Regulation of energy expenditure through BDNF neurons in the paraventricular hypothalamus

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PROJECT SUMMARY/ABSTRACT Obesity results from a chronic positive balance of energy intake and energy expenditure. To find therapeutic targets for obesity, this proposal focuses on elucidating neural circuits that govern energy expenditure. In the body, energy is stored as white adipose tissue (WAT) and expended in brown adipose tissue (BAT). Under certain physiological conditions such as cold, energy is dissipated from BAT in the form of heat. Under these same conditions, certain regions of WAT can convert to brown adipocyte-like cells, express thermogenic genes similar to BAT, and expend energy. Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), are implicit in the development of obesity. Mutations in BDNF and TrkB are associated with obesity in humans and mice. Recently, we reported that BDNF expression in the medial/lateral portion of the paraventricular hypothalamus (PVH) polysynaptically connects to interscapular brown adipose tissue (iBAT). Preliminary evidence suggests that BDNF-TrkB signaling via activation of PVHBDNF neurons can drive thermogenesis in iBAT because BDNF expression in the PVH increases in response to cold exposure. In contrast Bdnf gene ablation causes atrophy of sympathetic preganglionic neurons en route to iBAT and impaired thermogenesis in iBAT. Evidence also suggests that BDNF expression in the PVH stimulates thermogenesis in WAT. We performed retrograde transneuronal tracing via injection of pseudorabies virus (PRV) into the inguinal region of WAT (iWAT) and found infection in PVHBDNF neurons. This suggests a polysynaptic connection between PVHBDNF neurons and iWAT. However, the functional relationship between BDNF-TrkB signaling from PVH neurons to BAT and WAT is unknown. In the long-term I wish to explore neural circuits that regulate energy expenditure. I hypothesize that BDNF-TrkB signaling promotes adaptive thermogenesis in WAT and BAT. I will test this hypothesis with three aims: 1) to confirm that activation of PVHBDNF neurons stimulates adaptive thermogenesis in BAT without affecting sympathetic inputs to the heart and blood vessels, 2) to elucidate the synaptic properties of BDNF-TrkB signaling between PVHBDNF neurons and cholinergic sympathetic preganglionic neurons in the spinal cord, and 3) to determine if BDNF expression in the PVH is required to induce browning of WAT in response to cold exposure. To carry out these experiments, I will perform viral injections on transgenic mice to control BDNF-TrkB signaling. I will also use electrophysiology and metabolic measurements of BAT and WAT. Findings from this study will uncover an important relationship between BDNF-TrkB signaling and energy expenditure.