Biotech

Engineered Protein Makes Obese Mammals Shed Weight

The protein — GDF15 — caused mice, rats, and macaque monkeys to consume less food and lose weight, as well as lower cholesterol and insulin levels in the blood.

Crystal structure of a new engineered protein for treating obesity | Y. Xiong et al., Science Translational Medicine (2017)
Crystal structure of a new engineered protein for treating obesity | Y. Xiong et al., Science Translational Medicine (2017)

Researchers have engineered a protein that could become a potent weapon in the fight against obesity. 

The protein, GDF15, made obese mice, rats, and macaque monkeys eat less and lose weight, as well as lowering their cholesterol and bloodstream insulin levels, found researchers at Amgen pharmaceutical laboratory.

It even made overweight mice make “healthier" food choices, rejecting food enriched with fatty condensed milk in favor of standard food. The control group of mice gorged themselves on the high-calorie treats.

GDF15 is a stress response cytokine that occurs naturally in the body in response to certain diseases and other situations where there is significant metabolic demand on the body, such as pregnancy. Samuel Breit, an Australian immunologist and physician, first noticed spiking levels of GDF15 in humans with advanced cancer and its effect on appetite in 2011.

“GDF15 may get secreted to alleviate the worsening of the conditions that caused its increased levels,” research leader Dr. Murielle M. Vénian, scientific executive director of cardiometabolic disorders at Amgen, told Seeker.

That we associate hunger with the primal drives of survival and pleasure make obesity a challenge to treat, Vénian said. The brain may send signals to drive individuals to eat more each time body weight decreases. 

The protein worked on mice, rats, and monkeys that were genetically obese and those who had been given a high-calorie diet. After receiving GDF15 the animals voluntarily ate less food, lost weight, and their serum insulin levels dropped.

The research was published Oct. 18 in the journal Science Transitional Medicine.

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Researchers believe that GDF15 could potentially work well to treat obesity in humans. Vénian said that was the next step for their research, although cautioning that much clinical research was needed.

“It is always very challenging to predict if what we observe in animal models is going to translate to humans,” she said.

At the moment, the biggest challenge is the structure of the protein: naturally-occurring GDF15 has a short plasma half-life of only about three hours and is difficult to produce in large quantities, making it unsuitable as a drug treatment. Amgen researchers were able to engineer two fusion proteins that had the same appetite-suppressant qualities as GDF15, but that were more stable and gave higher yields.

They are keen to further extend the half-life for clinical trials.

Amgen is by no means the only pharmaceutical lab racing to study the weight loss effects of GDF15. Dr. Mads Tang-Christensen, Head of Obesity Research at Novo Nordisk lab in Denmark told Seeker there were currently five laboratories, including Amgen and Novo Nordisk, studying GDF15’s potential as an anti-obesity tool. He added that it was not a coincidence that all five labs were commercial, not academic.

“As you can imagine, there is a keen interest in developing this for the treatment of obesity in humans,” he said. “It's clear that overall this is a new and very interesting mechanism.”

Tan-Christensen participated in research led by Sebastian Beck Jørgensen that identified the specific receptor in the brain on which GDF15 acts — without this information, the protein is essentially useless. Their results were published in August in the journal Nature Medicine.

GDF15 is biologically unusual as it appears to work only with receptors located in one small area of the brain called the postrema, which serves as a sort of crossroads for signals from various parts of the body.

“If you remove that part of the brain, cut it out — and we’ve only done this in rat studies — but if you cut it out, the effect of GDF15 goes away,” Tang-Christensen said.

“It’s a very beautiful system,” he added. “It’s rare that you get these very simplistic systems when you’re dealing with biology.”

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Obesity is a huge public health problem in much of the developed world and is becoming increasingly widespread elsewhere. Almost four in 10 American adults are obese. The costs, personal and economic, are dire. Obesity increases the risk of heart disease, stroke, type 2 diabetes. and certain types of cancer, and obesity-related medical costs in the USA reached an estimated $147 billion in 2008, according to the US Centers on Disease Control and Prevention. The problem looks set to worsen with the next generation: A study from Imperial College London found childhood obesity has increased tenfold over the past 40 years, .        

While diet and exercise are the foundation of weight management, they may not always be enough to tackle obesity, said Katherine H. Saunders, a doctor of obesity medicine at Weill Cornell Medicine. A growing body of research suggests that the body of an obese person may change and adapt to fight weight loss, making it difficult to maintain. 

“Reduced caloric intake and increased energy expenditure are counteracted by adaptive physiologic responses,” Saunders said. “Resting metabolic rate slows and appetite increases out of proportion to what would be expected based on changes in body composition.” 

The phenomenon, called adaptive thermogenesis or metabolic adaptation, makes it incredibly difficult for many obese people to lose weight and keep it off.

Anti-obesity medication can offset these changes in appetite and energy expenditure, and can help patients stick to lifestyle changes, Saunders added.

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