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Ammy Marie Santiago
Pharmacology and Physiology Program
B.S. 2005, University of Texas, Austin
Thesis Advisor: Vanessa H. Routh, Ph.D.
Department of Pharmacology, Physiology and Neuroscience
Monday, April 11, 2016
1:00 P.M., MSB H609
Central regulation of glucose and energy homeostasis is sexually dimorphoic. 17β-Estradiol (17βE) is the main mediator of sex differences in energy balance. The mechanism(s) underlying 17βE’s effect on energy balance are still unclear; however glucose sensing neurons within the ventromedial hypothalamic nucleus (VMN) may play a role. Glucose silences VMN glucose-inhibited (GI) neurons and activates glucose-excited (GE) neurons. Within the ventrolateral portion of the VMN (VL-VMN), the distribution of estrogen receptors (ER) and GI and GE neurons overlap. We hypothesized (Hypothesis 1) that VL-VMN glucose sensing neurons were sexually dimorphic and regulated by 17βE. We also hypothesized (Hypothesis 2) that glucose tolerance and the response to insulin-induced hypoglycemia (IIH) would vary throughout the estrus cycle and coincide with estrus-dependent changes in hypothalamic glucose sensitivity.
We performed electrophysiological recordings of VL-VMN GI and GE neurons in female and male mice. Hypothesis 1 utilized prepubertal animals to avoid the impact of cycling ovarian hormones. Hypothesis 2 evaluated glucose tolerance and the response to IIH in intact females during each estrus phase. In addition, we evaluated hypothalamic glucose sensing neurons at each estrus phase and tested whether 17βE modulated VL-VMN GI and GE neurons in diestrus.
Interestingly, we characterized a novel type of VL-VMN GI neuron in both sexes and ages. In addition to “nonadapting” GE and GI neurons which show a sustained response to low glucose, we found a class of GI neurons whose response to low glucose was transient (‘adapting’ or AdGI). GE neurons were not sexually dimorphic, did not display cyclic changes in their glucose sensitivity and were not 17βE sensitive. In contrast, nonadapting GI, but not AdGI, neurons were sexually dimorphic. Moreover, 17βE blunted the activation of both GI neuron subtypes to decreased glucose via activation of ERβ and inhibition of AMP-activated kinase. The response to IIH and the activation of both GI neuron subtypes in low glucose peaked during diestrus. 17βE blunted this effect. Glucose tolerance did not correlate with changes in hypothalamic glucose sensitivity.
In summary, these data suggest that the sexual dimorphism and 17βE regulation of VMN hypothalamic glucose sensing may contribute to the observed sex differences in glucose homeostasis. Furthermore, physiological fluctuations in circulating 17βE lead to changes in hypothalamic glucose sensing and the response to IIH.