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Scientists engineer proteins that caused obese animals to lose weight and lower cholesterol

As the U.S. obesity rate has galloped toward 40%, doctors, drug designers and dispirited dieters have all wondered the same thing: What if a pill could deliver the benefits of weight-loss surgery, but without the knife?

New research brings that hope a notch closer.

Scientists from the biotechnology company Amgen Inc. report they have identified and improved upon a naturally occurring protein that brought about significant changes in obese mice and monkeys, including weight loss and rapid improvements on measures of metabolic and heart health.

The results, published Wednesday in Science Translational Medicine, approximate some of the mysteriously powerful effects of bariatric surgery, in which a surgeon reshapes the stomach and intestinal tract to reduce their capacity. Even before surgery patients lose a lot of weight, most see marked improvements in obesity-related conditions like insulin resistance, high circulating blood sugar and worrisome cholesterol levels.

In mice who got a bioengineered version of the GDF15 protein, the researchers observed even more remarkable changes. These obese mice turned their noses up at extra-rich condensed milk — a treat that normally prompts mice to gorge themselves. Given the choice, the treated mice tended to opt for standard mouse chow instead, or at least lowered their intake of the fattening condensed milk.

After 35 days, obese mice treated with the bioengineered GDF15 proteins lost roughly 20% of their body weight, while mice getting a placebo gained about 6% over their starting weight, according to the study. When mice were offered the rich condensed milk, triglyceride levels remained at baseline or rose by about 20% in those who got the engineered proteins, while levels more than doubled in the untreated mice. Insulin levels and total cholesterol readings were also significantly better in treated animals than in their untreated counterparts.

The results suggest that the GDF15 engineered by researchers had the power to turn off the kind of reward-driven eating (think doughnuts, milkshakes or bacon cheeseburgers) that drives many of us to become obese, or to regain lost weight.

Some of the weight-loss medications approved in recent years by the Food and Drug Administration — including Belviq, Contrave, Qsymia and Saxenda — appear to nudge the food preferences of obese patients in more healthful directions. But bariatric surgery has a pronounced effect in shifting patients’ preferences away from high-fat foods. Scientists just don’t know why.

The natural version of the GDF15 protein breaks down quickly in the blood. To be an effective weight-loss aid, it would need more staying power.

The Amgen researchers accomplished this by fusing the protein with other agents that would not break down so quickly. The two engineered versions of GDF15 remain biologically active in the blood for longer.

In the brains of the lab animals that received the treatment, the study authors detected activation in a population of brain-stem cells that transmits complex signals between the brain and gut.

In obese people, those signals — which urge us to eat when we’re hungry and to stop once we’ve eaten — become faulty, causing us to overeat and gain weight. Bariatric surgery appears to correct those signals.

So the suggestion that GDF15 might do the same is an exciting indication that a piece of bariatric surgery’s magic might be bottled up in a pill.

“This is a new system” involved in the regulation of appetite, said Dr. Ken Fujioka, a weight-loss specialist at Scripps Clinic Del Mar. “It’s not one we’ve seen before, and that’s a big deal.”

At the same time, the system manipulated by GDF15 is only one of the chemical signaling systems that goes awry in obesity, said Fujioka, an expert on brain-gut signaling who was not involved in the new research. If a drug is to help a wide range of patients with obesity — and to aid in the twin challenges of losing weight and keeping it off — it will need to activate many different systems at once.

While bariatric surgery has been shown to be effective in spurring weight loss and a broad range of other health improvements, it is invasive, costly and irreversible. And although about 196,000 Americans had the surgery in 2015, according to the American Society for Metabolic and Bariatric Surgery, that’s only a tiny fraction of the roughly 100 million adults who are now considered obese.

On Wednesday, Amgen called the new research “early,” but said its focus on obesity fits with its interest in drugs to treat cardiovascular disease.

New findings like these help put effective treatment in reach for a growing number of the obese, Fujioka said. Obesity is a diabolically complex disease with many contributing factors, “but someday I personally think we really will be there,” he added.

melissa.healy@latimes.com

@LATMelissaHealy

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