Beyond the BMI Paradox: Unraveling the Cellular and Molecular Determinants of Metabolic Health in Obesity.

Obesity has traditionally been considered a major risk factor for numerous metabolic disorders and diseases. However, a subset of individuals with obesity, classified as having "metabolically healthy obesity" (MHO), display relatively normal metabolic parameters despite excess adiposity. This review critically examines the current knowledge surrounding MHO, including its various definitions, prevalence, clinical characteristics, contributing factors, and long-term outcomes. While MHO carries lower health risks compared to metabolically unhealthy obesity (MUO), evidence consistently demonstrates increased disease risk compared to metabolically healthy normal-weight individuals, particularly for type 2 diabetes, cardiovascular disease, chronic kidney disease, and certain cancers. MHO prevalence ranges from 10 to 30% among individuals with obesity globally, varying by sex, age, BMI, and ethnicity. Multiple factors contribute to the MHO phenotype, including beneficial adipose tissue distribution patterns, enhanced adipocyte function, favorable genetic profiles, and lifestyle factors. Recent single-cell transcriptomic analyses have identified specific cell populations, particularly mesothelial cells, as key drivers of metabolic health in visceral adipose tissue. The discovery of persistent epigenetic memory of obesity provides molecular evidence for why MHO often represents a transient state, with many individuals progressing to MUO over time. Emerging evidence also reveals differential therapeutic responses to GLP-1 receptor agonists between MHO and MUO phenotypes, highlighting the need for precision medicine approaches. The concept of MHO has important clinical implications for risk stratification and personalized treatment approaches. This review synthesizes current evidence while highlighting knowledge gaps and future research directions in this rapidly evolving field.