Obesity is an epidemic internationally. While
weight loss interventions are efficacious, they are compounded by heterogeneity with regards to clinically relevant metabolic responses. Thus, we sought to identify metabolic
biomarkers that are associated with beneficial metabolic changes to
weight loss and which distinguish individuals with
obesity who would most benefit from a given type of intervention. Liquid chromatography mass spectrometry-based profiling was used to measure 765 metabolites in baseline plasma from three different
weight loss studies: WLM (behavioral intervention, N = 443), STRRIDE-PD (exercise intervention, N = 163), and CBD (surgical cohort, N = 125). The primary outcome was percent change in
insulin resistance (as measured by the Homeostatic Model Assessment of
Insulin Resistance [%ΔHOMA-IR]) over the intervention. Overall, 92 individual metabolites were associated with %ΔHOMA-IR after adjustment for multiple comparisons. Concordantly, the most significant metabolites were
triacylglycerols (TAGs;
p = 2.3e-5) and
diacylglycerols (DAGs; p = 1.6e-4), with higher baseline TAG and DAG levels associated with a greater improvement in
insulin resistance with
weight loss. In tests of heterogeneity, 50 metabolites changed differently between
weight loss interventions; we found
amino acids,
peptides, and their analogues to be most significant (4.7e-3) in this category. Our results highlight novel metabolic pathways associated with heterogeneity in response to
weight loss interventions, and related
biomarkers which could be used in future studies of personalized approaches to
weight loss interventions.