365-OR: Maladaptive Sensory Plasticity via α2δ1-subunit Promotes Adipose Tissue Lipolysis after Spinal Cord Injury

Spinal cord injury (SCI) leads to a progressive decline in metabolic homeostasis. Thus far, it is unclear whether the underlying cause of metabolic complications after SCI may be linked to the dysregulation of adipose tissue. The sympathetic nervous system and sensory neurons with cell bodies located in the dorsal root ganglia (DRG) innervate white adipose tissue (WAT). However, the extent to which sensory innervation drives WAT function under normal and pathophysiological conditions has remained elusive. To investigate structural changes in WAT, we subjected adult mice to a thoracic (T)12 SCI that completely transected sensory axons without impacting sympathetic nerve activity. Whereas no changes were observed in iWAT, we found an increase in the percentage of small-size adipocytes in eWAT, a phenotype associated with rapid lipid partitioning. Our biochemical and molecular analysis confirmed that SCI exacerbates lipolysis in eWAT but not in iWAT. After injury, maladaptive reorganization of neuronal circuits can cause aberrant neuron firing that eventually culminates in the onset of post-traumatic disorders. We and others have demonstrated a strong convergence between the rearrangement of neuronal circuits and the expression of α2δ subunits of VGCC. α2δ subunits positively regulate neurotransmitter release by increasing plasma membrane expression of VGCC. We discovered that α2δ1 expression increases in CGRP⁺ DRG neurons that project to eWAT 7 days after SCI. Conditional deletion of the gene encoding α2δ1 in these neurons normalizes eWAT lipolysis after SCI. Using a clinically relevant strategy, we demonstrated that α2δ1 pharmacological blockade also normalizes eWAT lipolysis after SCI, thereby preventing ectopic lipid accumulation in the liver. Thus, our study provides novel insight into the molecular basis of maladaptive sensory processing in eWAT, facilitating the development of strategies to promote metabolic health after SCI.