Ceramides are early responders in metabolic syndrome development

Image of overweight person on an escalator.
Excerpt from NIH National Heart, Lung and Blood Institute animated video: https://www.nhlbi.nih.gov/health/overweight-and-obesity

By Jordana Lenon
July 18, 2022  

You may have heard of ceramides as moisture-preserving molecules found in skin, but in the blood stream these molecules may be detectors of early risk for developing metabolic syndrome, a University of Wisconsin–Madison study has found.

Ceramides are a type of lipid and they are not only important in keeping skin healthy, hydrated and functioning as it should, but may also be the gatekeepers that sound the alarm on the possibility of developing metabolic syndrome.

Metabolic syndrome, which affects about a third of U.S. adults, is a constellation of conditions that can lead to increased risk for heart disease, stroke and type 2 diabetes. These conditions can include high blood sugar, high blood pressure, adiposity (obesity), and abnormal cholesterol or triglyceride levels.

Aggressive lifestyle changes related to diet, exercise and stress can delay or even prevent the development of serious health problems. Yet current clinical indicators of metabolic syndrome typically reveal already established impairment, preventing any lifestyle changes from having a preventive rather than corrective effect. So the need to establish early clinical indicators of metabolic syndrome, before it takes hold, is critical.

Toward this goal, the new study involving rhesus monkeys at the Wisconsin National Primate Research Center showed that circulating ceramides are altered in the very early stages of insulin resistance development. These molecules, part of the lipid family of sphingolipids, are fats that participate in tissue development, cell recognition and adhesion, and can participate in cell signaling. The study was published June 15, 2022 in Nature Scientific Reports.

Rhesus monkeys are similar in metabolic function to humans and, like people, can get obesity, diabetes, heart disease, high blood sugar and high blood pressure. The study began with 16 genetically diverse, overweight but healthy adult monkeys, all fed the same diet and maintained in a controlled environment. Half of the animals spontaneously developed metabolic syndrome over the next two years. The animals’ weights and adiposity did not differ from between the two groups and they all had normal blood sugar levels throughout the study.

Using mass spectrometry to identify different cells in tissues and blood, the researchers detected circulating sphingolipids – including ceramides and sphingomyelins – and quantified them for healthy and impaired animals at similar age points.

“At the time of metabolic syndrome diagnosis, we found significant differences in the composition of circulating ceramides between the healthy and impaired animals,” said Rozalyn Anderson, professor of medicine at the University of Wisconsin–Madison School of Medicine and Public Health.

Correlation analysis also revealed earlier ceramide differences between the animals that ended up being diagnosed with metabolic syndrome after two years and the ones that did not develop the syndrome.

“Seeing these differences earlier on, when animals were clinically indistinguishable from one another, provides a new insight on metabolic impairment, and how we might distinguish among individuals to identify those at elevated risk for disease,” Anderson said.

Overall, Anderson and her colleagues observed changes in lipid handling as animals progressed from healthy to insulin resistant. Specifically, the researchers found correlations between altered ceramides and early-stage markers of insulin resistance, diacylglycerols and non-esterified fatty acids in the impaired monkeys. Correlations between normal ceramides and adipose-derived adipokine adiponectin – a key regulator of insulin sensitivity and tissue inflammation – were apparent in healthy animals but not in the metabolically impaired animals, even in advance of their loss in insulin sensitivity.

Because the monkeys were initially matched for body weight and adiposity that remained unchanged over the study period, these changes could not be attributed to differences in body composition, Anderson explained.

“These data suggest that changes in circulating ceramides are clinically relevant and may be the basis for identifying disease risk independent of differences in adiposity”. Anderson said.” If our findings translate to humans, as we expect they will, this would be hugely beneficial clinically because it would allow early preventive strategies to be adopted.”

The study included researchers from the School of Medicine and Public Health, the Wisconsin National Primate Research Center, the William S. Middleton Memorial Veterans Hospital, and the University of Texas Southwestern Medical Center.