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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE228189 | GEO | 2023/09/20

REPOSITORIES: GEO

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Project description:Sensory neurons are distinguished by distinct signaling networks and receptive characteristics. Thus, sensory neuron types can be defined by linking transcriptome-based neuron typing with the sensory phenotypes. Here we classify somatosensory neurons of the mouse dorsal root ganglion (DRG) by high-coverage single-cell RNA-sequencing (10 950 Â± 1 218 genes per neuron) and neuron size-based hierarchical clustering. Moreover, single DRG neurons responding to cutaneous stimuli are recorded using an in vivo whole-cell patch clamp technique and classified by neuron-type genetic markers. Small diameter DRG neurons are classified into one type of low-threshold mechanoreceptor and five types of mechanoheat nociceptors (MHNs). Each of the MHN types is further categorized into two subtypes. Large DRG neurons are categorized into four types, including neurexophilin 1-expressing MHNs and mechanical nociceptors (MNs) expressing BAI1-associated protein 2-like 1 (Baiap2l1). Mechanoreceptors expressing trafficking protein particle complex 3-like and Baiap2l1-marked MNs are subdivided into two subtypes each. These results provide a new system for cataloging somatosensory neurons and their transcriptome databases. RNA-seq of mRNA levels in 197 individual DRG neurons We performed RNA-seq on total 203 individual DRG neurons. Six of them were not qualified and thus, were excluded for further analysis. To evaluate the quality of RNA-seq, we randomly devided No.72 neurons into two parts and performed RNA-seq seperately. Thus, we had 204 individual samples from 203 individual DRG and 198 individual qualified samples from 197 individual DRG. To evaluate the homogeneity of RNA-seq data from different mice at the same age just as used, we performed RNA-seq on 5 single DRG from different mice. Here, these data from DRG were also considered as experimental control. The 'DRG_neurons_RNA_Seq.txt' contains processed data for 204 samples and 'DRG_RNA_Seq.txt' for 5 samples.

Project description:Insulin receptor (Insr) protein can be found at higher levels in pancreatic b-cells than in most other cell types, but the consequences of b-cell insulin resistance remain enigmatic. Ins1cre allele was used to delete Insr specifically in b-cells of both female and male mice which were compared to Ins1cre-containing littermate controls at multiple ages and on multiple diets. RNA-seq of recombined b-cells revealed significant differences in multiple pathways previously implicated in insulin secretion and cellular fate, including rewired Ras and NFkB signaling. Male, but not female, bInsrKO mice had reduced oxygen consumption rate, while action potential and calcium oscillation frequencies were increased in Insr knockout b-cells from female, but not male mice. Female bInsrKO and bInsrHET mice exhibited elevated insulin release in perifusion experiments, during hyperglycemic clamps, and following i.p. glucose challenge. Deletion of Insr did not reduce b-cell mass up to 9 months of age, nor did it impair hyperglycemia-induced proliferation. Based on our data, we adapted a mathematical model to include b-cell insulin resistance, which predicted that b-cell Insr knockout would improve glucose tolerance depending on the degree of whole-body insulin resistance. Indeed, glucose tolerance was significantly improved in female bInsrKO and bInsrHET mice when compared to controls at 9, 21 and 39 weeks. We did not observe improved glucose tolerance in adult male mice or in high fat diet-fed mice, corroborating the prediction that global insulin resistance obscures the effects of b-cell specific insulin resistance. We further validated our in vivo findings using the Ins1-CreERT transgenic line and found improved glucose tolerance 4 weeks after tamoxifen-mediated Insr deletion. Collectively, our data show that loss of b-cell Insr alone is sufficient to drive glucose-induced hyperinsulinemia, thereby improving glucose homeostasis in otherwise insulin sensitive dietary and age contexts.

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

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