Two Enzymes Work Together to Promote Fat Cell Growth and Obesity

Researchers have identified two enzymes that cooperate to support the creation of fat cells, pointing to a possible new angle for treating metabolic disease. The study, published in Cellular & Molecular Biology Letters, shows that the deubiquitinases USP25 and USP28 function as complementary proteostatic hubs that help preserve the transcriptional programs that drive adipogenesis, the process that turns precursor cells into fat-storing adipocytes.

The team, led by Joong-Kwon Park, Jung-Hwan Baek, Zolzaya Erdenebileg, Kyung A. Kang, Hack Sun Choi and Kyung-Hee Chun, analyzed adipose tissue from obese human cohorts and from mice given a high-fat diet. In both cases, USP25 and USP28 were elevated at the same time, suggesting that increased activity of the two enzymes accompanies obesity in these models.

To examine their roles more closely, the researchers genetically reduced either USP25 or USP28 in experimental adipocyte-differentiation models. Suppressing either enzyme on its own lowered lipid buildup and weakened the expression of adipogenic genes, showing that both contribute to the fat-forming process. When both were inhibited together, the effect was much stronger, indicating that USP25 and USP28 act in a complementary way within the adipogenic regulatory network.

Follow-up mechanistic tests clarified how the two enzymes divide the work. USP28 was found to stabilize PPARγ, a nuclear receptor that helps drive adipocyte differentiation. USP25, meanwhile, directly bound to and stabilized C/EBPα and C/EBPβ through catalytic deubiquitination. The researchers showed that this activity depends on USP25’s catalytic function, since an inactive mutant, USP25C178S, eliminated the effect. This identifies USP25 as a previously unrecognized proteostatic regulator of the C/EBP adipogenic axis.

Using these molecular findings, the team tested AZ1, a pharmacological inhibitor that can block both USP25 and USP28, as a tool compound. In cell culture, AZ1 reduced adipogenesis and lipid accumulation, matching the results seen with genetic suppression.

Those effects also extended to living animals. In mice fed a high-fat diet, AZ1 reduced body-weight gain and limited the expansion of adipose tissue depots. Metabolic testing showed improved glucose tolerance and greater insulin sensitivity in treated animals. Analysis of adipose tissue confirmed reduced levels of adipogenic regulators, consistent with the compound’s proposed mechanism.

AZ1 also had clear effects in the liver. It lowered hepatic triglyceride and free fatty acid accumulation while increasing hepatic PPARα expression. The authors interpret these changes as evidence of broader metabolic improvement linked to altered communication between adipose tissue and the liver.

Taken together, the findings support a model in which abnormal fat formation is sustained by coordinated proteostatic control of multiple transcriptional pathways rather than by a single master regulator. USP25 stabilizes the C/EBPα/β branch, while USP28 stabilizes the PPARγ branch, and together these two deubiquitinase-dependent nodes maintain the adipogenic transcriptional network.

The authors say that disrupting these complementary DUB-regulated pathways could offer a useful strategy for intervening in metabolic disease. Because dual suppression produced a much stronger inhibitory effect than blocking either enzyme alone, targeting USP25 and USP28 at the same time may be more effective than focusing on just one. AZ1 provides proof of concept for this approach, although it was used here only as an experimental tool and not as a validated therapeutic candidate. Further studies will be needed to determine whether dual inhibition of these proteostatic nodes can be translated safely and effectively into human treatment.

Subject of Research: The complementary roles of deubiquitinases USP25 and USP28 in sustaining adipogenic transcriptional networks and metabolic dysfunction

Article Title: Complementary USP25 and USP28 proteostatic nodes sustain adipogenic transcriptional networks and metabolic dysfunction

Article References: Park, J.-K., Baek, J.-H., Erdenebileg, Z., Kang, K. A., Choi, H. S., & Chun, K.-H. (2026). Complementary USP25 and USP28 proteostatic nodes sustain adipogenic transcriptional networks and metabolic dysfunction. Cellular & Molecular Biology Letters. https://doi.org/10.1186/s11658-026-01044-1

Image Credits: AI Generated

Keywords: USP25, USP28, deubiquitinases, adipogenesis, PPARγ, C/EBPα, C/EBPβ, obesity, metabolic dysfunction, AZ1, proteostasis, high-fat diet

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Daisy Hatcher.

Daisy Hatcher. "Two Enzymes Work Together to Promote Fat Cell Growth and Obesity." Scienmag.