8154 The Pro-Fibrotic Transcriptional Profile of Adipose Tissue in Insulin Resistant Individuals
Authors: Choi M , Abdellatif A , Alba D L , Koliwad S K 
Published: October 2024

Disclosure: M. Choi: None. A. Abdellatif: None. D.L. Alba: None. S.K. Koliwad: None.

Introduction: Adipose tissue (AT) fibrosis is linked to AT dysfunction including insulin resistance, and individuals with type 2 diabetes (T2D) have higher AT fibrosis than do healthy individuals. However, the molecular pathways underlying the link between AT fibrosis and insulin resistance is not understood. Here we examined the transcriptional underpinnings of subcutaneous adipose tissue (SAT) fibrosis in non-diabetic individuals with divergent levels of insulin resistance. Methods: We analyzed individuals without T2D from the established Inflammation, Diabetes, Ethnicity, and Obesity (IDEO) cohort who undergo extensive metabolic phenotyping including SAT biopsy. The diverse racial and ethnic composition of the IDEO cohort offered a distinct advantage in investigating a wide range of SAT fibrosis and insulin sensitivity. AT fibrosis was quantified by measuring SAT hydroxyproline levels and by histology. A customized panel (Nanostring) was used to profile the fibrosis-related transcriptomes within the SAT. The panel included 14 probes for quality control, 8 for housekeeping genes (ACAD9, ARMH3, CNOT10, GUSB, MTMR14, NOL7, NUBP1, HPRT1) and 772 for fibrosis-associated genes. Participants were categorized as either insulin-sensitive (IS) or insulin-resistant (IR) based on HOMA-IR &lt;2.05 or ≥2.05. To identify differentially expressed genes between IS and IR individuals, we utilized an R package (NanostringDiff), correcting for confounders including age, sex, race, ethnicity, percent body fat and batch effects. Results: A total of 44 individuals were included in the analysis: 29 individuals were IR and 15 were IS. The mean ages were similar: 44 ± 12 years for IR and 46 ± 13 for IS (p&gt;0.05). Sex distribution was comparable: men making up 53% of the IR group and 47% of the IS group (p&gt;0.05). Notably, IR individuals had significantly higher levels of hydroxyproline in the SAT (190.9ng/mg, 572.5ng/mg, p&lt; 0.01). Among the 772 genes from the fibrosis panel, 93 genes were upregulated, and 22 genes were down regulated in the SAT of IR group compared to IS group. Upregulated genes included multiple genes encoding inflammatory chemokines (e.g. CCR2, CCR4), matrix metalloproteinases (e.g. MMP3, MMP7), and interestingly several genes associated with idiopathic pulmonary fibrosis (e.g. CSF3R, SERPINE1, S100A12). By contrast, downregulated mRNAs in the IR group included those of genes encoding proteins associated with glucose uptake and lipid storage (e.g. GLUT4, FASN). Conclusion: Among individuals without T2D, relative IR is associated with increased SAT fibrosis with increased transcription of specific genes encoding key inflammatory cytokines, matrix metalloproteinases, and interestingly proteins known to be involved in other pathologic forms of tissue fibrosis. These findings connect the AT fibrosis seen in the context of IR to a specific pro-fibrotic transcriptional landscape.

Presentation: 6/3/2024