Transcriptomic analysis in peripheral blood mononuclear cells from hyper and hypo weight-loss responders

Caloric restriction is so far the most effective strategy for weight management. Based on their weight loss response, individuals can be classified as hypo-responders or hyper-responders. Therefore, efforts have been made to understand the molecular mechanisms underlying these differential responses to develop more effective and personalized weight loss interventions. This study aimed to identify changes in gene expression patterns between hyper- and hypo-responders selected from a dietary intervention based on caloric restriction.

At the end of the intervention, both groups showed reductions in all evaluated anthropometric parameters. However, the hyper-responder group lost 82.3% more weight, 81.5% more in BMI, 68.9% more in hip circumference, and 47.97% more in waist circumference compared to the hypo-responder group, with statistically significant differences between groups. On the transcriptomic side, significant differences in gene expression (FDR ≤0.03) were observed between the hyper- and hypo-responder groups. A total of 1,581 genes were differentially expressed, of which only the GSPT1 gene (G1 to S Phase Transition 1) was upregulated, while the rest were downregulated in hypo-responders. Protein-protein interaction network analysis identified the Collagen Chain Trimerization and Collagen Biosynthesis and Modifying Enzymes pathways as significantly enriched (FDR = 0.0041), involving genes such as PLOD1, COL5A3, COL6A5, COL14A1, CRTAP, COL4A5, COL7A1, COL9A1, TLL2, COL20A1, COL4A2, COL24A1, COL16A1, COL5A2, COL15A1, COL4A1, and COL13A1. The upregulation of GSPT1 in hypo-responders may reflect an altered metabolic and inflammatory state that contributes to weight loss resistance. Many of the downregulated genes contribute directly to the mechanical properties of the extracellular matrix (ECM), suggesting a stiffer, less flexible ECM, an environment associated with fibrosis and insulin resistance in obese individuals.

This study provides novel evidence on how gene expression may contribute to the variability in weight loss responses, resulting in a hyper- or hypo-response to caloric restriction. The upregulation of GSPT1 and the downregulation of genes involved in collagen-related pathways are proposed as key molecular mechanisms influencing the hypo-response during caloric restriction.