Reducing adipose tissue dysfunction and metabolic complications by manipulating sensory processing after spinal cord injury

ABSTRACT Half of the spinal cord injury (SCI) individuals experience weight gain attributed to increased adiposity. Following SCI, increased lipid deposition is also observed in other organs including the liver, heart and skeletal muscle. Accumulating evidence indicates that pathological expansion of adipose tissue and ectopic lipid

accumulation increases the risk of cardiometabolic disorders including hypertension, dyslipidemia and insulin resistance. Under physiological conditions, an excess of energy is stored in adipose tissue in the form of triglycerides. During energy deprivation, the adipose tissue mobilizes triglycerides into fatty acids via lipolysis,

and these are used as fuel for brown adipose tissue, heart, liver, and muscle. When energy balance becomes dysregulated, ectopic accumulation of lipids in the liver and muscle as well as unresolved inflammation in adipose tissue contribute to insulin resistance. Whether the underlying cause of metabolic complications after

SCI may be linked to adipose tissue dysfunction is unclear. Also unknown are the mechanisms that cause or contribute to pathophysiological changes in white adipose tissue (WAT) structure and function after SCI. The sympathetic nervous system and sensory neurons with cell bodies located in dorsal root ganglia (DRG)

innervate WAT. Whereas the contribution of sympathetic innervation to WAT function has been characterized, the extent to which sensory innervation drives WAT function under normal and pathophysiological conditions has remained elusive. We and others have demonstrated a remarkable convergence between neuronal

circuits' structural and functional organization and expression of α2δ subunits of voltage-gated calcium channels (VGCC). α2δ subunits positively regulate synaptic transmission by increasing plasma membrane expression of VGCC. However, these subunits may also play a pathological role following neuronal injury. Our

preliminary data suggest that SCI exacerbates lipolysis in epididymal (e)WAT and that α2δ1 expression increases after a thoracic SCI in calcitonin gene-related peptide (CGRP) DRG neurons that project to eWAT. Concurrently, we found elevated CGRP content in eWAT and increased expression of the CGRP receptor

RAMP1 in eWAT seven days after SCI. Not only does CGRP activate lipolysis independent of sympathetic drive, but it also acts as a potent vasodilator. Changes in adipose tissue microcirculation have been associated with health complications including adiposity and altered metabolism. Accordingly, experiments in Aim 1 will

evaluate the extent to which α2δ1 silencing and pharmacological blockade normalize eWAT function after SCI. Aim 2 will dissect the cellular mechanism underlying α2δ1-dependent changes in eWAT lipolysis. Aim 3 will explore the role of vascular cells in eWAT dysfunction and inflammation after SCI. Successful completion of the

proposed study may provide novel insight into molecular causes and mechanistic underpinning of maladaptive sensory processing and WAT function after SCI, facilitating the development of strategies targeting WAT function to reduce metabolic and cardiovascular complications after SCI.