Engineering a Healthier Calorie: Metabolism Experts Leverage Plant Genetics to Tackle Twin Epidemics

It sounds like science fiction, but a Wisconsin Partnership Program (WPP) grant is helping UW researchers create corn and soybeans with much lower levels of the essential amino acids isoleucine and histidine. Research by metabolism expert Dudley Lamming, PhD, associate professor of medicine at the UW School of Medicine and Public Health, suggests that reducing these amino acids in the diet could lead to a 5 to 10 percent weight loss and better glucose tolerance. This could help improve public health in Wisconsin, where twin epidemics of obesity and diabetes mean that 70 percent of the people in the state are overweight, and another 30 percent are diabetic or prediabetic.

“We want to take a person eating a really unhealthy Western diet and substitute each component with components that are still delicious, but are just low in isoleucine,” said Lamming.

Lamming, who earned his PhD in experimental pathology at Harvard University, first used a WPP New Investigator grant in 2015 to show that reducing branched chain amino acids (BCAAs) in the diet of overweight, sedentary mice improved their insulin metabolism and weight without reducing the total number of calories they ate. His subsequent studies showed that reducing just one of the nine essential amino acids, isoleucine, was responsible.

“When we restricted the BCAAs, the fat mass and weight dropped dramatically and the mice became more insulin tolerant,’’ Lamming said. “They’re eating plenty of food, they’re happy, they’re healthy, but very little of their diet is isoleucine.’’

Lamming wondered if the mouse data translated to humans. He turned to colleagues at the Survey of the Health of Wisconsin (SHOW), an ongoing health survey and data repository of more than 6,000 Wisconsin residents. They analyzed SHOW data, including diet diaries and weight data from nearly 800 Wisconsinites, and found that people whose diets included a higher percentage of isoleucine and a second essential amino acid, histidine, in their diets also had higher body masses. This confirmed the mouse data.

While powdered medical diets exist that eliminate certain amino acids for people with metabolic syndromes — a group of conditions that can increase the risk of developing diabetes, heart disease and stroke — the powdered diets taste bitter, and people may not readily comply. Lamming envisions real food, only made with crops low in BCAAs.

Jacob Brunkard, PhD, an assistant professor of genetics in the UW–Madison College of Agricultural and Life Sciences, and an expert in plant metabolism, attended one of Lamming’s talks and was intrigued.

“I came up to him,” Brunkard recalled, “and said, ‘Should I just stop doing what I’m doing in my lab and make low isoleucine plants? Is that the way to go forward?’” And Lamming said, ‘Yes! Actually, it is!’ ‘’

Their interdisciplinary brainstorming led them to apply for a WPP Collaborative Health Sciences grant, resulting in an award of $600,000 over three years to Lamming and Brunkard and a multifacted team of UW–Madison collaborators.

Brunkard explained that plant breeders have been targeting essential amino acids for decades, trying to develop crops with a complete complement of protein. Their WPP research envisions Brunkard’s lab creating soy and corn plants with reduced levels of the problematic BCAAs, and then Lamming’s group feeding the beans and corn from those plants to the mice, to see if it improves their metabolism.

“The advantage of Jacob’s approach is that you’re going to make corn flour, and then you can make cornbread or chips, anything you can make with corn. Soy can be made into anything,’’ Lamming said.

Their findings will inform future studies that, if successful, may lead to a day when Wisconsin farmers grow crops that result in delicious real food that promotes health and reduces the risk of diseases like diabetes and obesity.