Pathological Adiposity: When Body Fat Becomes Dysfunctional

Adipose tissue is not an inert reserve. It is a dynamic organ that stores triglycerides, buffers nutrient flux, secretes adipokines and communicates with the liver, skeletal muscle, pancreas, vasculature and brain. Its expansion is therefore not pathological by definition. The problem begins when storage capacity, tissue remodelling and metabolic regulation no longer match the energy load.

This distinction matters because body mass index, or BMI, describes body size rather than tissue function. Two people with the same BMI may have very different amounts of visceral and ectopic fat, different muscle mass, and very different cardiometabolic risk. Conversely, a person with a BMI below the obesity threshold may already have adipose-tissue dysfunction and organ-level abnormalities.

The 2025 Lancet Commission sharpened this idea by distinguishing excess adiposity without current organ dysfunction from clinical obesity, in which excess adiposity is accompanied by objective impairment of tissues, organs, daily function or both. This framework does not make BMI useless; it places BMI in its proper role as a screening measure that requires clinical interpretation.

Healthy expansion versus dysfunctional expansion

A metabolically resilient subcutaneous depot can expand partly through adipogenesis: new adipocytes are recruited and excess lipid is distributed across a larger number of cells. A dysfunctional depot expands predominantly through hypertrophy. Enlarged adipocytes become less responsive to insulin, release more non-esterified fatty acids and are more likely to develop relative hypoxia, extracellular-matrix remodelling, fibrosis and immune-cell recruitment.

Once safe storage capacity is exceeded, lipid flux is redirected towards the liver, skeletal muscle, pancreas, epicardial tissue and perivascular depots. This is the basis of the adipose-tissue expandability model and the “personal fat threshold”: susceptibility depends not only on total fat mass, but also on where fat is stored and how well each depot can remodel.

Distribution matters

Subcutaneous gluteofemoral fat is generally less strongly associated with cardiometabolic disease and may act as a relatively safe storage compartment. Visceral fat drains partly into the portal circulation, has a more inflammatory and lipolytic profile, and tracks closely with insulin resistance, MASLD and cardiovascular risk. Waist circumference and waist-to-height ratio therefore add useful information to BMI.

Yet anthropometry remains an approximation. Sex, age, ancestry, menopausal status, medications, muscle mass and lipodystrophy can all alter the relationship between BMI, fat distribution and risk. Imaging can quantify visceral or hepatic fat more precisely, but is not required for routine assessment in most people.

How dysfunction is transmitted to other organs

Several pathways operate together:

• Impaired insulin suppression of lipolysis increases fatty-acid and glycerol delivery to the liver.
• Adipokine imbalance often includes reduced adiponectin signalling and relative leptin resistance.
• Immune remodelling activates stress and inflammatory pathways, including JNK, IKKβ/NF-κB and NLRP3.
• Ectopic lipid deposition exposes non-adipose tissues to lipid intermediates and organ-specific stress.
• Perivascular adipose dysfunction can impair local vascular signalling.
• Mechanical load and organ infiltration contribute to sleep apnoea, osteoarthritis, cardiac dysfunction and reduced mobility.

No single cytokine or pathway explains the entire syndrome. The phenotype emerges from energy balance, genetics, developmental history, tissue architecture, physical activity, sleep, medications and the capacity of individual organs to compensate.

Clinical assessment

A clinically useful assessment combines:

• BMI as an initial screening measure;
• waist circumference or waist-to-height ratio;
• blood pressure;
• fasting glucose and HbA1c;
• lipid profile;
• assessment for MASLD and fibrosis risk when indicated;
• symptoms and functional impairment, including breathlessness, mobility limitation and sleep-disordered breathing;
• relevant endocrine, reproductive, cardiovascular and musculoskeletal complications.

The aim is not to label every person with excess body fat as ill. It is to identify whether adiposity is already altering organ function, creating a high-risk preclinical state, or remaining relatively uncomplicated.

What is demonstrated, probable or uncertain?

Take-home message

Pathological adiposity is best understood as a failure of safe lipid storage and tissue function, not simply as a high number on the scale. Assessment should integrate body-fat distribution, metabolic and organ abnormalities, symptoms and function. This approach recognises risk earlier while avoiding the opposite error of treating BMI as a diagnosis.

Pathological Adiposity series

1. Pathological adiposity → 2. Metabolic inflammation → 3. Insulin resistance → 4. Ectopic fat → 5. Endothelial dysfunction and hypertension → 6. Reversibility.

Core updated sources

• Rubino F, et al. Definition and diagnostic criteria of clinical obesity. Lancet Diabetes & Endocrinology. 2025. DOI00316-4)
• World Health Organization. Obesity and overweight: fact sheet. Updated 2025.
• EASL–EASD–EASO. Clinical Practice Guidelines on MASLD. 2024.