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Peer-reviewedCC BY 4.0Biomolecules

Beyond BMI: Mapping Clinical, Mechanistic, and Imaging Evidence Relevant to the Thin Outside, Fat Inside Phenotype

  • Sorina Ispas1,2
  • Amit Gupta3,4
  • Maria Diaz-Gutierrez5
  • Victor Velásquez-Rimachi1,6
  • Zamar Anyela Malca Calderon1
  • Syed Arman Rabbani7
  • Dario Madera8
  • Ana Clara Felix de Farias Santos9
  • Sunil Kumar10
  • Jerry Li1,11
  • Darlene Hannele Huanca Salazar1,12
  • Viorel Ispas2
2 more authors
  • Imran Rashid Rangraze13
  • Manfredi Rizzo7,14
14 affiliations
  1. 1Principles and Practice of Clinical Research Program, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
  2. 2Department of Anatomy, Faculty of General Medicine, Ovidius University, 900470 Constanța, Romania
  3. 3Centre for Diabetes Care, Greater Noida 201310, India
  4. 4Department of Medicine, Kasturba Medical College, Manipal Academy of Higher Education (MAHE), Manipal 576104, India
  5. 5Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC 20052, USA
  6. 6Grupo de Investigación Neurociencias, Metabolismo, Efectividad Clínica y Sanitaria (NEMECS), Universidad Científica del Sur, Lima 15001, Peru
  7. 7RAK College of Pharmacy, RAK Medical and Health Sciences University, Ras Al Khaimah 11172, United Arab Emirates
  8. 8Vascular Surgery Department, Hospital de Clínicas Dr. Manuel Quintela, Montevideo 11600, Uruguay
  9. 9City University of São Paulo (UNICID), São Paulo 05305-000, Brazil
  10. 10WHO Collaborating Centre, Imperial College London, London SW7 2AZBW, UK
  11. 11Department of Health and Kinesiology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
  12. 12Universidad Peruana Unión, Lima 15472, Peru
  13. 13RAK College of Medical Sciences, RAK Medical and Health Sciences University, Ras Al Khaimah 11172, United Arab Emirates
  14. 14School of Medicine, PROMISE Department of Health Promotion Sciences, Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, 90133 Palermo, Italy
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Abstract

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 a 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. Evidence from related human phenotypes and experimental models suggests that impaired adipose tissue expandability, visceral and ectopic fat accumulation, inflammation, mitochondrial stress, and lipotoxicity may help explain metabolic dysfunction despite a normal BMI. These mechanisms remain incompletely characterized in populations explicitly defined as TOFI. 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 individuals with a normal BMI.

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Cite

BibTeXRIS
BibTeX
@article{ispas2026beyond,
  title = {{Beyond BMI: Mapping Clinical, Mechanistic, and Imaging Evidence Relevant to the Thin Outside, Fat Inside Phenotype}},
  author = {Sorina Ispas and Amit Gupta and Maria Diaz-Gutierrez and Victor Velásquez-Rimachi and Zamar Anyela Malca Calderon and Syed Arman Rabbani and Dario Madera and Ana Clara Felix de Farias Santos and Sunil Kumar and Jerry Li and Darlene Hannele Huanca Salazar and Viorel Ispas and Imran Rashid Rangraze and Manfredi Rizzo},
  journal = {Biomolecules},
  year = {2026},
  month = oct,
  doi = {10.3390/biom16111543},
  url = {https://www.mdpi.com/2218-273X/16/11/1543},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Beyond BMI: Mapping Clinical, Mechanistic, and Imaging Evidence Relevant to the Thin Outside, Fat Inside Phenotype
AU  - Sorina Ispas
AU  - Amit Gupta
AU  - Maria Diaz-Gutierrez
AU  - Victor Velásquez-Rimachi
AU  - Zamar Anyela Malca Calderon
AU  - Syed Arman Rabbani
AU  - Dario Madera
AU  - Ana Clara Felix de Farias Santos
AU  - Sunil Kumar
AU  - Jerry Li
AU  - Darlene Hannele Huanca Salazar
AU  - Viorel Ispas
AU  - Imran Rashid Rangraze
AU  - Manfredi Rizzo
PY  - 2026
DA  - 2026/10/22
JO  - Biomolecules
DO  - 10.3390/biom16111543
UR  - https://www.mdpi.com/2218-273X/16/11/1543
AB  - 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 a 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. Evidence from related human phenotypes and experimental models suggests that impaired adipose tissue expandability, visceral and ectopic fat accumulation, inflammation, mitochondrial stress, and lipotoxicity may help explain metabolic dysfunction despite a normal BMI. These mechanisms remain incompletely characterized in populations explicitly defined as TOFI. 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 individuals with a normal BMI.
SN  - 2218-273X
ER  -