T‐Cell Signaling Pathways, Including Exhaustion, Predominate in Unhealthy Visceral and Subcutaneous Adipose Tissues

OBJECTIVE: Obesity is an imperfect correlate of metabolic health. Visceral adipose tissue (VAT) characteristics are considered determinants of poor health and subcutaneous adipose tissue (SAT) considered protective. There is a gap in knowledge regarding shared vs. unique SAT and VAT function across the metabolic syndrome (MetS) spectrum. METHODS: We quantified SAT and VAT transcriptomes in a nonhuman primate model of MetS. We calculated quantitative MetS risk scores using composite factors, applied unbiased clustering methods (weighted gene correlation network analysis) to identify transcripts that correlated with MetS risk scores, and performed pathway enrichment analysis. RESULTS: We found convergence in SAT and VAT on T-cell signaling genes and pathways, with T-cell exhaustion signaling prominent. Pathways unique to VAT highlighted interferon signaling and innate/adaptive immune cross talk in response to pathogens. Pathways unique to SAT included innate immune cell signaling, centered on vascular involvement. Although molecular signatures highlight T-cell signaling, T-cell abundance in VAT was unrelated to MetS scores. CONCLUSIONS: T-cell signaling and exhaustion predominate in metabolically unhealthy adaptations of both SAT and VAT. This novel handling of transcript data using an unbiased clustering approach and the creation of continuous MetS scores lead to new insights regarding adipose depot responses and T-cell biology.