Trying to lose weight to stay healthy? Most people think that the less body fat they have, the lower their risk of diabetes. But what if losing the wrong kind of fat could actually harm your metabolism?

A new study published in the Journal of Clinical Investigation suggests exactly that. Researchers found that healthy fat tissue is an active organ essential for storing fat, regulating hormones and maintaining blood sugar levels. When this healthy fat tissue becomes damaged and disappears, it can disrupt metabolism and contribute to diabetes, even in people who are not obese.

How can losing fat increase the risk of diabetes?

Too much body fat is a well-known risk factor for diabetes, heart disease and other metabolic disorders. However, scientists say losing healthy fat tissue can also have serious consequences. This is seen in a rare inherited condition called familial partial lipodystrophy type 2 (FPLD2), in which people gradually lose fat from certain parts of the body while accumulating it in others. Despite having less body fat overall, many develop insulin resistance, diabetes and abnormal cholesterol levels.

FPLD2 is caused by disease-causing variants in the LMNA gene, which produces lamin A/C proteins that help maintain the structure and function of the cell nucleus. Although the condition is rare, researchers say it offers valuable insight into why healthy fat tissue is essential for metabolic health.

To investigate the disease, researchers recruited eight families with developing or established FPLD2 and performed clinical assessments, microscopic examination of fat tissue and gene-expression analyses of subcutaneous fat biopsies. They also studied genetically engineered mice lacking lamin A/C in fat cells and laboratory-grown cells carrying similar defects.

The researchers found that people in the early stages of FPLD2 already had lower body fat than healthy individuals, even before developing obvious metabolic problems. However, diabetes-related abnormalities, including elevated HbA1c and abnormal blood lipids, became apparent only after substantial fat loss.

According to the researchers, “Even before overt adipose loss and metabolic dysfunction, participants with developing FPLD2 displayed reduced total body fat. Only patients with developed FPLD2 had elevated HbA1c, hyperlipidemia, and FGF21, indicating that systemic metabolic dysfunction emerges later with severe adipose loss.”

Microscopic examination showed that although fat cell size initially remained similar, fibrosis appeared to increase in some patients. In mice, fat cells eventually became shrunken, irregular and gradually disappeared. Although the body attempted to regenerate new fat cells, the recovery remained incomplete.

“We propose that LMNA-variant precursors form adipocytes early in life, but as mature adipocytes turn over (~10-year lifespan), new adipocytes fail to efficiently replace them,” the researchers proposed.  

What happens when healthy fat cells disappear?

The researchers found that fat cells lose their normal function long before they die.

Gene-expression analyses showed that pathways responsible for fat production, lipid storage and mitochondrial energy production were significantly reduced, while inflammatory pathways became increasingly active.

Across human tissue, mouse models and laboratory cells, important genes involved in lipid metabolism – including SCD1, ChREBP and SREBP1- were consistently suppressed. As a result, fat cells gradually lost their ability to safely store lipids.

The study also found impaired mitochondrial function, suggesting that fat cells were producing less energy. According to the researchers, defects in lipid metabolism appeared before mitochondrial dysfunction, indicating they may be among the earliest changes driving disease progression.

Inflammation also increased. Interestingly, the inflammation appeared to arise from the fat cells themselves rather than from invading immune cells.

The researchers wrote, “RT-qPCR showed upregulation of immune genes within Lmna-KO adipocytes, suggesting adipocyte-intrinsic inflammation.”

The team also observed changes in several other cell types within adipose tissue. Stem and precursor cells increased, suggesting the body was attempting to regenerate lost fat, while specialised macrophages became more abundant, likely helping clear lipids released from dying fat cells.

By comparing different fat depots, researchers found that supporting cells behaved differently in various regions of the body, which may explain why some fat stores disappear while others enlarge.

“Collectively, our findings support a model in which lamin A/C disruption broadly impairs chromatin organization, driving lipid, mitochondrial, and inflammatory dysregulation across cell types,” they added. 

What are the limitations of the study?

The researchers acknowledged several limitations. The human study included a relatively small number of participants spanning a wide age range and both sexes, which may have introduced variability. Fat tissue from the legs, one of the earliest regions affected in FPLD2, was not examined.

Because mature fat cells are fragile, the researchers used single-nucleus RNA sequencing rather than single-cell RNA sequencing, limiting the detection of certain cellular transcripts.

The mouse model also does not exactly replicate the human disease.

According to the researchers, “Our adipocyte-specific Lmna-KO model does not genetically mirror human FPLD2; future studies should employ knockin models to assess pathogenic LMNA variants in WAT.”

The authors also noted that tamoxifen, used to induce gene deletion in mice, can itself cause fat loss at higher doses. To minimise this effect, they used lower doses and treated control animals identically.

“Lamin A/C is essential for adipocyte homeostasis, survival, lipid metabolism, and mitochondrial function; its disruption drives inflammation, adipocyte shrinkage, and eventual cell loss,” they concluded. 

Expert insights: What should people know before trying to lose weight? 

According to Dr Mahesh D M, Senior Consultant – Endocrinology, Aster CMI Hospital, Bengaluru, the study reinforces that body fat should not be viewed merely as excess weight but as a vital metabolic organ that plays an essential role in maintaining overall health.

He explained that healthy fat tissue safely stores excess lipids, produces hormones involved in regulating appetite and insulin sensitivity, and helps maintain normal blood sugar levels. When healthy fat tissue is lost, as seen in familial partial lipodystrophy type 2 (FPLD2), fat can no longer be stored properly and instead accumulates in organs such as the liver and muscles, contributing to insulin resistance and diabetes.

“These findings reinforce that both the quantity and quality of fat matter. While obesity remains a major diabetes risk factor, inadequate or dysfunctional fat tissue can also impair metabolism, emphasising the importance of maintaining healthy, functional fat rather than focusing solely on reducing body fat,” he said.

Dr Mahesh cautioned that the findings should be interpreted carefully because FPLD2 is a rare inherited disorder and differs significantly from obesity seen in the general population. He emphasised that for most people, gradual weight loss through a balanced diet, regular physical activity and medically supervised weight-loss treatments improves insulin sensitivity and lowers the risk of diabetes.

However, he said the study serves as an important reminder that preserving healthy fat function is equally important.

“Rapid, extreme or poorly monitored weight loss, severe calorie restriction or inappropriate use of weight-loss medications may negatively affect muscle mass and fat health in some individuals. The goal should be sustainable fat loss while maintaining overall metabolic health,” he added.

Addressing whether unhealthy fat loss can be detected early, Dr Mahesh said there is currently no single routine test that directly measures healthy fat tissue function. Instead, doctors rely on a combination of clinical examination, blood tests and imaging studies.

He explained that “unexplained loss of fat from the limbs, buttocks or face, along with increasing fat around the abdomen or neck, may indicate abnormal fat distribution and should prompt further evaluation. Blood tests sucsah as fasting glucose, HbA1c, fasting insulin, lipid profile and liver function tests can help detect early metabolic abnormalities, while DEXA scans or MRI may be used in selected cases to assess body fat distribution.”

“For people with a strong family history or suspected genetic lipodystrophy, genetic testing and specialist evaluation can help establish an early diagnosis before significant metabolic complications develop,” he added. 

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