Integrated Analysis of Transcriptome and Secretome of Sensory Neurons Reveals Sex Difference in Pathways Relevant to Insulin Sensitivity and Insulin Secretion

Sensory neurons in the dorsal root ganglia (DRG) convey somatosensory and metabolic cues to the central nervous system and release substances locally from stimulated terminal endings in peripheral organs. Sex-biased variations driven by the sex chromosome complement (XX and XY) have been implicated in the sensory-islet crosstalk. However, the identity of the molecules underlying male-female differences is not known. Here, we aim to characterize the molecular repertoire and the secretome profile of the spinal sensory neurons in sexually immature male and female mice to identify molecules with sex-biased insulin sensing- and/or insulin secretion-modulating activity. We used transcriptomics and proteomics to uncover differentially expressed genes and secreted molecules in DRG sensory neurons derived from 3-week-old male and female C57BL/6J mice. Comparative transcriptome and proteome analyses revealed differential gene expression and protein secretion in DRG neurons in males and females. Interestingly, gene ontology annotation highlighted sex differences in epigenetic regulation, cell cycle, DNA replication and insulin signaling pathways. Secretome analysis uncovered several sex-based variations in conventionally and unconventionally sensory-secreted proteins with potential roles in β-cell function-modulating activity. Collectively, we provide a valuable resource of molecular and secretory targets that can be leveraged for understanding sex differences in DRG sensory neurons. Some of these candidates have translational value as they can inform the development of novel sex-based therapeutic opportunities for individuals with compromised β-cell activity. We used transcriptomics and proteomics to uncover differentially expressed genes and secreted molecules in DRG sensory neurons derived from 3-week-old male and female C57BL/6J mice.