The World Obesity Atlas 2023 report stated that 38 percent of the global population was either overweight or obese, and by 2035, the global overweight and obesity prevalence is projected to reach 51 percent (1). This rise in excess body fat, stored primarily in adipose tissue, is closely linked to metabolic disorders like type 2 diabetes and cardiovascular diseases. Understanding the mechanisms behind how adipose tissue forms is therefore critical.

In a recent study, geneticist Bart Deplancke and his team at the Swiss Federal Institute of Technology Lausanne, discovered a cell type in adipose tissue that may be a target for obesity treatment (2). This research provides a greater understanding of adipose regulation, essential in metabolic complications like type 2 diabetes, and may lead to new therapies for these conditions.

“The major driver behind the study was to understand the different cell types in adipose tissue from different anatomical depots and how this would influence disease outcomes,” said Deplancke. 

Fat distribution plays a critical role in health, with omental adipose tissue (OMAT) accumulation around abdominal organs posing a significant threat. Unlike subcutaneous fat, which sits directly under the skin as a long-term energy reserve, OMAT can contribute to metabolic disorders. 

OMAT secretes pro-inflammatory cytokines, which result in a chronic low-grade inflammatory state. This inflammation disrupts insulin signaling and can damage blood vessels, increasing the risk of cardiovascular diseases like atherosclerosis and heart attack. OMAT can also impair the function of the liver, leading to fatty liver disease and potentially more severe complications like cirrhosis. The cellular mechanisms surrounding how OMAT cells grow larger and how they form a distinct compartment from subcutaneous fat remain unclear.

To understand these mechanisms, the researchers conducted single-cell RNA sequencing on tissue biopsies from the subcutaneous adipose tissue and the OMAT from 30 patients. They identified a unique cell population in OMAT: mesothelial cells, which form a single layer of epithelial cells that line internal body cavities to protect them. However, the researchers identified a subset of mesothelial cells in the OMAT expressing high levels of insulin-like growth factor binding protein 2 (IGFBP2). Previous studies established IGFBP2 as a negative regulator of adipogenesis, acting as a brake on the differentiation of preadipocytes into mature fat cells (3).

“The ability of cell types in the omentum to prevent adipogenesis was previously not studied,” Deplancke added.

The ability of cell types in the omentum to prevent adipogenesis has not been found previously.
- Bart Deplanke, Swiss Federal Institute of Technology Lausanne

The researchers used an enzyme-linked immunosorbent assay to confirm that these mesothelial cells secreted IGFBP2, creating a local microenvironment that disfavors adipogenesis. They then co-cultured human adipocytes from OMAT with IGFBP2 alongside its target insulin-like growth factor (IGF), which promotes adipogenesis. Immunofluorescence demonstrated that co-culture of IGFBP2 and IGF decreased adipogenesis compared to cells treated with IGF alone. This confirmed that IGFBP2 secreted from mesothelial cells in the OMAT may play a role in mitigating adipogenesis. 

Beyond the IGFBP2-positive population, the team identified another group of mesothelial cells in OMAT that lacked IGFBP2 expression and possessed the qualities of mesenchymal cells — stem cells that can form fatty tissue. “Finding two different cell types, the mesothelial cells positive for IGFBP2 and the mesenchymal-like cells, was surprising,” said Deplanke. 

“The science is solid and gives a new understanding of heterogeneity and different cell types within tissues that drive important physiological functions,” said Jerome Feige, a geneticist from the Nestlé Institute of Health Sciences who was not part of this study. “It deepens our understanding of fat accumulation and obesity.”

In the future, Deplanke hopes to use mouse models to study how manipulating IGFBP2 affects molecular pathways of fat accumulation. This will hopefully lead to the discovery of targets for new therapeutics for different metabolic disorders. 

References

1. Koliaki, C., Dalamaga, M. & Liatis, S. Update on the Obesity Epidemic: After the Sudden Rise, Is the Upward Trajectory Beginning to Flatten? Curr Obes Rep  12, 514–527 (2023)
2. Ferrero, R. et al. A human omentum-specific mesothelial-like stromal population inhibits adipogenesis through IGFBP2 secretion. Cell Metab  36, 1566-1585 (2024) 
3. Boughanem, H., Yubero-Serrano, E. M., López-Miranda, J., Tinahones, F. J. & Macias-Gonzalez, M. Potential Role of Insulin Growth-Factor-Binding Protein 2 as Therapeutic Target for Obesity-Related Insulin Resistance. Int J Mol Sci  22, 1133 (2021)