Unexpected lipid drop in obesity may hold key to new treatments

A new study has turned a long-standing belief about cardiovascular disease on its head. Rather than being caused by a build-up of fat molecules called ceramides, researchers have found that in obesity and diabetes, it’s actually the decrease of these fats in blood vessels that may lead to health problems.

Published in Nature Communications the research challenges the idea that ceramides accumulate in blood vessels to drive inflammation. Instead, it shows that ceramides in the endothelial cells, the thin layer lining blood vessels, are reduced in obesity, contributing to a range of metabolic and cardiovascular disorders.

“Until now, it was widely assumed that high ceramide levels in blood vessels were harmful. But that was based mostly on lab-based studies,” explained lead author Dr Annarita Di Lorenzo, Professor of Pathology and Laboratory Medicine at Weill Cornell Medicine. “This is the first time we've measured ceramides in vivo in endothelial cells of an animal model. What we found was quite unexpected — ceramide levels were actually lower in obese mice fed a high-fat diet compared to lean controls.”

Ceramides are waxy lipid molecules found throughout the body. In blood vessels, they play a vital role in regulating tone and blood flow, preventing clotting, and modulating blood pressure. The team, including co-first authors Dr Onorina L. Manzo and Luisa Rubinelli, believe these lipids are more protective than previously thought.

The study also sheds light on the role of two proteins, Nogo-B and ORMDL, which suppress ceramide production. In obese mice, high levels of Nogo-B led to a drop in both ceramides and their protective by-product, sphingosine-1-phosphate (S1P). This imbalance triggered inflammation, raised blood pressure, impaired vascular function, and disrupted glucose metabolism — all hallmarks of cardiometabolic disease.

Intriguingly, when researchers deleted Nogo-B specifically in the endothelial cells of obese mice, they saw a significant improvement in vascular health — even though the animals maintained the same weight and diabetic profile.

“This clearly shows that it’s not just fat or sugar causing damage, but how lipids like ceramides are regulated in the blood vessels,” said Dr Di Lorenzo. “By preserving ceramide levels, we can protect vascular function, even in the presence of obesity and diabetes.”

The findings point to a promising new therapeutic target. If scientists can develop a drug to block Nogo-B, it may be possible to restore healthy ceramide levels, improving cardiovascular health and helping to manage conditions such as type 2 diabetes, hypertension, and coronary artery disease.

“This research turns our thinking upside down,” added Dr Di Lorenzo. “Rather than trying to lower ceramides, we may need to preserve or even boost them to support blood vessel health in people with obesity.”