Corvera Lab Reveals How a Rare Genetic Disorder Causes Fat Cells to Lose Their Identity
A new study from the laboratory of Silvia Corvera, MD, sheds light on why people with a rare condition called congenital generalized lipodystrophy type 2 (CGL2) cannot maintain healthy body fat — and how their fat cells gradually stop functioning over time.
CGL2 is caused by mutations in the BSCL2 gene, which encodes the protein seipin. Patients with this condition lack almost all adipose (fat) tissue and develop serious metabolic complications early in life.
“For years, we believed seipin was mainly needed to form lipid droplets,” said Dr. Corvera, Professor, Program in Molecular Medicine, Endowed Chair in Diabetes Research, T.H. Chan School of Medicine. “What we found is that seipin is actually essential for organizing them correctly.”
Seipin’s real job: helping fat droplets get “wrapped” properly
Inside every fat cell are tiny bubbles of stored fat called lipid droplets. A protein called Perilipin-1 (PLIN1) normally coats these droplets and protects them. Using CRISPR-edited human adipocyte progenitor cells, the team discovered:
- Seipin is not required to make lipid droplets
- It is required to recruit PLIN1 to the droplet surface
“Without seipin, PLIN1 can’t reach the droplet, and the entire architecture of the fat cell becomes unstable,” Dr. Corvera explained. “This triggers a chain reaction inside the cell, which loses its identity as a fat cell.”
Rather than dying, many cells revert toward a progenitor-like state. They can then re-enter the fat-cell program temporarily, only to lose identity again.
“This was one of the most surprising findings,” said Dr. Corvera. “The cells don’t simply die — they de-differentiate. They forget they are adipocytes.”
A “quality-control checkpoint” inside fat cells
The team’s data, published as a bioRxiv preprint, suggests that lipid droplets are more than storage sites.
“We believe lipid droplets act as a quality-control checkpoint,” Dr. Corvera said. “If the droplet is not built correctly, the cell shuts down the adipocyte program.”
Some cells bypass this checkpoint and form a single giant droplet, but these enlarged cells are dysfunctional and cannot support healthy adipose tissue.
Future plans
When the researchers transplanted the edited cells into mice, seipin-deficient cells initially formed human fat tissue — but their function declined more rapidly, mirroring what happens in CGL2 patients.
The study showcases the power of human adipocyte progenitor models developed at UMass Chan Medical School for uncovering disease mechanisms in rare adipose disorders. This platform can now be used to test candidate genes and drugs that might restore healthy lipid droplet architecture and protect fat cell identity.
“Now that we know where the breakdown occurs,” said Dr. Corvera, “we can begin to think about how to prevent it.”
The findings suggest new potential therapeutic directions for rare forms of lipodystrophy by preserving or restoring healthy fat tissue, improving metabolic control, or boosting PLIN1 recruitment or stabilizing cells in an earlier, still functional state. It also extends beyond lipodystrophy. In obesity, adipocytes are also dysfunctional, leading to insulin resistance and type 2 diabetes. Understanding how lipid droplets regulate adipocyte health can help us develop strategies to maintain normal adipocytes in a functional, insulin-sensitive state.
Seipin mediates Perilipin-1 recruitment to lipid droplets to preserve human adipocyte identity
Zhong D, Stavrakaki I, Desai A, DeSouza T, Linskey S, Joyce S, Hatton C, Garcia D, Kassam R, Hendricks G, Reddig K, Gao G, Xie J, Gonzalez-Perez MP, Vieira AFC, Chidley CL, Haley JA, Corvera S.
bioRxiv [Preprint]. 2025 Nov 10:2025.11.09.687445. doi: 10.1101/2025.11.09.687445.
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