The findings challenge the idea that metabolic disease is caused only by having too much body fat. They show that losing healthy adipose tissue can also destabilise blood sugar regulation by forcing fat into organs that are poorly equipped to store it.
Researchers examined familial partial lipodystrophy type 2, or FPLD2, a disorder marked by the progressive loss and redistribution of fat. People with the condition can appear lean in parts of the body while accumulating fat elsewhere, including around abdominal organs. Many develop severe insulin resistance, diabetes, high triglycerides and fatty liver disease.
The disorder is linked to harmful variants in the LMNA gene, which provides instructions for producing the structural proteins lamin A and lamin C. These proteins help maintain the shape and function of the cell nucleus and influence gene activity.
The investigation combined fat-tissue samples from 16 people belonging to eight families with confirmed LMNA variants with experiments in mice and cultured cells. It was the largest FPLD2 biopsy cohort examined using single-cell analysis of adipose gene activity.
The results indicated that affected fat cells progressively lost the molecular machinery needed to manufacture, process and store lipids. Genes involved in fatty-acid metabolism, triglyceride production and mitochondrial activity became less active, while inflammatory and cell-death programmes intensified.
Mitochondria, the structures that generate energy inside cells, also became disorganised and less efficient. These failures appeared before the fat cells visibly deteriorated, suggesting that metabolic disruption begins well before the tissue disappears.
In an inducible mouse model, scientists switched off Lmna only in mature fat cells. The cells initially appeared broadly normal despite an early decline in fat mass. They later became smaller and misshapen, developed irregular membranes and were almost entirely absent from some fat deposits within 16 weeks.
The disappearing cells were not simply emptying their stored fat through conventional lipolysis. Measurements of glycerol release, gene activity and lipid-breaking proteins indicated that excessive fat mobilisation was not the main cause. The evidence instead pointed to progressive cellular degeneration followed by clearance from the tissue.
Affected adipocytes also produced inflammatory signals themselves. This was important because inflammation in dysfunctional fat is commonly attributed to invading immune cells. The mouse tissue showed no early rise in major populations of macrophages or T cells, indicating that the fat cells could initiate inflammatory activity before substantial immune-cell accumulation.
Healthy adipose tissue acts as a metabolic buffer. It stores surplus energy as triglycerides, releases hormones such as adiponectin and helps regulate how the body responds to insulin. When that storage capacity is lost, circulating fatty acids can accumulate in the liver, skeletal muscle and pancreas.
This ectopic fat can impair insulin signalling, increase liver-fat production and place greater pressure on pancreatic beta cells, which manufacture insulin. Blood glucose can then rise even when a person does not carry a large overall volume of body fat.
The mechanism helps explain why people with lipodystrophy may develop severe metabolic disease despite having limited subcutaneous fat. It also supports a broader distinction between the quantity and quality of adipose tissue.
Some people with obesity retain relatively functional fat tissue that continues to expand and store lipids beneath the skin. Others develop enlarged, inflamed or fibrotic fat deposits that can no longer accommodate additional energy. The overflow into other organs is strongly associated with insulin resistance and type 2 diabetes.
The findings do not mean that ordinary weight loss raises diabetes risk. Intentional loss of excess body weight generally improves insulin sensitivity and reduces harmful fat around internal organs. The study concerns pathological destruction or dysfunction of adipocytes, particularly in a rare genetic condition, rather than fat reduction achieved through diet, exercise or medical treatment.
Researchers said the work could guide therapies designed to preserve fat-cell function before tissue loss becomes advanced. Potential approaches may involve restoring lipid-processing pathways, protecting mitochondrial activity or reducing inflammation generated within adipocytes.
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