Beyond BMI: Molecular Mechanisms, Preclinical Models, and Imaging Strategies for the Thin Outside, Fat Inside Phenotype

Body mass index (BMI) is widely used in clinical practice, but it does not directly reflect fat distribution, ectopic adiposity, or adipose tissue function. Individuals with normal or near-normal BMI may still have excess visceral fat. The Thin Outside, Fat Inside (TOFI) phenotype describes this mismatch between external body size and internal adiposity. This structured narrative review examined TOFI and related normal-weight phenotypes, focusing on visceral and ectopic fat, adipose tissue dysfunction, molecular mechanisms, imaging, and organ-specific risk. A literature search was conducted in PubMed/MEDLINE, Scopus, and Web of Science for English-language studies published mainly between 2021 and 2026. Earlier seminal and directly relevant studies were also included. Current evidence suggests that TOFI-related biology may involve visceral, hepatic, pancreatic, epicardial, perivascular, and intramuscular fat, along with impaired adipose tissue expandability, hypoxia, inflammation, adipokine imbalance, mitochondrial stress, lipotoxicity, and insulin resistance. Preclinical models and imaging methods may help characterize TOFI-like features. Diagnostic criteria are still heterogeneous, and TOFI-specific longitudinal and intervention data remain limited. TOFI may serve as a useful translational framework for identifying hidden adiposity and metabolic risk in people with normal BMI.