Energy and glucose homeostasis are complex processes controlled in part by central neural circuits. Within the brain, the hypothalamus receives and integrates peripheral energy status signals and responds by altering feeding behavior and energy expenditure to meet the nutritional demands of the organism. Brain- derived neurotrophic factor (BDNF) signaling in the ventromedial hypothalamus (VMH) is critical for the regulation of food intake, body weight and glucose balance. Expression of BDNF is robustly induced in the fed state, where BDNF activation of its neuronal receptor tyrosine receptor kinase B (TrkB) drives activity of anorexigenic VMH neurons to decrease food intake and lower blood glucose levels. BDNF mutations in both mouse models and in humans are associated with severe obesity and impaired glycemic control. In addition to its robust effects on neuronal plasticity, BDNF has been shown to regulate astrocyte morphology and calcium signaling through activation of a TrkB splice variant, TrkB.T1. It is well established that astrocytes play an active role regulating neuronal activity. They are in contact with the blood supply and communicate with neurons, which make them an excellent yet understudied candidate for sensing peripheral metabolic signals to accordingly shape the appropriate neuronal and metabolic responses. The proposed work will test the hypothesis that VMH astrocytes are key regulators of energy and glucose balance, and that BDNF signaling in this cell population is critical for these effects. In support, preliminary data suggest that BDNF and energy status dynamically regulate function and structural plasticity of VMH astrocytes to mediate energy balance control. Proposed experiments will use advanced behavioral, molecular and electrophysiological techniques to ascertain the role of VMH astrocyte BDNF/TrkB.T1 signaling on energy and glucose balance, and examine the effects of BDNF/TrkB.T1 signaling on VMH astrocyte-neuron interactions. A better understanding of the central circuitry and cell types controlling energy and glucose balance is required for treatment of our nations obesity epidemic. The proposed study will inform novel molecular mechanisms involved in the regulation of central feeding circuits and provide a stepping-stone for identification of potential therapeutic targets in treating obesity and metabolic disorder. Importantly, the novel hypothesis and multifaceted experiments proposed will provide an excellent training opportunity for me as a developing scientist in the field of central control of energy and glucose balance. !
Roughly 1/3 of the United States population is obese, an epidemic influenced by a variety of lifestyle and biological factors, resulting in an estimated $147 billion in annual medical costs from associated comorbidities. Experiments outlined in this proposal seek to better understand the role that astrocytes within the hypothalamus play in influencing feeding behavior and metabolism. Results will better inform novel molecular mechanisms regulating central feeding circuits and bring us closer to identifying potential therapeutic targets in treating obesity and metabolic disorder.
