Fat isn’t necessarily fat

By Corinne Johannssen-Hodel

There are two scenarios for weight gain: either the additional fat is absorbed by existing fat cells, which causes them to grow in size (A), or it is distributed among newly formed fat cells (B). Some 20 percent of overweight people are healthy and have smaller fat cells. Their risk of developing diabetes or cardiovascular disease is very low compared to most overweight people, who have enlarged fat cells. That’s why ETH professor Christian Wolfrum and his team are looking for ways to encourage the formation of fat cells. (Graphic: www.tnb.ethz.ch/research/adipofunc, Crafft)

There are two scenarios for weight gain: either the additional fat is absorbed by existing fat cells, which causes them to grow in size (A), or it is distributed among newly formed fat cells (B). Some 20 percent of overweight people are healthy and have smaller fat cells. Their risk of developing diabetes or cardiovascular disease is very low compared to most overweight people, who have enlarged fat cells. That’s why ETH professor Christian Wolfrum and his team are looking for ways to encourage the formation of fat cells. (Graphic: www.tnb.ethz.ch/research/adipofunc, Crafft)

ETH professor Christian Wolfrum is seeking out new substances with which to combat diabetes. One particular bile acid already looks promising – but he isn’t satisfied, so the search goes on.

“We’re looking for ways to encourage fat cells to form,” says Christian Wolfrum, ETH professor of translational nutrition biology, “because that’s good for your health.” The idea that additional fat cells could improve your health might seem counterintuitive, but it’s been known for over 100 years that having more fat cells doesn’t automatically mean you weigh more. “The more fat cells we have, the smaller each cell is, since the fat present in our bodies is spread across many cells,” Wolfrum explains. And that’s healthier than having fewer, bigger cells. “It’s an aspect that’s always underestimated,” he adds, “since in fact it’s cell size that plays the biggest role in the development of diabetes.”

Once fat cells expand beyond a certain volume, they are no longer able to absorb fatty acids, but instead release them into the bloodstream. If the level of fatty acids in the blood is permanently high, fat is deposited in the liver and muscles. Worse, insulin – whose job it is to regulate the release of fatty acids into the blood – becomes ineffective. The result is insulin resistance and, ultimately, the metabolic disease known as type 2 diabetes.

However, in slim people – but also in overweight people with small fat cells – the risk of type 2 diabetes is low. This could be the case because these people’s fat cells are able to store the fatty acids, releasing them in a controlled way and only when necessary. During fasting, for instance, fatty acids are released, which are absorbed by the liver and then converted into energy. That’s why certain diabetes medications are designed to regulate the formation of new fat cells. This leaves patients no less overweight than they already were, but healthier. However, these medications can have major long-term side effects, which is why scientists around the world are looking for new substances for type 2 diabetes treatment.

Microscope images of large (left) and small (right) fat cells (Photo: Laboratory of Translational Nutritional Biology)

Microscope images of large (left) and small (right) fat cells (Photo: Laboratory of Translational Nutritional Biology)

New factors identified

Wolfrum and his team are looking for factors that stimulate the formation of fat cells. Until now it was always assumed that fat cells secrete substances that prevent precursor cells from turning into fat cells. “It makes physiological sense: if you already have lots of fat, you don’t want even more,” Wolfrum explains. But it’s actually more complicated than that, as a new study by his team demonstrates. A detailed analysis has shown that such suppressive secretions do exist, and that their effect dominates overall. But the ETH researchers also found substances that stimulate the formation of new fat cells – which is precisely what Wolfrum is looking for.

“We still have no idea what effect these factors have on metabolism, because many of them are completely unknown,” Wolfrum says. However, some of the data in human fat cells show a clear correlation with insulin sensitivity. “We now need to follow that up and work out these factors’ physiological role,” he adds. In the process, he always bears his main question in mind: Which factors control the formation of new fat cells, and how can it be modulated in the fight against diabetes?

One such modulator is the bile acid THBA. Its lock-and-key bond with the RORγ receptor serves to inhibit the receptor’s activity, which promotes the formation of new fat cells. This mechanism has been understood for some time; what Wolfrum and his team have succeeded in doing is to identify the bile acid THBA as a modulator. “There was a bit of luck involved, too,” Wolfrum admits. He goes on: “We were coming from fundamental research, but it was definitely worthwhile researching further.” There’s no doubt about that: the discovery that the bile acid THBA can modulate fat cell formation is what led to the formation of the spin-off Glycemicon – which after just three years managed to take ninth place in Switzerland’s TOP 100 Startup Awards 2015. With the first set of preclinical tests now concluded, clinical trials are set to go ahead next year.

Every improvement is worth it

This kind of success is something to be celebrated, but Wolfrum takes a more sober line: “Diabetes can’t be cured, but perhaps we can use the bile acid THBA to delay the progress of the disease.” If it means patients can wait ten years before moving on to stronger medication with more side effects, then that’s already a major benefit. “With diabetes, every improvement is fantastic,” Wolfrum stresses. When it comes to this metabolic disease, it’s worth thinking for the long term.

Currently the spin-off is also analysing which foods naturally contain the bile acid. Initial results suggest that it is most prevalent in meat products such as liver or kidney. But Wolfrum is unwilling to give advice on what people should eat. “You basically can’t go wrong if you eat a wide variety of foods,” he says, “not least because of the millions of substances in food that have yet to be identified but are surely important.” Wolfrum does have a clear idea of the best way to combat diabetes, however, and there are scientific studies to back him up: weight loss is much more effective than any medication. “Move more and eat less – it’s the first rule of thermodynamics,” is Wolfrum’s succinct take on the theory. If only it were that easy in practice.

Source: ETH Zurich  press release