Looking at human tissues has given British researchers a new window into the relationship between adipose tissue and disease cardiovascular disease risk.

In their studies, the authors showed that the release of Wnt5a from adipose tissue directly affected arteries through a signaling pathway that increased oxidative stress in the arteries.

Patients with coronary artery disease had higher levels of Wnt5a than healthy controls that were matched for BMI, age and gender. They also had lower levels of SFRP5, a protein which decreases Wnt5a signaling.

Previous work had suggested an indirect effect of Wnt signaling on cardiovascular disease risk due to the effects on inflammation and insulin resistance, but the work is the first time that a direct effect of an adipokine on cardiovascular disease risk, and the mechanism of that risk, have been described.

"We have, for the first time, a clear molecule that is released from human adipose tissue in obesity, and has a direct effect on disease," Charalambos Antoniades, professor of cardiovascular medicine and deputy head of the division of cardiovascular medicine at the University of Oxford, told BioWorld.

Additionally, the team unraveled the downstream effects of Wnt5a signaling, and as a result, "we now have a pathway to focus on, in order to reprogram our fat in the future, and turn it from an enemy into an ally."

Antoniades is the senior author of the paper reporting the findings, which appeared in the Sept. 18, 2019, issue of Science Translational Medicine.

He cautioned that although his team is investigating how to reduce Wnt5a levels, or its signaling through the Frizzled 2 and Frizzled 5 receptors, "we are not there yet," and for now the recommendations for how to avoid cardiovascular disease remain the same: eat well and exercise.

Already, though, the work brings a fresh perspective to the complicated relationship between weight and health – a relationship whose scientific understanding has been hampered by the enormous cultural baggage surrounding weight.

Though one would not know it from most writing, and even the majority of medical advice, the relationship between fat and health is weak, and many metabolism researchers have so far considered it to be indirect and not necessarily causal.

High-weight individuals have a higher incidence of metabolic syndrome, a constellation of risk factors that increase the risk of heart disease and stroke.

However, one theory has been that fat tissue itself is a signal for, but not the cause of, metabolic syndrome.

The research by Antoniades and his colleagues suggests that it is fat itself that is problematic.

But there is healthy as well as unhealthy fat, so the answer is not necessarily to shed fat.

"Fat is not necessarily bad," Antoniades said. "If it's producing anti-oxidant and anti-inflammatory factors, then it's healthy. . . . It becomes bad when it starts secreting [certain] factors."

That distinction between healthy and unhealthy fat is different from current ways of classifying fat. Metabolically unhealthy fat is often equated with fat that is insulin-resistant. But Antoniades said that "we, as a field, probably need to revisit this definition."

By the definition of insulin resistance, "in patients like the ones we looked at, adipose tissue is mostly dysfunctional," he said. But only Wnt5a-producing fat raised the risk of cardiovascular disease.

Antoniades said that fat should be judged by the factors it is producing and secreting, rather than by its sensitivity or lack thereof to insulin signaling.

A final message of the investigators' work is that their results, which relied heavily on studies of human fat and human explanted arteries, are "very different from what was seen in mouse models," Antoniades said.

"We tried for many years to work with this pathway in animal models, he said. But when they are engineered to overexpress Wnt5a, "mice die, and they die because they lose weight."

That weight loss is not due to loss of fat mass, but loss of water – "they get dehydrated."

Other studies in mice have identified SFRP5 as an important adipokine.

"However, when you try to measure it in the human fat, it's barely dIetectable," Antoniades said. "What is produced in huge amounts in human fat is the bad guy – Wnt5a."

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