Metabolically healthy obesity: unraveling phenotypic heterogeneity, biomarker signatures, and risks of progression

The global increase in obesity, driven by socioeconomic development, poses significant public health challenges owing to its phenotypic heterogeneity. Individuals with obesity, according to body mass index (BMI) and metabolism health, are classified into six common subgroups: metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUHNW), metabolically healthy overweight (MHOW), metabolically unhealthy overweight (MUHOW), metabolically healthy obesity (MHO), and metabolically unhealthy obesity (MUHO). Populations with MHO exhibit high BMI but maintain normal glucose, lipid, and insulin levels. However, their long-term risks and mechanisms remain unclear. The relationship between MHO, its biomarkers, and disease risks was examined in this review, emphasizing its clinical significance. Adipose tissue dysfunction driven by chronic inflammation, oxidative stress, and adipokine imbalance underlies metabolic dysregulation. BMI remains widely used as a primary diagnostic tool; nevertheless, its limitation in differentiating MHO from MUHO highlights the importance of incorporating more precise biomarkers, including inflammatory markers, adipokines, myokines, epigenetic regulators, and other clinical indices. Individuals with MHO may initially exhibit a relatively benign metabolic profile; however, they remain at an increased risk of developing type 2 diabetes, cardiovascular diseases, and other cardiometabolic conditions. We propose risk factors for predicting MHO progression, providing critical insights for early intervention and personalized management.