The ventromedial hypothalamus (VMH) plays paramount roles in the regulation of energy and glucose balance. It contains a heterogeneous population of neurons, mostly glutamatergic that promote satiety and regulate energy expenditure and glycemic control. Our previous studies revealed a critical role for brain-derived neurotrophic factor (BDNF) in central neural circuits controlling food intake and identified the VMH as an important cellular substrate mediating these actions. Accordingly, expression of BDNF and its receptor TrkB in VMH is robustly induced in the fed state and selective targeting of BDNF in this region triggers hyperphagia, obesity and hyperglycemia. In addition to being a chief regulator of neuronal plasticity, BDNF is a multifunctional growth factor with reported effects on astrocyte morphology and calcium signaling. These effects have been identified in several brain regions, but not in feeding circuits. This research area warrants examination as it is well established that astrocytes play an active role in regulating neuronal activity via gliotransmitter release, glutamate clearance and synapse remodeling and their role in energy and glucose balance regulation has been under studied. The current proposal builds on a recently completed R21 project revealing that energy status and BDNF regulate astrocyte function in the VMH, including structural plasticity and glutamate uptake kinetics. It will test the hypothesis that increased BDNF signaling in VMH astrocytes during conditions of positive energy balance is required to increase the excitatory drive onto energy and glucose balance-regulating VMH neurons and mediate appetite suppression and glucose metabolism.
Aim 1 will examine the effects of selective known down of TrkB.T1 in VMH astrocytes in mice, as this is the only TrkB receptor subtype expressed by that cell population. As we propose that some of the effects of BDNF in the VMH are mediated through regulation of the astrocytic glutamate transporter, GLT-1, Aim 2 will investigate the consequences of deleting GLT-1 in VMH astrocytes on neuronal activity in the fed and fasted states and in the regulation of energy and glucose balance. Finally, Aim 3 will define mechanisms downstream of BDNF/TrkB.T1 signaling in VMH astrocytes mediating changes in the excitatory drive of VMH neurons and energy and glucose homeostasis. The planned studies will elucidate novel mechanisms involving glial-neuron communication in the VMH that regulate activity of feeding circuits and satiety and thereby identify new targets for therapeutic strategies to treat obesity.

Public Health Relevance

This proposal seeks to investigate the role of brain-derived neurotrophic factor (BDNF) signaling in astrocytes in the ventromedial hypothalamus (VMH), facilitating body weight and glycemic control. We will identify mechanisms by which BDNF acts in this cell population to control activity of VMH neurons regulating appetite and glucose metabolism. These investigations will facilitate the creation of new avenues for the treatment of obesity and associated disorders including diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK117935-02
Application #
9914255
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Hyde, James F
Project Start
2019-04-15
Project End
2023-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Tufts University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111