Finely manipulating metabolic processes by limiting intake of a specific building block of proteins caused obese, pre-diabetic mice to shed most of their fat and improve blood glucose control-even though the dietary intervention occurred over a short time span (one month), and their overall caloric intake was unrestricted. 

The study, conducted by researchers in the laboratory of Dudley Lamming, PhD (pictured at right), assistant professor, Endocrinology, Diabetes and Metabolism, was published in The FASEB Journal on January 30, 2018. 

Scientists speculate that the approach may mimic some aspects of a plant-only vegan diet, since many plant proteins tend to be low in methionine. Because long-term adherence to dietary restrictions is notoriously difficult for many people, the research team investigated whether they could improve metabolic health of mice that were initially placed on high-fat, high-sugar "Western" diets to induce obesity and blood glucose dysregulation, and then shifted for up to five weeks to either the Western diet with defined levels of all amino acids, or the Western diet without methionine. A control group of lean mice on a standard lab chow was used for comparison. 

The results were striking. "Feeding a low methionine diet to mice that are obese and pre-diabetic rapidly restored their metabolic health. They lost weight, with a profound reduction in fat - they lost about 70% of their fat in one month. This happened even though they could eat as much food as they wanted and they actually moved less. We referred to them as 'couch potatoes,'" said Dr. Lamming.

Further analysis indicated that the temporary low-methionine diet triggered increased energy expenditure and altered metabolic processes in the liver and fat cells. The beneficial effects of reduced adiposity and improved blood glucose regulation were not dependent on a key regulator of liver metabolism called mTORC1. While both male and female mice showed the physiological changes, scientists did observe sex-specific differences at the molecular level: blood levels of a hormone called Fgf21 that is involved in energy balance regulation was increased in male mice but not female mice. 

The team hopes to pursue human clinical trials to assess whether the approach will be translatable to humans, but Dr. Lamming cautions that interventions similar to the extremely methionine-restricted mouse diets used in this study would require careful medical supervision as methionine is an essential amino acid. "If these results apply to humans, it's possible that this could be a short-term intervention that could be used with people who are morbidly obese or who need to lose weight rapidly for health reasons. It's unlikely to be widely used for most people as it is very severe and there is rapid weight loss, as well as some loss of lean mass," he said. 

"We are also working to identify the precise molecular mechanisms that drive the effects of dietary methionine on metabolic health, because methionine-free medical food isn't very tasty."  

This research was spearheaded by Deyang Yu (pictured above), a graduate student in the Lamming laboratory. Faculty collaborators included Michelle Kimple, PhD, assistant professor, Endocrinology, Diabetes and Metabolism, and Vincent Cryns, MD, Marian A. and Rodney P. Burgenske Chair in Diabetes Research and head of Endocrinology, Diabetes and Metabolism.

The work was supported in part by the National Institutes of Health, the Wisconsin Partnership Program, the V Foundation for Cancer Research, the Glenn Foundation Award for Cancer Research, predoctoral fellowship funding from the American Heart Association, a training grant from the UW Institute on Aging, and startup funds from the UW-Madison School of Medicine and Public Health and the Department of Medicine, and facilities and resources from the UW Carbone Cancer Center and the William S. Middleton Memorial Veterans Hospital. 

Figure caption (below): Placing obese mice on a short-term diet with low levels of the amino acid methionine caused them to lose about 70 percent of their fat in one month. A micrograph shows liver lipid droplet size from female mice on (left to right): control diet with defined levels of amino acids (Control AA), high-fat and high-sucrose Western diet (WD), or Western diet with low levels of methionine (WD MD). Similar results were seen for male mice.

Resources:

• Yu D, Yang S, Miller BR, Wisinski JA, Sherman DS, Brinkman JA, Tomasiewicz JL, Cummings NE, Kimple ME, Cryns VL, Lamming DW. 2018. Short-term methionine deprivation improves metabolic health via sexually dimorphic, mTORC1-independent mechanisms. FASEB J. [Epub ahead of print]