obesity drug development: The critical role of hunger-promoting neurons. Nature Reviews Drug Discovery, 11(9), 675–691.CrossRefPubMedGoogle Scholar
  30. Dong, M., Yang, X., Lim, S., Cao, Z., Honek, J., Lu, H., Zhang, C., Seki, T., Hosaka, K., Wahlberg, E., Yang, J., Zhang, L., Lanne, T., Sun, B., Li, X., Liu, Y., Zhang, Y., & Cao, Y. (2013). Cold exposure promotes atherosclerotic plaque growth and instability via UCP1-dependent lipolysis. Cell Metabolism, 18(1), 118–129.CrossRefPubMedCentralPubMedGoogle Scholar
  31. Edens, N. K., & Wade, G. N. (1983). Effects of estradiol on tissue distribution of newly-synthesized fatty acids in rats and hamsters. Physiology & Behavior, 31(5), 703–709.CrossRefGoogle Scholar
  32. Feldman, D. (1978). Evidence that brown adipose tissue is a glucocorticoid target organ. Endocrinology, 103(6), 2091–2097.CrossRefPubMedGoogle Scholar
  33. Finan, B., Yang, B., Ottaway, N., Stemmer, K., Muller, T. D., Yi, C. X., Habegger, K., Schriever, S. C., Garcia-Caceres, C., Kabra, D. G., Hembree, J., Holland, J., Raver, C., Seeley, R. J., Hans, W., Irmler, M., Beckers, J., De, M. H., Angelis, J. P., Tiano, F. M.-J., Perez-Tilve, D., Pfluger, P., Zhang, L., Gelfanov, V., DiMarchi, R. D., & Tschop, M. H. (2012). Targeted estrogen delivery reverses the metabolic syndrome. Nature Medicine, 18(12), 1847–1856.CrossRefPubMedCentralPubMedGoogle Scholar
  34. Frank, A., Brown, L. M., & Clegg, D. J. (2014). The role of hypothalamic estrogen receptors in metabolic regulation. Frontiers in Neuroendocrinology, 35(4), 550–557.CrossRefPubMedCentralPubMedGoogle Scholar
  35. Frias, J. P., Macaraeg, G. B., Ofrecio, J., Yu, J. G., Olefsky, J. M., & Kruszynska, Y. T. (2001). Decreased susceptibility to fatty acid-induced peripheral tissue insulin resistance in women. Diabetes, 50(6), 1344–1350.CrossRefPubMedGoogle Scholar
  36. Futai, M., Noumi, T., & Maeda, M. (1989). ATP synthase (H+−ATPase): Results by combined biochemical and molecular biological approaches. Annual Review of Biochemistry, 58, 111–136.CrossRefPubMedGoogle Scholar
  37. Gao, Q., & Horvath, T. L. (2008). Cross-talk between estrogen and leptin signaling in the hypothalamus. American Journal of Physiology Endocrinology and Metabolism, 294(5), E817–E826.CrossRefPubMedGoogle Scholar
  38. Gao, H., Bryzgalova, G., Hedman, E., Khan, A., Efendic, S., Gustafsson, J. A., & Dahlman-Wright, K. (2006). Long-term administration of estradiol decreases expression of hepatic lipogenic genes and improves insulin sensitivity in ob/ob mice: A possible mechanism is through direct regulation of signal transducer and activator of transcription 3. Molecular Endocrinology, 20(6), 1287–1299.CrossRefPubMedGoogle Scholar
  39. Gao, Q., Mezei, G., Nie, Y., Rao, Y., Choi, C. S., Bechmann, I., Leranth, C., Toran-Allerand, D., Priest, C. A., Roberts, J. L., Gao, X. B., Mobbs, C., Shulman, G. I., Diano, S., & Horvath, T. L. (2007). Anorectic estrogen mimics leptin’s effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals. Nature Medicine, 13(1), 89–94.CrossRefPubMedGoogle Scholar
  40. Garcia, M. C., Lopez, M., Gualillo, O., Seoane, L. M., Dieguez, C., & Senaris, R. M. (2003). Hypothalamic levels of NPY, MCH, and prepro-orexin mRNA during pregnancy and lactation in the rat: Role of prolactin. The FASEB Journal, 17(11), 1392–1400.CrossRefPubMedGoogle Scholar
  41. Gautron, L., Elmquist, J. K., & Williams, K. W. (2015). Neural control of energy balance: Translating circuits to therapies. Cell, 161(1), 133–145.CrossRefPubMedCentralPubMedGoogle Scholar
  42. Geary, N., Asarian, L., Korach, K. S., Pfaff, D. W., & Ogawa, S. (2001). Deficits in E2-dependent control of feeding, weight gain, and cholecystokinin satiation in ER-alpha null mice. Endocrinology, 142(11), 4751–4757.CrossRefPubMedGoogle Scholar
  43. Gonzalez, C. R., Novelle, M. G., Caminos, J. E., Vazquez, M. J., Luque, R. M., Lopez, M., Nogueiras, R., & Dieguez, C. (2012). Regulation of lipin1 by nutritional status, adiponectin, sex and pituitary function in rat white adipose tissue. Physiology & Behavior, 105(3), 777–783.CrossRefGoogle Scholar
  44. Grumbach, M. M., & Auchus, R. J. (1999). Estrogen: Consequences and implications of human mutations in synthesis and action. Journal of Clinical Endocrinology and Metabolism, 84(12), 4677–4694.PubMedGoogle Scholar
  45. Guerra, C., Navarro, P., Valverde, A. M., Arribas, M., Bruning, J., Kozak, L. P., Kahn, C. R., & Benito, M. (2001). Brown adipose tissue-specific insulin receptor knockout shows diabetic phenotype without insulin resistance. The Journal of Clinical Investigation, 108(8), 1205–1213.CrossRefPubMedCentralPubMedGoogle Scholar
  46. Hardie, D. G., Ross, F. A., & Hawley, S. A. (2012). AMPK: A nutrient and energy sensor that maintains energy homeostasis. Nature Reviews Molecular Cell Biology, 13(4), 251–262.CrossRefPubMedCentralPubMedGoogle Scholar
  47. Heine, P. A., Taylor, J. A., Iwamoto, G. A., Lubahn, D. B., & Cooke, P. S. (2000). Increased adipose tissue in male and female estrogen receptor-alpha knockout mice. Proceedings of the National Academy of Sciences of the United States of America, 97(23), 12729–12734.CrossRefPubMedCentralPubMedGoogle Scholar
  48. Hetherington, A. W., & Ranson, S. W. (1942). The spontaneous activity and food intake of rats with hypothalamic lesions. American Journal of Physiology, 136, 609–617.Google Scholar
  49. Hevener, A., Reichart, D., Janez, A., & Olefsky, J. (2002). Female rats do not exhibit free fatty acid-induced insulin resistance. Diabetes, 51(6), 1907–1912.CrossRefPubMedGoogle Scholar
  50. Hewitt, K. N., Pratis, K., Jones, M. E., & Simpson, E. R. (2004). Estrogen replacement reverses the hepatic steatosis phenotype in the male aromatase knockout mouse. Endocrinology, 145(4), 1842–1848.CrossRefPubMedGoogle Scholar
  51. Hondares, E., Rosell, M., Gonzalez, F. J., Giralt, M., Iglesias, R., & Villarroya, F. (2010). Hepatic FGF21 expression is induced at birth via PPARalpha in response to milk intake and contributes to thermogenic activation of neonatal brown fat. Cell Metabolism, 11(3), 206–212.CrossRefPubMedCentralPubMedGoogle Scholar
  52. Hu, E., Liang, P., & Spiegelman, B. M. (1996). AdipoQ is a novel adipose-specific gene dysregulated in obesity. The Journal of Biological Chemistry, 271(18), 10697–10703.CrossRefPubMedGoogle Scholar
  53. Iverius, P. H., & Brunzell, J. D. (1988). Relationship between lipoprotein lipase activity and plasma sex steroid level in obese women. Journal of Clinical Investigation, 82(3), 1106–1112.CrossRefPubMedCentralPubMedGoogle Scholar
  54. Jespersen, N. Z., Larsen, T. J., Peijs, L., Daugaard, S., Homoe, P., Loft, A., de Jong, J., Mathur, N., Cannon, B., Nedergaard, J., Pedersen, B. K., Moller, K., & Scheele, C. (2013). A classical brown adipose tissue mRNA signature partly overlaps with brite in the supraclavicular region of adult humans. Cell Metabolism, 17(5), 798–805.CrossRefPubMedGoogle Scholar
  55. de Jesus, L. A., Carvalho, S. D., Ribeiro, M. O., Schneider, M., Kim, S. W., Harney, J. W., Larsen, P. R., & Bianco, A. C. (2001). The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue. The Journal of Clinical Investigation, 108(9), 1379–1385.CrossRefPubMedCentralPubMedGoogle Scholar
  56. Jones, M. E., Thorburn, A. W., Britt, K. L., Hewitt, K. N., Wreford, N. G., Proietto, J., Oz, O. K., Leury, B. J., Robertson, K. M., Yao, S., & Simpson, E. R. (2000). Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity. Proceedings of the National Academy of Sciences of the United States of America, 97(23), 12735–12740.CrossRefPubMedCentralPubMedGoogle Scholar
  57. Jones, M. E., Thorburn, A. W., Britt, K. L., Hewitt, K. N., Misso, M. L., Wreford, N. G., Proietto, J., Oz, O. K., Leury, B. J., Robertson, K. M., Yao, S., & Simpson, E. R. (2001). Aromatase-deficient (ArKO) mice accumulate excess adipose tissue. The Journal of Steroid Biochemistry and Molecular Biology, 79(1–5), 3–9.CrossRefPubMedGoogle Scholar
  58. Kamei, Y., Suzuki, M., Miyazaki, H., Tsuboyama-Kasaoka, N., Wu, J., Ishimi, Y., & Ezaki, O. (2005). Ovariectomy in mice decreases lipid metabolism-related gene expression in adipose tissue and skeletal muscle with increased body fat. Journal of Nutritional Science and Vitaminology (Tokyo), 51(2), 110–117.CrossRefGoogle Scholar
  59. Key, T. J., Allen, N. E., Verkasalo, P. K., & Banks, E. (2001). Energy balance and cancer: The role of sex hormones. Proceedings of the Nutrition Society, 60(1), 81–89.CrossRefPubMedGoogle Scholar
  60. Kharitonenkov, A., Shiyanova, T. L., Koester, A., Ford, A. M., Micanovic, R., Galbreath, E. J., Sandusky, G. E., Hammond, L. J., Moyers, J. S., Owens, R. A., Gromada, J., Brozinick, J. T., Hawkins, E. D., Wroblewski, V. J., Li, D. S., Mehrbod, F., Jaskunas, S. R., & Shanafelt, A. B. (2005). FGF-21 as a novel metabolic regulator. The Journal of Clinical Investigation, 115(6), 1627–1635.CrossRefPubMedCentralPubMedGoogle Scholar
  61. Kim, M., Neinast, M. D., Frank, A. P., Sun, K., Park, J., Zehr, J. A., Vishvanath, L., Morselli, E., Amelotte, M., Palmer, B. F., Gupta, R. K., Scherer, P. E., & Clegg, D. J. (2014a). ERalpha upregulates Phd3 to ameliorate HIF-1 induced fibrosis and inflammation in adipose tissue. Molecular Metabolism, 3(6), 642–651.CrossRefPubMedCentralPubMedGoogle Scholar
  62. Kim, J. H., Meyers, M. S., Khuder, S. S., Abdallah, S. L., Muturi, H. T., Russo, L., Tate, C. R., Hevener, A. L., Najjar, S. M., Leloup, C., & Mauvais-Jarvis, F. (2014b). Tissue-selective estrogen complexes with bazedoxifene prevent metabolic dysfunction in female mice. Molecular Metabolism, 3(2), 177–190.CrossRefPubMedCentralPubMedGoogle Scholar
  63. Kim, S. N., Jung, Y. S., Kwon, H. J., Seong, J. K., Granneman, J. G., & Lee, Y. H. (2016). Sex differences in sympathetic innervation and browning of white adipose tissue of mice. Biology of Sex Differences, 7, 67.CrossRefPubMedCentralPubMedGoogle Scholar
  64. Lage, R., Diéguez, C., Vidal-Puig, A., & López, M. (2008). AMPK: A metabolic gauge regulating whole-body energy homeostasis. Trends in Molecular Medicine, 14(12), 539–549.CrossRefPubMedGoogle Scholar
  65. Lage, R., Vázquez, M. J., Varela, L., Saha, A. K., Vidal-Puig, A., Nogueiras, R., Diéguez, C., & López, M. (2010). Ghrelin effects on neuropeptides in the rat hypothalamus depend on fatty acid metabolism actions on BSX but not on gender. The FASEB Journal, 24(8), 2670–2679.CrossRefPubMedCentralPubMedGoogle Scholar
  66. Lapid, K., Lim, A., Clegg, D. J., Zeve, D., & Graff, J. M. (2014). Oestrogen signalling in white adipose progenitor cells inhibits differentiation into brown adipose and smooth muscle cells. Nature Communications, 5, 5196.CrossRefPubMedCentralPubMedGoogle Scholar
  67. López, M., & Tena-Sempere, M. (2015). Estrogens and the control of energy homeostasis: A brain perspective. Trends in Endocrinology and Metabolism, 26(8), 411–421.CrossRefPubMedGoogle Scholar
  68. López, M., Tovar, S., Vázquez, M. J., Williams, L. M., & Diéguez, C. (2007). Peripheral tissue-brain interactions in the regulation of food intake. Proceedings of the Nutrition Society, 66(1), 131–155.CrossRefPubMedGoogle Scholar
  69. Lopez, M., Lage, R., Saha, A. K., Perez-Tilve, D., Vazquez, M. J., Varela, L., Sangiao-Alvarellos, S., Tovar, S., Raghay, K., Rodriguez-Cuenca, S., Deoliveira, R. M., Castaneda, T., Datta, R., Dong, J. Z., Culler, M., Sleeman, M. W., Alvarez, C. V., Gallego, R., Lelliott, C. J., Carling, D., Tschop, M. H., Dieguez, C., & Vidal-Puig, A. (2008). Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin. Cell Metabolism, 7, 389–399.CrossRefPubMedGoogle Scholar
  70. Lopez, M., Varela, L., Vazquez, M. J., Rodriguez-Cuenca, S., Gonzalez, C. R., Velagapudi, V. R., Morgan, D. A., Schoenmakers, E., Agassandian, K., Lage, R., Martinez de Morentin, P. B., Tovar, S., Nogueiras, R., Carling, D., Lelliott, C., Gallego, R., Oresic, M., Chatterjee, K., Saha, A. K., Rahmouni, K., Dieguez, C., & Vidal-Puig, A. (2010). Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nature Medicine, 16(9), 1001–1008.CrossRefPubMedCentralPubMedGoogle Scholar
  71. López, M., Alvarez, C. V., Nogueiras, R., & Diéguez, C. (2013). Energy balance regulation by thyroid hormones at central level. Trends in Molecular Medicine, 19(7), 418–427.CrossRefPubMedGoogle Scholar
  72. Lopez, M., Nogueiras, R., Tena-Sempere, M., & Dieguez, C. (2016). Hypothalamic AMPK: A canonical regulator of whole-body energy balance. Nature Reviews Endocrinology, 12(7), 421–432.CrossRefPubMedGoogle Scholar
  73. López, M., Nogueiras, R., Tena-Sempere, M., & Dieguez, C. (2016). Hypothalamic AMPK: A canonical regulator of whole-body energy balance. Nature Reviews Endocrinology, 12(7), 421–432.CrossRefPubMedGoogle Scholar
  74. Lovejoy, J. C., & Sainsbury, A. (2009). Sex differences in obesity and the regulation of energy homeostasis. Obesity Reviews, 10(2), 154–167.CrossRefPubMedGoogle Scholar
  75. Marken Lichtenbelt, W. D., Vanhommerig, J. W., Smulders, N. M., Drossaerts, J. M., Kemerink, G. J., Bouvy, N. D., Schrauwen, P., & Teule, G. J. (2009). Cold-activated brown adipose tissue in healthy men. The New England Journal of Medicine, 360(15), 1500–1508.CrossRefPubMedGoogle Scholar
  76. Martinez de Morentin, P. B., Whittle, A. J., Ferno, J., Nogueiras, R., Dieguez, C., Vidal-Puig, A., & Lopez, M. (2012). Nicotine induces negative energy balance through hypothalamic AMP-activated protein kinase. Diabetes, 61(4), 807–817.CrossRefPubMedCentralPubMedGoogle Scholar
  77. Martinez de Morentin, P. B., Gonzalez-Garcia, I., Martins, L., Lage, R., Fernandez-Mallo, D., Martinez-Sanchez, N., Ruiz-Pino, F., Liu, J., Morgan, D. A., Pinilla, L., Gallego, R., Saha, A. K., Kalsbeek, A., Fliers, E., Bisschop, P. H., Dieguez, C., Nogueiras, R., Rahmouni, K., Tena-Sempere, M., & Lopez, M. (2014). Estradiol regulates brown adipose tissue thermogenesis via hypothalamic AMPK. Cell Metabolism, 20(1), 41–53.CrossRefPubMedCentralPubMedGoogle Scholar
  78. Martinez de Morentin, P. B., Lage, R., Gonzalez-Garcia, I., Ruiz-Pino, F., Martins, L., Fernandez-Mallo, D., Gallego, R., Ferno, J., Senaris, R., Saha, A. K., Tovar, S., Dieguez, C., Nogueiras, R., Tena-Sempere, M., & Lopez, M. (2015). Pregnancy induces resistance to the anorectic effect of hypothalamic malonyl-CoA and the thermogenic effect of hypothalamic AMPK inhibition in female rats. Endocrinology, 156(3), 947–960.CrossRefPubMedGoogle Scholar
  79. Martinez De, M. R., Scanlan, T. S., & Obregon, M. J. (2010). The T3 receptor beta1 isoform regulates UCP1 and D2 deiodinase in rat brown adipocytes. Endocrinology, 151(10), 5074–5083.CrossRefGoogle Scholar
  80. Martinez-Sanchez, N., Alvarez, C. V., Ferno, J., Nogueiras, R., Dieguez, C., & Lopez, M. (2014). Hypothalamic effects of thyroid hormones on metabolism. Best Practice & Research Clinical Endocrinology & Metabolism, 28(5), 703–712.CrossRefGoogle Scholar
  81. Mauvais-Jarvis, F., Clegg, D. J., & Hevener, A. L. (2013). The role of estrogens in control of energy balance and glucose homeostasis. Endocrine Reviews, 34(3), 309–338.CrossRefPubMedCentralPubMedGoogle Scholar
  82. Merchenthaler, I., Lane, M. V., Numan, S., & Dellovade, T. L. (2004). Distribution of estrogen receptor alpha and beta in the mouse central nervous system: In vivo autoradiographic and immunocytochemical analyses. The Journal of Comparative Neurology, 473(2), 270–291.CrossRefPubMedGoogle Scholar
  83. Miao, Y. F., Su, W., Dai, Y. B., Wu, W. F., Huang, B., Barros, R. P., Nguyen, H., Maneix, L., Guan, Y. F., Warner, M., & Gustafsson, J. A. (2016). An ERbeta agonist induces browning of subcutaneous abdominal fat pad in obese female mice. Science Reporter, 6, 38579.CrossRefGoogle Scholar
  84. Minami, T., Oomura, Y., Nabekura, J., & Fukuda, A. (1990). 17 beta-estradiol depolarization of hypothalamic neurons is mediated by cyclic AMP. Brain Research, 519(1–2), 301–307.CrossRefPubMedGoogle Scholar
  85. Monjo, M., Rodriguez, A. M., Palou, A., & Roca, P. (2003). Direct effects of testosterone, 17 beta-estradiol, and progesterone on adrenergic regulation in cultured brown adipocytes: Potential mechanism for gender-dependent thermogenesis. Endocrinology, 144(11), 4923–4930.CrossRefPubMedGoogle Scholar
  86. Morrison, S. F., Madden, C. J., & Tupone, D. (2012). Central control of brown adipose tissue thermogenesis. Frontiers in Endocrinology (Lausanne), 3(5).Google Scholar
  87. Morrison, S. F., Madden, C. J., & Tupone, D. (2014). Central neural regulation of brown adipose tissue thermogenesis and energy expenditure. Cell Metabolism, 19(5), 741–756.CrossRefPubMedCentralPubMedGoogle Scholar
  88. Moss, R. L., & Dudley, C. A. (1984). Molecular aspects of the interaction between estrogen and the membrane excitability of hypothalamic nerve cells. Progress in Brain Research, 61, 3–22.CrossRefPubMedGoogle Scholar
  89. Musatov, S., Chen, W., Pfaff, D. W., Mobbs, C. V., Yang, X. J., Clegg, D. J., Kaplitt, M. G., & Ogawa, S. (2007). Silencing of estrogen receptor alpha in the ventromedial nucleus of hypothalamus leads to metabolic syndrome. Proceedings of the National Academy of Sciences of the United States of America, 104(7), 2501–2506.CrossRefPubMedCentralPubMedGoogle Scholar
  90. Mystkowski, P., Seeley, R. J., Hahn, T. M., Baskin, D. G., Havel, P. J., Matsumoto, A. M., Wilkinson, C. W., Peacock-Kinzig, K., Blake, K. A., & Schwartz, M. W. (2000). Hypothalamic melanin-concentrating hormone and estrogen-induced weight loss. The Journal of Neuroscience, 20(22), 8637–8642.PubMedGoogle Scholar
  91. Nedergaard, J., & Cannon, B. (2014). The browning of white adipose tissue: Some burning issues. Cell Metabolism, 20(3), 396–407.CrossRefPubMedGoogle Scholar
  92. Nedergaard, J., Bengtsson, T., & Cannon, B. (2007). Unexpected evidence for active brown adipose tissue in adult humans. American Journal of Physiology Endocrinology and Metabolism, 293(2), E444–E452.CrossRefPubMedGoogle Scholar
  93. Nicholls, D. G., & Locke, R. M. (1984). Thermogenic mechanisms in brown fat. Physiological Reviews, 64(1), 1–64.CrossRefPubMedGoogle Scholar
  94. Ohlsson, C., Hellberg, N., Parini, P., Vidal, O., Bohlooly, M., Rudling, M., Lindberg, M. K., Warner, M., Angelin, B., & Gustafsson, J. A. (2000). Obesity and disturbed lipoprotein profile in estrogen receptor-alpha-deficient male mice. Biochemical and Biophysical Research Communications, 278(3), 640–645.CrossRefPubMedGoogle Scholar
  95. Ortega-Molina, A., Efeyan, A., Lopez-Guadamillas, E., Munoz-Martin, M., Gomez-Lopez, G., Canamero, M., Mulero, F., Pastor, J., Martinez, S., Romanos, E., Mar Gonzalez-Barroso, M., Rial, E., Valverde, A. M., Bischoff, J. R., & Serrano, M. (2012). Pten positively regulates brown adipose function, energy expenditure, and longevity. Cell Metabolism, 15(3), 382–394.CrossRefPubMedGoogle Scholar
  96. Ortega-Molina, A., Lopez-Guadamillas, E., Mattison, J. A., Mitchell, S. J., Munoz-Martin, M., Iglesias, G., Gutierrez, V. M., Vaughan, K. L., Szarowicz, M. D., Gonzalez-Garcia, I., Lopez, M., Cebrian, D., Martinez, S., Pastor, J., De, C. R., & Serrano, M. (2015). Pharmacological inhibition of PI3K reduces adiposity and metabolic syndrome in obese mice and rhesus monkeys. Cell Metabolism, 21(4), 558–570.CrossRefPubMedCentralPubMedGoogle Scholar
  97. Osterlund, M., Kuiper, G. G., Gustafsson, J. A., & Hurd, Y. L. (1998). Differential distribution and regulation of estrogen receptor-alpha and -beta mRNA within the female rat brain. Brain Research Molecular Brain Research, 54(1), 175–180.CrossRefPubMedGoogle Scholar
  98. Palmer, B. F., & Clegg, D. J. (2015). The sexual dimorphism of obesity. Molecular and Cellular Endocrinology, 402, 113–119.CrossRefPubMedGoogle Scholar
  99. Pelletier, G., Li, S., Luu-The, V., & Labrie, F. (2007). Oestrogenic regulation of pro-opiomelanocortin, neuropeptide Y and corticotrophin-releasing hormone mRNAs in mouse hypothalamus. Journal of Neuroendocrinology, 19(6), 426–431.CrossRefPubMedGoogle Scholar
  100. Perkins, M. N., Rothwell, N. J., Stock, M. J., & Stone, T. W. (1981). Activation of brown adipose tissue thermogenesis by the ventromedial hypothalamus. Nature, 289(5796), 401–402.CrossRefPubMedGoogle Scholar
  101. Pfaff, D. W., & McEwen, B. S. (1983). Actions of estrogens and progestins on nerve cells. Science, 219(4586), 808–814.CrossRefPubMedGoogle Scholar
  102. Pfaff, D. W., Vasudevan, N., Kia, H. K., Zhu, Y. S., Chan, J., Garey, J., Morgan, M., & Ogawa, S. (2000). Estrogens, brain and behavior: Studies in fundamental neurobiology and observations related to women’s health. The Journal of Steroid Biochemistry and Molecular Biology, 74(5), 365–373.CrossRefPubMedGoogle Scholar
  103. Qiao, L., Yoo, H., Bosco, C., Lee, B., Feng, G. S., Schaack, J., Chi, N. W., & Shao, J. (2014). Adiponectin reduces thermogenesis by inhibiting brown adipose tissue activation in mice. Diabetologia, 57(5), 1027–1036.CrossRefPubMedCentralPubMedGoogle Scholar
  104. Ribeiro, M. O., Lebrun, F. L., Christoffolete, M. A., Branco, M., Crescenzi, A., Carvalho, S. D., Negrao, N., & Bianco, A. C. (2000). Evidence of UCP1-independent regulation of norepinephrine-induced thermogenesis in brown fat. American Journal of Physiology Endocrinology and Metabolism, 279(2), E314–E322.CrossRefPubMedGoogle Scholar
  105. Ribeiro, M. O., Bianco, S. D., Kaneshige, M., Schultz, J. J., Cheng, S. Y., Bianco, A. C., & Brent, G. A. (2010). Expression of uncoupling protein 1 in mouse brown adipose tissue is thyroid hormone receptor-beta isoform specific and required for adaptive thermogenesis. Endocrinology, 151(1), 432–440.CrossRefPubMedGoogle Scholar
  106. Richard, D. (1986). Effects of ovarian hormones on energy balance and brown adipose tissue thermogenesis. The American Journal of Physiology, 250(2), R245–R249.CrossRefPubMedGoogle Scholar
  107. Richard, D., Monge-Roffarello, B., Chechi, K., Labbe, S. M., & Turcotte, E. E. (2012). Control and physiological determinants of sympathetically mediated brown adipose tissue thermogenesis. Frontiers in Endocrinology (Lausanne), 3, 36.Google Scholar
  108. Rodriguez, A. M., Monjo, M., Roca, P., & Palou, A. (2002). Opposite actions of testosterone and progesterone on UCP1 mRNA expression in cultured brown adipocytes. Cellular and Molecular Life Sciences, 59(10), 1714–1723.CrossRefPubMedGoogle Scholar
  109. Rodriguez-Cuenca, S., Monjo, M., Gianotti, M., Proenza, A. M., & Roca, P. (2007a). Expression of mitochondrial biogenesis-signaling factors in brown adipocytes is influenced specifically by 17beta-estradiol, testosterone, and progesterone. American Journal of Physiology Endocrinology and Metabolism, 292(1), E340–E346.CrossRefPubMedGoogle Scholar
  110. Rodriguez-Cuenca, S., Monjo, M., Frontera, M., Gianotti, M., Proenza, A. M., & Roca, P. (2007b). Sex steroid receptor expression profile in brown adipose tissue. Effects of hormonal status. Cellular Physiology and Biochemistry, 20(6), 877–886.CrossRefPubMedGoogle Scholar
  111. Roesch, D. M. (2006). Effects of selective estrogen receptor agonists on food intake and body weight gain in rats. Physiology & Behavior, 87(1), 39–44.CrossRefGoogle Scholar
  112. Rogers, N. H., Perfield, J. W., Strissel, K. J., Obin, M. S., & Greenberg, A. S. (2009a). Reduced energy expenditure and increased inflammation are early events in the development of ovariectomy-induced obesity. Endocrinology, 150(5), 2161–2168.CrossRefPubMedCentralPubMedGoogle Scholar
  113. Rogers, N. H., Witczak, C. A., Hirshman, M. F., Goodyear, L. J., & Greenberg, A. S. (2009b). Estradiol stimulates Akt, AMP-activated protein kinase (AMPK) and TBC1D1/4, but not glucose uptake in rat soleus. Biochemical and Biophysical Research Communications, 4, 646–650.CrossRefGoogle Scholar
  114. Santollo, J., Wiley, M. D., & Eckel, L. A. (2007). Acute activation of ER alpha decreases food intake, meal size, and body weight in ovariectomized rats. American Journal of Physiology Regulatory, Integrative and Comparative Physiology, 293(6), R2194–R2201.CrossRefPubMedGoogle Scholar
  115. Schneeberger, M., & Claret, M. (2012). Recent insights into the role of hypothalamic AMPK signaling cascade upon metabolic control. Frontiers in Neuroscience, 6, 185.CrossRefPubMedCentralPubMedGoogle Scholar
  116. Schneeberger, M., Gomis, R., & Claret, M. (2014). Hypothalamic and brainstem neuronal circuits controlling homeostatic energy balance. The Journal of Endocrinology, 220(2), T25–T46.CrossRefPubMedGoogle Scholar
  117. Schneider, J. E., Palmer, L. A., & Wade, G. N. (1986). Effects of estrous cycles and ovarian steroids on body weight and energy expenditure in Syrian hamsters. Physiology & Behavior, 38(1), 119–126.CrossRefGoogle Scholar
  118. Scott, R., Tan, T., & Bloom, S. (2013). Gut hormones and obesity: Physiology and therapies. Vitamins and Hormones, 91, 143–194.CrossRefPubMedGoogle Scholar
  119. Scott, M. M., Xu, Y., Elias, C. F., & Williams, K. W. (2014). Central regulation of food intake, body weight, energy expenditure, and glucose homeostasis. Frontiers in Neuroscience, 8, 384.CrossRefPubMedCentralPubMedGoogle Scholar
  120. Seoane-Collazo, P., Martinez de Morentin, P. B., Ferno, J., Dieguez, C., Nogueiras, R., & Lopez, M. (2014). Nicotine improves obesity and hepatic steatosis and ER stress in diet-induced obese male rats. Endocrinology, 155(5), 1679–1689.CrossRefPubMedGoogle Scholar
  121. Shimizu, H., Arima, H., Watanabe, M., Goto, M., Banno, R., Sato, I., Ozaki, N., Nagasaki, H., & Oiso, Y. (2008). Glucocorticoids increase neuropeptide Y and agouti-related peptide gene expression via AMP-activated protein kinase signaling in the arcuate nucleus of rats. Endocrinology, 149(9), 4544–4553.CrossRefPubMedGoogle Scholar
  122. Silva, J. E. (2006). Thermogenic mechanisms and their hormonal regulation. Physiological Reviews, 86(2), 435–464.CrossRefPubMedGoogle Scholar
  123. Simerly, R. B., Chang, C., Muramatsu, M., & Swanson, L. W. (1990). Distribution of androgen and estrogen receptor mRNA-containing cells in the rat brain: An in situ hybridization study. The Journal of Comparative Neurology, 294(1), 76–95.CrossRefPubMedGoogle Scholar
  124. Simonian, S. X., & Herbison, A. E. (1997). Differential expression of estrogen receptor alpha and beta immunoreactivity by oxytocin neurons of rat paraventricular nucleus. Journal of Neuroendocrinology, 9(11), 803–806.CrossRefPubMedGoogle Scholar
  125. Sohn, J. W., Elmquist, J. K., & Williams, K. W. (2013). Neuronal circuits that regulate feeding behavior and metabolism. Trends in Neurosciences, 36(9), 504–512.CrossRefPubMedCentralPubMedGoogle Scholar
  126. Soumano, K., Desbiens, S., Rabelo, R., Bakopanos, E., Camirand, A., & Silva, J. E. (2000). Glucocorticoids inhibit the transcriptional response of the uncoupling protein-1 gene to adrenergic stimulation in a brown adipose cell line. Molecular and Cellular Endocrinology, 165(1–2), 7–15.CrossRefPubMedGoogle Scholar
  127. Storlien, L. H., James, D. E., Burleigh, K. M., Chisholm, D. J., & Kraegen, E. W. (1986). Fat feeding causes widespread in vivo insulin resistance, decreased energy expenditure, and obesity in rats. The American Journal of Physiology, 251(5), E576–E583.PubMedGoogle Scholar
  128. Stubbins, R. E., Holcomb, V. B., Hong, J., & Nunez, N. P. (2012). Estrogen modulates abdominal adiposity and protects female mice from obesity and impaired glucose tolerance. European Journal of Nutrition, 51(7), 861–870.CrossRefPubMedGoogle Scholar
  129. Suarez-Zamorano, N., Fabbiano, S., Chevalier, C., Stojanovic, O., Colin, D. J., Stevanovic, A., Veyrat-Durebex, C., Tarallo, V., Rigo, D., Germain, S., Ilievska, M., Montet, X., Seimbille, Y., Hapfelmeier, S., & Trajkovski, M. (2015). Microbiota depletion promotes browning of white adipose tissue and reduces obesity. Nature Medicine, 21(12), 1497–1501.CrossRefPubMedCentralPubMedGoogle Scholar
  130. Tanida, M., Yamamoto, N., Shibamoto, T., & Rahmouni, K. (2013). Involvement of hypothalamic AMP-activated protein kinase in leptin-induced sympathetic nerve activation. PLoS One, 8(2), e56660.CrossRefPubMedCentralPubMedGoogle Scholar
  131. Tiano, J. P., & Mauvais-Jarvis, F. (2012). Importance of oestrogen receptors to preserve functional beta-cell mass in diabetes. Nature Reviews Endocrinology, 8(6), 342–351.CrossRefPubMedGoogle Scholar
  132. Tritos, N. A., Segal-Lieberman, G., Vezeridis, P. S., & Maratos-Flier, E. (2004). Estradiol-induced anorexia is independent of leptin and melanin-concentrating hormone. Obesity Research, 12(4), 716–724.CrossRefPubMedGoogle Scholar
  133. Tschop, M. H., Finan, B., Clemmensen, C., Gelfanov, V., Perez-Tilve, D., Muller, T. D., & DiMarchi, R. D. (2016). Unimolecular polypharmacy for treatment of diabetes and obesity. Cell Metabolism, 24(1), 51–62.CrossRefPubMedGoogle Scholar
  134. Van Den Beukel, J. C., Grefhorst, A., Hoogduijn, M. J., Steenbergen, J., Mastroberardino, P. G., Dor, F. J., & Themmen, A. P. (2015). Women have more potential to induce browning of perirenal adipose tissue than men. Obesity (Silver Spring), 23(8), 1671–1679.CrossRefGoogle Scholar
  135. Velickovic, K., Cvoro, A., Srdic, B., Stokic, E., Markelic, M., Golic, I., Otasevic, V., Stancic, A., Jankovic, A., Vucetic, M., Buzadzic, B., Korac, B., & Korac, A. (2014). Expression and subcellular localization of estrogen receptors alpha and beta in human fetal brown adipose tissue. The Journal of Clinical Endocrinology and Metabolism, 99(1), 151–159.CrossRefPubMedGoogle Scholar
  136. Viengchareun, S., Penfornis, P., Zennaro, M. C., & Lombes, M. (2001). Mineralocorticoid and glucocorticoid receptors inhibit UCP expression and function in brown adipocytes. American Journal of Physiology Endocrinology and Metabolism, 280(4), E640–E649.CrossRefPubMedGoogle Scholar
  137. Virtanen, K. A., Lidell, M. E., Orava, J., Heglind, M., Westergren, R., Niemi, T., Taittonen, M., Laine, J., Savisto, N. J., Enerback, S., & Nuutila, P. (2009). Functional brown adipose tissue in healthy adults. The New England Journal of Medicine, 360(15), 1518–1525.CrossRefPubMedGoogle Scholar
  138. Voisin, D. L., Simonian, S. X., & Herbison, A. E. (1997). Identification of estrogen receptor-containing neurons projecting to the rat supraoptic nucleus. Neuroscience, 78(1), 215–228.CrossRefPubMedGoogle Scholar
  139. Von, B. C., Wiedenmann, A., & Dimroth, P. (2009). Essentials for ATP synthesis by F1F0 ATP synthases. Annual Review of Biochemistry, 78, 649–672.CrossRefGoogle Scholar
  140. Wade, G. N., & Gray, J. M. (1978). Cytoplasmic 17 beta-[3H]estradiol binding in rat adipose tissues. Endocrinology, 103(5), 1695–1701.CrossRefPubMedGoogle Scholar
  141. Whittle, A. J., Lopez, M., & Vidal-Puig, A. (2011). Using brown adipose tissue to treat obesity – the central issue. Trends in Molecular Medicine, 17(8), 405–411.CrossRefPubMedGoogle Scholar
  142. Whittle, A. J., Carobbio, S., Martins, L., Slawik, M., Hondares, E., Vazquez, M. J., Morgan, D., Csikasz, R. I., Gallego, R., Rodriguez-Cuenca, S., Dale, M., Virtue, S., Villarroya, F., Cannon, B., Rahmouni, K., Lopez, M., & Vidal-Puig, A. (2012). BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions. Cell, 149(4), 871–885.CrossRefPubMedCentralPubMedGoogle Scholar
  143. Wren, B. G. (2009). The benefits of oestrogen following menopause: Why hormone replacement therapy should be offered to postmenopausal women. The Medical Journal of Australia, 190(6), 321–325.PubMedGoogle Scholar
  144. Wu, J., Bostrom, P., Sparks, L. M., Ye, L., Choi, J. H., Giang, A. H., Khandekar, M., Virtanen, K. A., Nuutila, P., Schaart, G., Huang, K., Tu, H., van Marken Lichtenbelt, W. D., Hoeks, J., Enerback, S., Schrauwen, P., & Spiegelman, B. M. (2012). Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell, 150(2), 366–376.CrossRefPubMedCentralPubMedGoogle Scholar
  145. Xu, Y., Nedungadi, T. P., Zhu, L., Sobhani, N., Irani, B. G., Davis, K. E., Zhang, X., Zou, F., Gent, L. M., Hahner, L. D., Khan, S. A., Elias, C. F., Elmquist, J. K., & Clegg, D. J. (2011). Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction. Cell Metabolism, 14(4), 453–465.CrossRefPubMedCentralPubMedGoogle Scholar
  146. Yepuru, M., Eswaraka, J., Kearbey, J. D., Barrett, C. M., Raghow, S., Veverka, K. A., Miller, D. D., Dalton, J. T., & Narayanan, R. (2010). Estrogen receptor-{beta}-selective ligands alleviate high-fat diet- and ovariectomy-induced obesity in mice. The Journal of Biological Chemistry, 285(41), 31292–31303.CrossRefPubMedCentralPubMedGoogle Scholar
  147. Yonezawa, R., Wada, T., Matsumoto, N., Morita, M., Sawakawa, K., Ishii, Y., Sasahara, M., Tsuneki, H., Saito, S., & Sasaoka, T. (2012). Central versus peripheral impact of estradiol on the impaired glucose metabolism in ovariectomized mice on a high-fat diet. American Journal of Physiology Endocrinology and Metabolism, 303(4), E445–E456.CrossRefPubMedGoogle Scholar
  148. Yoshida, T., Nishioka, H., Yoshioka, K., & Kondo, M. (1987). Reduced norepinephrine turnover in interscapular brown adipose tissue of obese rats after ovariectomy. Metabolism, 36(1), 1–6.CrossRefPubMedGoogle Scholar
  149. Yoshimatsu, H., Egawa, M., & Bray, G. A. (1993). Sympathetic nerve activity after discrete hypothalamic injections of L-glutamate. Brain Research, 601(1–2), 121–128.CrossRefPubMedGoogle Scholar
  150. Zennaro, M. C., Le, M. D., Viengchareun, S., Walker, F., Ricquier, D., & Lombes, M. (1998). Hibernoma development in transgenic mice identifies brown adipose tissue as a novel target of aldosterone action. The Journal of Clinical Investigation, 101(6), 1254–1260.CrossRefPubMedCentralPubMedGoogle Scholar
  151. Zingaretti, M. C., Crosta, F., Vitali, A., Guerrieri, M., Frontini, A., Cannon, B., Nedergaard, J., & Cinti, S. (2009). The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. The FASEB Journal, 23(9), 3113–3120.CrossRefPubMedGoogle Scholar

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© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of PhysiologyCIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria (IDIS)Santiago de CompostelaSpain
  2. 2.CIBER Fisiopatología de la Obesidad y NutriciónInstituto de Salud Carlos IIIMadridSpain
  3. 3.Department of Cell Biology, Physiology and ImmunologyUniversity of CórdobaCórdobaSpain
  4. 4.Instituto Maimónides de Investigación Biomédica (IMIBIC)/Hospital Reina SofíaCórdobaSpain
  5. 5.FiDiPro Program, Department of Physiology, University of TurkuTurkuFinland

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