Whole-genome transcriptomic insights into protective molecular mechanisms in metabolically healthy obese African Americans

Amadou Gaye, Ayo P Doumatey, Sharon K Davis, Charles N Rotimi, Gary H Gibbons, Amadou Gaye, Ayo P Doumatey, Sharon K Davis, Charles N Rotimi, Gary H Gibbons

Abstract

Several clinical guidelines have been proposed to distinguish metabolically healthy obesity (MHO) from other subgroups of obesity but the molecular mechanisms by which MHO individuals remain metabolically healthy despite having a high fat mass are yet to be elucidated. We conducted the first whole blood transcriptomic study designed to identify specific sets of genes that might shed novel insights into the molecular mechanisms that protect or delay the occurrence of obesity-related co-morbidities in MHO. The study included 29 African-American obese individuals, 8 MHO and 21 metabolically abnormal obese (MAO). Unbiased transcriptome-wide network analysis was carried out to identify molecular modules of co-expressed genes that are collectively associated with MHO. Network analysis identified a group of 23 co-expressed genes, including ribosomal protein genes (RPs), which were significantly downregulated in MHO subjects. The three pathways enriched in the group of co-expressed genes are EIF2 signaling, regulation of eIF4 and p70S6K signaling, and mTOR signaling. The expression of ten of the RPs collectively predicted MHO status with an area under the curve of 0.81. Triglycerides/HDL (TG/HDL) ratio, an index of insulin resistance, was the best predictor of the expression of genes in the MHO group. The higher TG/HDL values observed in the MAO subjects may underlie the activation of endoplasmic reticulum (ER) and related-stress pathways that lead to a chronic inflammatory state. In summary, these findings suggest that controlling ER stress and/or ribosomal stress by downregulating RPs or controlling TG/HDL ratio may represent effective strategies to prevent or delay the occurrence of metabolic disorders in obese individuals.

Conflict of interest statement

The authors declare no competing financial interests.

Figures

Fig. 1
Fig. 1
Plots of the normalized expression of the top 7 DE genes in the lightpink module and the top gene (RPL37A) in the khaki4 module
Fig. 2
Fig. 2
Model performance and ranking of (a) 15 genes from the lightpink module and (b) a subset of 10 genes identified through variable selection that collectively predict MHO with the same performance
Fig. 3
Fig. 3
Prediction of gene expression using individual components of MHO definition: TG/HDL ratio is the best predictor of MHO status
Fig. 4
Fig. 4
Graphical depiction of the three complementary analytical strategies implemented in this study

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