The normal-weight metabolic syndrome: Clinical manifestations and pathogenic mechanisms

Metabolic syndrome (MetS), conventionally associated with obesity, also occurs in individuals with a normal body mass index (BMI), revealing an important discordance between body weight and metabolic health. This phenotype, variably described as normal-weight metabolic syndrome (NWMS), metabolically obese normal weight (MONW), or metabolically unhealthy normal weight (MUNW), is characterized by metabolic abnormalities despite the absence of generalized obesity. Reported prevalence varies substantially across populations because of heterogeneity in phenotype definitions, BMI thresholds, metabolic criteria, and population characteristics, and the global burden remains uncertain. Nevertheless, affected individuals have an increased risk of type 2 diabetes and cardiovascular disease compared with metabolically healthy normal-weight individuals. This review critically synthesizes current evidence on the epidemiology, clinical manifestations, diagnostic approaches, and pathogenic mechanisms of NWMS. Visceral and ectopic adiposity, insulin resistance, adipose tissue dysfunction, and chronic low-grade inflammation represent the most consistently supported pathogenic pathways. In contrast, gut microbiota dysbiosis, oxidative stress, ferroptosis, and related molecular processes remain emerging mechanisms with limited evidence specific to normal-weight populations. Recognition of metabolic risk beyond BMI is therefore important, particularly in susceptible populations. A risk-based approach incorporating conventional metabolic assessment, measures of central adiposity, and selective body-composition assessment may improve identification of affected individuals. Harmonized phenotype definitions and studies across geographically and ethnically diverse populations are needed to define the global burden and inform targeted prevention and management strategies.