Figure 5.

Polygenic risk effects for insulin resistance affect lipid degradation in differentiated visceral adipocytes

(A) Donors from the bottom and top 25 percentiles of genome-wide PRS for three T2D-related traits (HOMA-IR, T2D, WHRadjBMI) were selected to compare LipocyteProfiles across the time course of visceral and subcutaneous adipocyte differentiation.

(B) LipocyteProfiler applied to visceral and subcutaneous differentiating adipocytes reveals trait-specific polygenic effects on image-based cellular signatures for HOMA-IR in differentiated visceral AMSCs (day 14; largely Lipid features) and WHRadjBMI in subcutaneous adipocytes (day 14, largely Mito and Lipid features), but no effect for T2D. See also Figures S5A and S5D (days 0, 3, and 8).

(C) HOMA-IR polygenic risk in visceral AMSCs manifested in altered lipid texture, lipid granularity, and cell shape features, resembling an inhibition of lipolysis. y axis shows LP units (normalized LP values across eight batches, see STAR Methods). See also Figure 4B (isoproterenol stimulation).

(D) Linear regression of gene expression levels of 512 genes known to be involved in adipocyte function with HOMA-IR PRS.

(E) Pathway enrichment analysis of genes that correlate with HOMA-IR PRSs (FDR < 10%) in visceral adipocytes highlight biological processes related to glucose metabolism, fatty acid transport, degradation, and lipolysis (KEGG pathways 2019).

(F) Representative genes that associate with HOMA-IR PRS in visceral adipocytes.