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Origins and Functions of the Ventrolateral VMH: A Complex Neuronal Cluster Orchestrating Sex Differences in Metabolism and Behavior

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Sex and Gender Factors Affecting Metabolic Homeostasis, Diabetes and Obesity

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

Abstract

The neuroendocrine brain or hypothalamus has emerged as one of the most highly sexually dimorphic brain regions in mammals, and specifically in rodents. It is not surprising that hypothalamic nuclei play a pivotal role in controlling sex-dependent physiology. This brain region functions as a chief executive officer or master regulator of homeostatic physiological systems to integrate both external and internal signals. In this review, we describe sex differences in energy homeostasis that arise in one area of the hypothalamus, the ventrolateral subregion of the ventromedial hypothalamus (VMHvl) with a focus on how male and female neurons function in metabolic and behavioral aspects. Because other chapters within this book provide details on signaling pathways in the VMH that contribute to sex differences in metabolism, our discussion will be limited to how the sexually dimorphic VMHvl develops and what key regulators are thought to control the many functional and physiological endpoints attributed to this region. In the last decade, several exciting new studies using state-of-the-art genetic and molecular tools are beginning to provide some understanding as to how specific neurons contribute to the coordinated physiological responses needed by male and females. New technology that combines intersectional spatial and genetic approaches is now allowing further refinement in how we describe, probe, and manipulate critical male and female neurocircuits involved in metabolism.

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References

  • Brailoiu, E., Dun, S. L., Brailoiu, G. C., Mizou, K., Sklar, L. A., Oprea, T. I., Prossnitz, E. R., & Dun, N. J. (2007). Distribution and characterization of estrogen receptor G protein-coupled receptor 30 in the rat central nervous system. The Journal of Endocrinology, 193, 311–321.

    Article  CAS  PubMed  Google Scholar 

  • Braz, J. M., Rico, B., & Basbaum, A. I. (2002). Transneuronal tracing of diverse CNS circuits by Cre-mediated induction of wheat germ agglutinin in transgenic mice. Proceedings of the National Academy of Sciences of the United States of America, 99, 15148–15153.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Brobeck, J. R., Wheatland, M., & Strominger, J. L. (1947). Variations in regulation of energy exchange associated with estrus, diestrus and pseudopregnancy in rats. Endocrinology, 40, 65–72.

    Article  CAS  PubMed  Google Scholar 

  • Brock, O., De Mees, C., & Bakker, J. (2015). Hypothalamic expression of oestrogen receptor alpha and androgen receptor is sex-, age- and region-dependent in mice. Journal of Neuroendocrinology, 27, 264–276.

    Article  CAS  PubMed  Google Scholar 

  • Budefeld, T., Tobet, S. A., & Majdic, G. (2011). Altered position of cell bodies and fibers in the ventromedial region in SF-1 knockout mice. Experimental Neurology, 232, 176–184.

    Article  PubMed Central  PubMed  Google Scholar 

  • Cheung, C. C., Krause, W. C., Edwards, R. H., Yang, C. F., Shah, N. M., Hnasko, T. S., & Ingraham, H. A. (2015). Sex-dependent changes in metabolism and behavior, as well as reduced anxiety after eliminating ventromedial hypothalamus excitatory output. Molecular Metabolism, 4, 857–866.

    Google Scholar 

  • Cheung, C. C., Kurrasch, D. M., Liang, J. K., & Ingraham, H. A. (2012). Genetic labeling of steroidogenic factor-1 (SF-1) neurons in mice reveals ventromedial nucleus of the hypothalamus (VMH) circuitry beginning at neurogenesis and development of a separate non-SF-1 neuronal cluster in the ventrolateral VMH. The Journal of Comparative Neurology, 521, 1268–1288.

    Article  Google Scholar 

  • Cheung, C. C., Kurrasch, D. M., Liang, J. K., & Ingraham, H. A. (2013). Genetic labeling of steroidogenic factor-1 (SF-1) neurons in mice reveals ventromedial nucleus of the hypothalamus (VMH) circuitry beginning at neurogenesis and development of a separate non-SF-1 neuronal cluster in the ventrolateral VMH. The Journal of Comparative Neurology, 521, 1268–1288.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chimento, A., Sirianni, R., Casaburi, I., & Pezzi, V. (2014). Role of estrogen receptors and g protein-coupled estrogen receptor in regulation of hypothalamus-pituitary-testis axis and spermatogenesis. Frontiers in Endocrinology (Lausanne), 5, 1.

    Google Scholar 

  • Collins, S., Martin, T. L., Surwit, R. S., & Robidoux, J. (2004). Genetic vulnerability to diet-induced obesity in the C57BL/6J mouse: Physiological and molecular characteristics. Physiology & Behavior, 81, 243–248.

    Article  CAS  Google Scholar 

  • Correa, S. M., Newstorm, 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, 62–74.

    Article  CAS  PubMed  Google Scholar 

  • Davis, A. M., Seney, M. L., Stallings, N. R., Zhao, L., Parker, K. L., & Tobet, S. A. (2004). Loss of steroidogenic factor 1 alters cellular topography in the mouse ventromedial nucleus of the hypothalamus. Journal of Neurobiology, 60, 424–436.

    Article  CAS  PubMed  Google Scholar 

  • Della Torre, S., & Maggi, A. (2017). Sex differences: A resultant of an evolutionary pressure? Cell Metabolism, 25, 499–505.

    Article  CAS  PubMed  Google Scholar 

  • Dhillon, H., Zigman, J. M., Ye, C., Lee, C. E., McGovern, R. A., Tang, V., Kenny, C. D., Christiansen, L. M., White, R. D., Edelstein, E. A., Coppari, R., Balthazar, N., Cowley, M. A., Chua, S., Jr., Elmquist, J. K., & LOWELL, B. B. (2006). Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis. Neuron, 49, 191–203.

    Article  CAS  PubMed  Google Scholar 

  • Dornan, W. A., Akesson, T. R., & Micevych, P. E. (1990). A substance P projection from the VMH to the dorsal midbrain central gray: Implication for lordosis. Brain Research Bulletin, 25, 791–796.

    Article  CAS  PubMed  Google Scholar 

  • Fahrbach, S. E., Meisel, R. L., & Pfaff, D. W. (1985). Preoptic implants of estradiol increase wheel running but not the open field activity of female rats. Physiology & Behavior, 35, 985–992.

    Article  CAS  Google Scholar 

  • Fremeau, R. T., Jr., Troyer, M. D., Pahner, I., Nygaard, G. O., Tran, C. H., Reimer, R. J., Bellochio, E. E., Fortin, D., Storm-Mathisen, J. Edwards, R. H. 2001. The expression of vesicular glutamate transporters defines two classes of excitatory synapse. Neuron, 31, 247–260.

    Article  CAS  PubMed  Google Scholar 

  • Fu, L. Y., & Van Den Pol, A. N. (2008). Agouti-related peptide and MC3/4 receptor agonists both inhibit excitatory hypothalamic ventromedial nucleus neurons. The Journal of Neuroscience, 28, 5433–5449.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hagihara, K., Hirata, S., Osada, T., Hirai, M., & Kato, J. (1992). Distribution of cells containing progesterone receptor mRNA in the female rat di- and telencephalon: An in situ hybridization study. Brain Research Molecular Brain Research, 14, 239–249.

    Article  CAS  PubMed  Google Scholar 

  • Hathout, G. M., & Bhidayasiri, R. (2005). Midbrain ataxia: An introduction to the mesencephalic locomotor region and the pedunculopontine nucleus. AJR American Journal of Roentgenology, 184, 953–956.

    Article  PubMed  Google Scholar 

  • Ikeda, Y., Shen, W. H., Ingraham, H. A., & Parker, K. L. (1994). Developmental expression of mouse steroidogenic factor-1, an essential regulator of the steroid hydroxylases. Molecular Endocrinology, 8, 654–662.

    CAS  PubMed  Google Scholar 

  • Ikeda, Y., Luo, X., Abbud, R., Nilson, J. H., & Parker, K. L. (1995). The nuclear receptor steroidogenic factor 1 is essential for the formation of the ventromedial hypothalamic nucleus. Molecular Endocrinology, 9, 478–486.

    CAS  PubMed  Google Scholar 

  • Ikeda, Y., Takeda, Y., Shikayama, T., Mukai, T., Hisano, S., & Morohashi, K. I. (2001). Comparative localization of Dax-1 and Ad4BP/SF-1 during development of the hypothalamic-pituitary-gonadal axis suggests their closely related and distinct functions. Developmental Dynamics, 220, 363–376.

    Article  CAS  PubMed  Google Scholar 

  • Ingraham, H. A., Lala, D. S., Ikeda, Y., Luo, X., Shen, W. H., Nachtigal, M. W., Abbud, R., Nilson, J. H., & Parker, K. L. (1994). The nuclear receptor steroidogenic factor 1 acts at multiple levels of the reproductive axis. Genes & Development, 8, 2302–2312.

    Article  CAS  Google Scholar 

  • Karagiannides, I., Bakirtzi, K., Kokkotou, E., Stavrakis, D., Margolis, K. G., Thomou, T., Giorgadze, N., Kirkland, J. L., & Pothoulakis, C. (2011a). Role of substance P in the regulation of glucose metabolism via insulin signaling-associated pathways. Endocrinology, 152, 4571–4580.

    Google Scholar 

  • Karagiannides, I., Stavrakis, D., Bakirtzi, K., Kokkotou, E., Pirtskhalava, T., Nayeb-Hashemi, H., Bowe, C., Bugni, J. M., Nuno, M., Lu, B., Gerard, N. P., Leeman, S. E., Kirkland, J. L., & Pothoulakis, C. (2011b). Substance P (SP)-neurokinin-1 receptor (NK-1R) alters adipose tissue responses to high-fat diet and insulin action. Endocrinology, 152, 2197–2205.

    Google Scholar 

  • Kimura, S., Hara, Y., Pineau, T., Fernandez-Salguero, P., Fox, C. H., Ward, J. M., & Gonzales, F. J. (1996). The T/ebp null mouse: Thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary. Genes & Development, 10, 60–69.

    Article  CAS  Google Scholar 

  • Koch, M. (1990). Effects of treatment with estradiol and parental experience on the number and distribution of estrogen-binding neurons in the ovariectomized mouse brain. Neuroendocrinology, 51, 505–514.

    Google Scholar 

  • Kopp, C., Ressel, V., Wigger, E., & Tobler, I. (2006). Influence of estrus cycle and ageing on activity patterns in two inbred mouse strains. Behavioural Brain Research, 167, 165–174.

    Article  CAS  PubMed  Google Scholar 

  • Kurrasch, D. M., Cheung, C. C., Lee, F. Y., Tran, P. V., Hata, K., & Iingraham, H. A. (2007). The neonatal ventromedial hypothalamus transcriptome reveals novel markers with spatially distinct patterning. The Journal of Neuroscience, 27, 13624–13634.

    Article  CAS  PubMed  Google Scholar 

  • Lee, H., Kim, D. W., Remedios, R., Anthoby, T. E., Chang, A., Madisen, L., Zeng, H., & Anderson, D. J. (2014). Scalable control of mounting and attack by Esr1+ neurons in the ventromedial hypothalamus. Nature, 509, 627–632.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lunahn, D. B., Moyer, J. S., Golding, T. S., Couse, J. F., Korach, K. S., & Smithies, O. (1993). Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proceedings of the National Academy of Sciences of the United States of America, 90, 11162–11166.

    Article  Google Scholar 

  • Marin, O., Baker, J., Puelles, L., & Rubenstein, J. L. (2002). Patterning of the basal telencephalon and hypothalamus is essential for guidance of cortical projections. Development, 129, 761–773.

    CAS  PubMed  Google Scholar 

  • Mastronardi, C., Smiley, G. G., Raber, J., Kusakabe, T., Kawaguchi, A., Matagne, V., Dietzel, A., Heger, S., Mungenast, A. E., Cabrera, R., Kimura, S., & Ojeda, S. R. (2006). Deletion of the Ttf1 gene in differentiated neurons disrupts female reproduction without impairing basal ganglia function. The Journal of Neuroscience, 26, 13167–13179.

    Article  CAS  PubMed  Google Scholar 

  • Mccall, K. (2004). Eggs over easy: Cell death in the drosophila ovary. Developmental Biology, 274, 3–14.

    Article  CAS  PubMed  Google Scholar 

  • McClallan, K. M., Parker, K. L., & Tobet, S. (2006). Development of the ventromedial nucleus of the hypothalamus. Frontiers in Neuroendocrinology, 27, 193–209.

    Article  Google Scholar 

  • Montgomery, M. K., Hallahan, N. L., Brown, S. H., Liu, M., Mitchell, T. W., Cooney, G. J., & Turner, N. (2013). Mouse strain-dependent variation in obesity and glucose homeostasis in response to high-fat feeding. Diabetologia, 56, 1129–1139.

    Article  CAS  PubMed  Google Scholar 

  • Musatov, S., Chen, W., Pfaff, D. W., Kaplitt, M. G., & Ogawa, S. (2006). RNAi-mediated silencing of estrogen receptor {alpha} in the ventromedial nucleus of hypothalamus abolishes female sexual behaviors. Proceedings of the National Academy of Sciences of the United States of America, 103, 10456–10460.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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, 2501–2506.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Narita, K., Yokawa, T., Nidhihara, M., & Takahashi, M. (1993). Interaction between excitatory and inhibitory amino acids in the ventromedial nucleus of the hypothalamus in inducing hyper-running. Brain Research, 603, 243–247.

    Article  CAS  PubMed  Google Scholar 

  • Ogawa, S., Eng, V., Taylor, J., Lubahn, D. B., Korach, K. S., & Pfaff, D. W. (1998). Roles of estrogen receptor-alpha gene expression in reproduction-related behaviors in female mice. Endocrinology, 139, 5070–5081.

    Article  CAS  PubMed  Google Scholar 

  • Prendergast, B. J., Onishi, K. G., & Zucker, I. (2014). Female mice liberated for inclusion in neuroscience and biomedical research. Neuroscience and Biobehavioral Reviews, 40, 1–5.

    Article  PubMed  Google Scholar 

  • Prossnitz, E. R., Arterburn, J. B., Smith, H. O., Oprea, T. I., Sklar, L. A., & Hathaway, H. J. (2008). Estrogen signaling through the transmembrane G protein-coupled receptor GPR30. Annual Review of Physiology, 70, 165–190.

    Article  CAS  PubMed  Google Scholar 

  • Salvatierra, J., Lee, D. A., Zibetti, C., Duran-Moreno, M., Yoo, S., Newman, E. A., Wang, H., Bedont, J. L., De Melo, J., Miranda-Angulo, A. L., Gil-Perotin, S., Garcia-Verdugo, J. M., & Blackshaw, S. (2014). The LIM homeodomain factor Lhx2 is required for hypothalamic tanycyte specification and differentiation. The Journal of Neuroscience, 34, 16809–16820.

    Article  PubMed Central  PubMed  Google Scholar 

  • Shen, W. H., Moore, C. C., Ikeda, Y., Parker, K. L., & Ingraham, H. A. (1994). Nuclear receptor steroidogenic factor 1 regulates the mullerian inhibiting substance gene: A link to the sex determination cascade. Cell, 77, 651–661.

    Article  PubMed  Google Scholar 

  • Shimamura, K., & Rubenstein, J. L. (1997). Inductive interactions direct early regionalization of the mouse forebrain. Development, 124, 2709–2718.

    CAS  PubMed  Google Scholar 

  • Silva, B. A., Mattucci, C., Krzywkowski, P., Murana, E., Illarionova, A., Grinevich, V., Canteras, N. S., Ragozzino, D., & Gross, C. T. (2013). Independent hypothalamic circuits for social and predator fear. Nature Neuroscience, 16, 1731–1733.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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, 76–95.

    Article  CAS  PubMed  Google Scholar 

  • Skinner, R. D., & Garcia-rill, E. (1984). The mesencephalic locomotor region (MLR) in the rat. Brain Research, 323, 385–389.

    Article  CAS  PubMed  Google Scholar 

  • Spiteri, T., Ogawa, S., Musatov, S., Pfaff, D. W., & Agmo, A. (2012). The role of the estrogen receptor alpha in the medial preoptic area in sexual incentive motivation, proceptivity and receptivity, anxiety, and wheel running in female rats. Behavioural Brain Research, 230, 11–20.

    Article  CAS  PubMed  Google Scholar 

  • Stanic, D., Dubois, S., Chua, H. K., Tonge, B., Rinehart, N., Horne, M. K., & Boon, W. C. (2014). Characterization of aromatase expression in the adult male and female mouse brain. I. Coexistence with oestrogen receptors alpha and beta, and androgen receptors. PLoS One, 9, e90451.

    Article  PubMed Central  PubMed  Google Scholar 

  • Sternson, S. M., Shepherd, G. M., & Friedman, J. M. (2005). Topographic mapping of VMH –> arcuate nucleus microcircuits and their reorganization by fasting. Nature Neuroscience, 8, 1356–1363.

    Article  CAS  PubMed  Google Scholar 

  • Sussel, L., Kalamaras, J., Hartigan-O'Connor, D. J., Meneses, J. J., Pedersen, R. A., Rubenstein, J. L., & German, M. S. (1998). Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic beta cells. Development, 125, 2213–2221.

    CAS  PubMed  Google Scholar 

  • Sussel, L., Marin, O., Kimura, S., & Rubenstein, J. L. (1999). Loss of Nkx2.1 homeobox gene function results in a ventral to dorsal molecular respecification within the basal telencephalon: Evidence for a transformation of the pallidum into the striatum. Development, 126, 3359–3370.

    CAS  PubMed  Google Scholar 

  • Tong, Q., Ye, C., McCrimmon, R. J., Dhillon, H., Choi, B., Kramer, M. D., Yu, J., Yang, Z., Christainsen, L. M., Lee, C. E., Choi, C. S., Zigman, J. M., Shulman, G. I., Sherwin, R. S., Elmquist, J. K., & Lowell, B. B. (2007). Synaptic glutamate release by ventromedial hypothalamic neurons is part of the neurocircuitry that prevents hypoglycemia. Cell Metabolism, 5, 383–393.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tran, P. V., Lee, M. B., Marin, O., Xu, B., Jones, K. R., Reichardt, L. F., Rubenstein, J. R., & Ingraham, H. A. (2003). Requirement of the orphan nuclear receptor SF-1 in terminal differentiation of ventromedial hypothalamic neurons. Molecular and Cellular Neurosciences, 22, 441–453.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wu, M. V., Manoli, D. S., Fraser, E. J., Coats, J. K., Tollkuhn, J., Honda, S., Harada, N., & Shah, N. M. (2009). Estrogen masculinizes neural pathways and sex-specific behaviors. Cell, 139, 61–72.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Xu, Y., Nedugadi, 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, 453–465.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yang, C. F., & Shah, N. M. (2014). Representing sex in the brain, one module at a time. Neuron, 82, 261–278.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yang, C. F., Chiang, M. C., Gray, D. C., Prabhakaran, M., Alvarado, M., Juntti, S. A., Unger, E. K., Wells, J. A., & Shah, N. M. (2013). Sexually dimorphic neurons in the ventromedial hypothalamus govern mating in both sexes and aggression in males. Cell, 153, 896–909.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yee, C. L., Wang, Y., Anderson, S., Ekker, M., & Rubenstein, J. L. (2009). Arcuate nucleus expression of NKX2.1 and DLX and lineages expressing these transcription factors in neuropeptide Y(+), proopiomelanocortin(+), and tyrosine hydroxylase(+) neurons in neonatal and adult mice. The Journal of Comparative Neurology, 517, 37–50.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ziegler, D. R., Cullinan, W. E., & Herman, J. P. (2002). Distribution of vesicular glutamate transporter mRNA in rat hypothalamus. The Journal of Comparative Neurology, 448, 217–229.

    Article  CAS  PubMed  Google Scholar 

  • Zuloaga, D. G., Zuloaga, K. L., Hinds, L. R., Carbone, D. L., & Handa, R. J. (2014). Estrogen receptor beta expression in the mouse forebrain: Age and sex differences. The Journal of Comparative Neurology, 522, 358–371.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA

    William C. Krause & Holly A. Ingraham

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  1. William C. Krause
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  2. Holly A. Ingraham
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Correspondence to Holly A. Ingraham .

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  1. Department of Medicine, Section of Endocrinology and Metabolism, Tulane University Health Sciences Center, School of Medicine, New Orleans, Louisiana, USA

    Franck Mauvais-Jarvis

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Krause, W.C., Ingraham, H.A. (2017). Origins and Functions of the Ventrolateral VMH: A Complex Neuronal Cluster Orchestrating Sex Differences in Metabolism and Behavior. In: Mauvais-Jarvis, F. (eds) Sex and Gender Factors Affecting Metabolic Homeostasis, Diabetes and Obesity. Advances in Experimental Medicine and Biology, vol 1043. Springer, Cham. https://doi.org/10.1007/978-3-319-70178-3_10

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