Characterization of Estrogen Sensitive Hypothalamic Glucose Sensing Neurons


Principal Investigator: AMMY MARIE SANTIAGO
Abstract: DESCRIPTION (provided by applicant): Glucose sensing neurons (GSN) of the ventromedial hypothalamus (VMH) are believed to play a role in the regulation of energy and glucose homeostasis. However, the underlying mechanisms by which GSNs fulfill this role remain elusive. The current obesity epidemic and the rise in the prevalence of Type II Diabetes Mellitus (TIIDM) underscore the necessity to clarify these mechanisms and potentially illuminate novel therapeutic targets for these diseases. This is especially important for females since there is a greater incidence of obesity and TIIDM in females yet virtually all studies of GSNs have been performed in males. We have previously shown, in male mice, that VMH GSNs are dysfunctional during TIIDM. The strong correlation between estrogen receptor (ER) expression, in both sexes, and the location of VMH GSNs within the ventrolateral VMH suggests that estrogen regulates GSNs. This project hypothesizes that ER activation attenuates VMH GSN sensitivity to decreased glucose. Thus diminished estrogen levels following menopause may enhance responsiveness of GSNs to glucose decreases. This could lead to inappropriate signals of energy deficit and initiation of inappropriate compensatory mechanisms during energy sufficiency. Such a response may explain the increased susceptibility to TIIDM in post-menopausal females. To test this hypothesis, the pre-doctoral fellow will first determine whether glucose-excited or glucose-inhibited neurons are ER positive (either alpha or beta) using immunohistochemical and single-cell PCR methodologies. The neurotransmitter phenotype of these neurons will also be determined in order to better understand their role in energy homeostasis. Secondly, electrophysiological patch-clamp techniques will be used to determine how estrogen and the membrane impermeable BSA-conjugated estrogen regulate the acute activity as well as the glucose sensitivity of GSNs. The fellow will also utilize inhibitors of potential ER signaling molecules and western blot analysis to understand the mechanism of estrogenic regulation of VMH GSNs sensitivity. Using these same techniques, the fellow will investigate the effects of ER1 or ER2 ablation on the glucose sensitivity of VMH GSNs via the use of steroidogenic factor-1 driven ER1- or ER2-knockout mice (VMH exclusive knockout) and selective ER1 or ER2 antagonist application. Finally, using a fluorescent retrograde tracer, the fellow will determine whether estrogen-sensitive GSNs project directly to the anterior pituitary or to the preoptic area where they could potentially relay nutrient status information influencing the reproductive state of the individual.
Funding Period: 2011-07-01 - 2015-06-30
more information: NIH RePORT

Detail Information

Research Grants62

  1. Endophenotypes of Sleep Apnea and Role of Obesity
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    ..It will lead to a new molecular signature of OSA that could transform the practice of medicine in this area in a new, cost-effective way. ..
  2. Glucagon-like peptide-1 in brainstem integration of energy balance control
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  3. Neuroendocrine regulation of the reproductive axis during puberty and development
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    ..This information could provide important insight into the mechanisms underlying hypogonadotropic hypogonadism, precious puberty, and delayed puberty. ..
  4. Mechanisms of Steroid Action in Brain
    MARC JEFFREY TETEL; Fiscal Year: 2013
  5. Program Project: Growth, Differentiation and Disease of Urothelium
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  6. CNS circuits mediating estrogenic regulation on energy and glucose homeostasis
    Yong Xu; Fiscal Year: 2013
  7. Novel Methods to Assess the Effects of Chemicals on Child Development
    Susan L Schantz; Fiscal Year: 2013
    ..This Center's research will fill an important gap in our knowledge by investigating the effects of these chemicals, both alone and combination with a high fat diet on reproductive and neural development. ..
  8. Central actions of estrogens: Effects of GnRH neurons
    Suzanne M Moenter; Fiscal Year: 2013
    ..Integration of the data resulting from the study of an excitatory and an inhibitory afferet network into existing knowledge will increase our understanding of the central neuronal control of ovulation by estradiol. ..
  9. Role of leptin-mediated PI3 Kinase signaling on reproductive control
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    ..Obesity and diabetes can also negatively affect fertility. Thus, it is hoped that our studies may open new fronts for the understanding and for further treatment of reproductive deficits caused by metabolic dysfunctions. ..
  10. Hormonal regulation of a Ca2+/AMPK signaling pathway
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    ..Because inflammation is such a prevalent cause of or response to numerous human diseases we believe our studies will reveal CaMKK2 to be an important, novel target for therapeutic intervention. ..
  11. Neural Basis for Leptin Control of Energy Balance
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    ..Our hypothesized model is of interest because leptin-responsive GABAergic neurons could be important substrates for nutritional programming and/or metabolic plasticity. ..
  12. LKB1- AMPK pathway regulation of glucose metabolism and metformin action in liver
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    ..These studies disecting the role of the LKB1- AMPK pathway in liver will increase the understanding of how existing widely used diabetes modalities work, and identify critical new targets for future type 2 diabetes therapeutics. ..
    John V Fahy; Fiscal Year: 2013
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  14. Neurobiology of Aggression Co-morbidity in Mouse Model of Idic15 Autism
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  15. Cross-talk between Leptin and Estrogen Signaling in Hypothalamic Arcuate Neurons
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    ..Understanding the convergence of leptin and E2 signaling in arcuate kisspeptin neurons will provide insight into the fundamental role of these hormones in conveying metabolic cues to the reproductive axis. ..
  16. Cellular Mechanisms of Hypothalamic Inflammation in High Fat Diet-Induced Obesity
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    ..This research focuses on the brain's role in high-fat diet-induced weight gain with an effort to develop therapies to reduce weight gain. ..
  17. Mechanisms underlying sexually differentiated brain remodeling during adolescence
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  18. Neural Functioning of Feeding Centers in Obese Youth
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  20. Novel Mechanistic Targets of Steroid Hormones in the Brain
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  22. Cellular Mechanisms for Increased Gluconeogenesis in Type 2 Diabetes
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  23. Neural basis of leptin action on reproduction
    Carol Fuzeti Elias; Fiscal Year: 2013
    ..In addition, we will also assess the requirement of leptin signaling in both (PMV and Kiss1) neuronal population (Aim3) for the full rescue of the infertility phenotype of LepR null mice. ..
  24. Mechanisms of Health Effects of Exercise in Children
    Dan M Cooper; Fiscal Year: 2013
    ..Collectively, the PPG will promote novel preventive and adjunctive exercise therapies in children with chronic inflammation- therapies grounded in a firm understanding of biological mechanisms. ..
  25. Leptin Action and Central Melanocortin Systems
    Joel K Elmquist; Fiscal Year: 2013
    ..Finally, we will also determine if blocking glucagon action blunts the disruptions in glucose homeostasis induced by MC4-R deletion in autonomic preganglionic neurons. ..
  26. Estrogen Receptor and Cardiovascular Function
    Ellis R Levin; Fiscal Year: 2013
    ..These data may justify in the future initial translational trials in post-menopausal women, including veterans. ..
  27. Circadian Clock Disruption: A Mechanism for Dioxin-induced Metabolic Syndrome
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  28. Gender differences in aortic baroreceptor function and neural integration
    John H Schild; Fiscal Year: 2013
    ..Evidence for a gender-related difference in baroreceptors could potentially lead to novel advances in the effective management of cardiovascular health and disease in the female population. ..
  29. MAP Kinase Phosphatase 3 (MKP-3) and Obesity-related Gluconeogenesis
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  30. Estrogen Modulation of Bursting Activity in GnRH Neurons
    Oline K Ronnekleiv; Fiscal Year: 2013
    ..It is envisioned that the results from the proposed experiments will help mold a cellular model of burst firing of GnRH neurons, pulsatile neurosecretion, and ultimately ovulation in the female. ..
  31. Impact of Catecholamines to Insulin-Glucose Homeostasis in IUGR Fetuses
    Sean W Limesand; Fiscal Year: 2013
    ..Therefore, we plan to determine how a key stress response alters the developmental program in the fetal 2-cells to impair glucose homeostasis and lead to adulthood pathologies, such as Type 2 Diabetes Mellitus. ..
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  33. Coenzyme A Regulation of Metabolism
    Suzanne Jackowski; Fiscal Year: 2013
    ..This original approach to reprogramming intermediary metabolism will define the role of CoA in hepatic gluconeogenesis and provide insight into the factors that give rise to human disorders of lipid and glucose homeostasis. ..
  34. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
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  35. Novel molecular and cellular approaches for alcoholism medication development
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    ..The PPG has both internal and external advisory board members, providing expert guidance from scientists with a wide range of expertise in drug development and therapeutics. ..
  36. Estrogen regulation of channels involved in the control of energy homeostasis
    TROY ADAM ROEPKE; Fiscal Year: 2013
    ..The final aim will detennine the electrophysiological effects of bisphenol A on arcuate POMC and NPY neurons that control energy homeostasis. ..
    JAMEY MARTH; Fiscal Year: 2013
    ..Combined, the proposed research is structured to achieve a more integrated understanding of the pathogenesis of diabetes and the molecular mechanisms governing metabolism, which could translate to more effective therapeutic approaches. ..
  38. Function of 9-cis-retinoic acid
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    ..This project should contribute novel insight into mechanisms of retinoid action, nuclear hormone receptor function, regulation of Glut2 and GK, and insulin secretion. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page ..
  39. Characterization of Portal Vein Glucose Sensor Responsible for Satiety Control
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  43. Integration of Feeding and Glucose Metabolism by the Circadian Gene Network
    JOSEPH T BASS; Fiscal Year: 2013
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  44. A Gene therapeutic approach to stable suppression of HIV-1 replication
    MICHAEL R FARZAN; Fiscal Year: 2013
    ..These studies will establish principles and protocols directly applicable to subsequent human clinical trials. ..
  45. Developmental Programs of Neural Circuits in the Mouse Medial Hypothalamus
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    ..Accordingly, results from the proposed studies may provide a new arsenal to combat the growing and costly effects of obesity and Type 2 diabetes. ..
  46. Metabolic Determinants of Cardiovascular Dysfunction in Obesity
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    ..Successful completion of these aims may identify new targets to aid in the treatment of the most common clinical outcomes of obesity. ..