Scientists have found that visceral fat and subcutaneous fat produce different responses to obesity in male mice and human patients and identified an important regulator of these processes [1].
The tale of the two fats
It has been known that visceral fat, which accumulates around organs in the abdomen, and subcutaneous fat, which accumulates under the skin, are different. Epidemiological studies have shown a stronger correlation with metabolic dysfunction, disease, and mortality for the former than the latter [2]. However, the reasons for that are not entirely understood.
Fat tissue is also highly vascularized, since it plays a crucial role in regulating energy metabolism. A new study, coming from the German Centre for Cardiovascular Research (DZHK) and published in Nature Communications, uses state-of-the-art tools to analyze how endothelial cells (EC), which line our blood vessels, behave in white adipose tissue (WAT) under the stressful conditions of diet-induced obesity.
A new cell type and the factor that protects it
The researchers worked with mice fed either a normal or a high-fat diet (HFD) for eight weeks. In response to HFD, mice showed a significant reduction in blood vessel density in both subcutaneous WAT (sWAT) and visceral WAT (vWAT), a phenomenon known as vascular rarefaction [3].
Using a high-throughput single-cell RNA sequencing analysis of ECs from both sWAT and vWAT depots in mice, the researchers discovered a unique subset of ECs in sWAT characterized by “fenestrae,” or pores. Those “fenestrated” ECs were more abundant in the sWAT of lean mice but greatly reduced in obese ones. These cells’ molecular marker, ITM2A, was also significantly downregulated in tissues from human patients with obesity compared to lean individuals.
Based on what is known about the function of similar cells in other endocrine organs, the authors suggest that fenestrated ECs facilitate fast and efficient exchange of nutrients, hormones, and signal molecules between the fat tissue and the bloodstream. Their loss during obesity could therefore impair the healthy metabolic function of the fat depot.
The study identified vascular endothelial growth factor A (VEGFA) as essential for maintaining these specialized cells. VEGFA levels were significantly reduced in the obese mice, but this occurred only in sWAT and not in vWAT. Interestingly, the study also revealed a time-dependent effect: a four-week HFD actually caused a temporary VEGFA upregulation, suggesting a short-lived compensatory response.
To prove VEGFA’s role, the researchers first systemically blocked VEGFA in mice with an antibody, which caused a reduction in both total blood vessel density and the specific population of fenestrated vessels in sWAT. They then experimented with Vegfa gene loss of function, which also resulted in a significant decrease in fenestrated vessels. Finally, in a gain-of-function experiment, mice with genetically increased VEGFA levels showed higher overall vascular density.
“This mechanism can be observed not only in mice but also in human fat tissue,” said Prof. Andreas Fischer, director of the Department of Clinical Chemistry at the University Medical Center Göttingen. “It opens up new strategies for preserving or restoring vascular health in obesity.”
Different responses
The researchers also found that vWAT and sWAT responded differently to HFD-induced obesity. ECs in vWAT ran what the researchers call a vascular augmentation program, seemingly in an attempt to keep up with the expanding tissue. This included upregulation of factors that have been previously shown to cause pathogenic angiogenesis and fibrosis. ECs in sWAT, in contrast, reacted by upregulating inflammation-related factors, such as the RAGE pathway.
“Our findings show that vascular changes in obesity begin earlier than previously thought and that they differ considerably depending on fat location,” Fischer noted. “This places the blood vessels themselves more at the center of research on obesity and metabolic diseases.”
“These results provide a valuable foundation for future therapies, such as approaches to specifically improve blood vessel function in fat tissue and prevent secondary diseases like diabetes or heart attacks,” Dr. Sana Hasan, the study’s first author, said.
However, no VEGFA gain-of-function experiments were conducted in HFD-fed mice, so its therapeutic potential for obesity was not tested in this proof-of-concept study. Notably, since VEGFA causes vascular growth, it might exacerbate obesity-related changes in vWAT, despite its seemingly protective role in sWAT.
Another important limitation was the exclusive use of male mice and tissues from male human patients. The biology of fat tissue is known to be different between the sexes [4], which reduces the study’s generalizability, despite its valuable insights.
Literature
[1] Hasan, S.S., John, D., Rudnicki, M. et al. Obesity drives depot-specific vascular remodeling in male white adipose tissue. (2025) Nat Commun 16, 5392.
[2] Kuk, J. L., Katzmarzyk, P. T., Nichaman, M. Z., Church, T. S., Blair, S. N., & Ross, R. (2006). Visceral fat is an independent predictor of all‐cause mortality in men. Obesity, 14(2), 336-341.
[3] Paavonsalo, S., Hariharan, S., Lackman, M. H., & Karaman, S. (2020). Capillary rarefaction in obesity and metabolic diseases—organ-specificity and possible mechanisms. Cells, 9(12), 2683.
[4] Power, M. L., & Schulkin, J. (2008). Sex differences in fat storage, fat metabolism, and the health risks from obesity: possible evolutionary origins. British journal of nutrition, 99(5), 931-940.
