Boosting a liver protein may mimic the brain benefits of exercise

By Laura Sanders

Exercise’s power to boost the brain might require a little help from the liver.

A chemical signal from the liver, triggered by exercise, helps elderly mice keep their brains sharp, suggests a study published in the July 10 Science. Understanding this liver-to-brain signal may help scientists develop a drug that benefits the brain the way exercise does.

Lots of studies have shown that exercise helps the brain, buffering the memory declines that come with old age, for instance. Scientists have long sought an “exercise pill” that could be useful for elderly people too frail to work out or for whom exercise is otherwise risky. “Can we somehow get people who can’t exercise to have the same benefits?” asks Saul Villeda, a neuroscientist at the University of California, San Francisco.

Villeda and colleagues took an approach similar to experiments that revealed the rejuvenating effects of blood from young mice (SN: 5/5/14). But instead of youthfulness, the researchers focused on fitness. The researchers injected sedentary elderly mice with plasma from elderly mice that had voluntarily run on wheels over the course of six weeks. After eight injections over 24 days, the sedentary elderly mice performed better on memory tasks, such as remembering where a hidden platform was in a pool of water, than elderly mice that received injections from sedentary mice.

Comparing the plasma of exercised mice with that of sedentary mice showed an abundance of proteins produced by the liver in mice that ran on wheels.

The researchers closely studied one of these liver proteins produced in response to exercise, called GPLD1. GPLD1 is an enzyme, a type of molecular scissors. It snips other proteins off the outsides of cells, releasing those proteins to go do other jobs. Targeting these biological jobs with a molecule that behaves like GPLD1 might be a way to mimic the brain benefits of exercise, the researchers suspect.

Old mice that were genetically engineered to make more GPLD1 in their livers performed better on the memory tasks than other old sedentary mice, the researchers found. The genetically engineered sedentary mice did about as well in the pool of water as the mice that exercised. “Getting the liver to produce this one enzyme can actually recapitulate all these beneficial effects we see in the brain with exercise,” Villeda says.

Blood samples from elderly people also hint that exercise raises GPLD1 levels. Elderly people who were physically active (defined as walking more than 7,100 steps a day) had more of the protein than elderly people who were more sedentary, data on step-counters showed.

GPLD1 seems to exert its effects from outside of the brain, perhaps by changing the composition of the blood in some way, the researchers suspect.

But the role of GPLD1 is far from settled, cautions Irina Conboy, a researcher at the University of California, Berkeley who studies aging. There’s evidence that GPLD1 levels are higher in people with diabetes, she points out, hinting that the protein may have negative effects. And different experiments suggest that GPLD1 levels might actually fall in response to certain kinds of exercise in rats with markers of diabetes.

“We know for sure that exercise is good for you,” Conboy says. “And we know that this protein is present in the blood.” But whether GPLD1 is good or bad, or whether it goes up or down with exercise, she says, “we don’t know yet.”

A. M. Horowitz et al. Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain. Science. Vol. 369, July 10, 2020, p. 167. doi: 10.1126/science.aaw2622.

Boosting a liver protein may mimic the brain benefits of exercise

UMass Amherst Chemists Develop New Blood Test to Detect Liver Damage in Under an Hour

Chemist Vincent Rotello at the University of Massachusetts Amherst, with colleagues at University College London (UCL), U.K., announce today that they have developed a “quick and robust” blood test that can detect liver damage before symptoms appear, offering what they hope is a significant advance in early detection of liver disease. Details appear in Advanced Materials.

Their new method can detect liver fibrosis, the first stage of liver scarring that can lead to fatal disease if left unchecked, from a blood sample in 30-45 minutes, the authors note. They point out that liver disease is a leading cause of premature mortality in the United States and U.K., and is rising. It often goes unnoticed until late stages of the disease when the damage is irreversible.

For this work, Rotello and his team at UMass Amherst’s Institute of Applied Life Sciences (IALS) designed a sensor that uses polymers coated with fluorescent dyes that bind to blood proteins based on their chemical processes. The dyes change in brightness and color, offering a different signature or blood protein pattern.

He says, “This platform provides a simple and inexpensive way of diagnosing disease with potential for both personal health monitoring and applications in developing parts of the world.” Rotello and colleagues hope the new test can be used routinely in medical offices, clinics and hospitals to screen people with elevated liver disease risk so they can be treated “before it’s too late.”

The UCL team tested the sensor by comparing results from small blood samples equivalent to finger-prick checks from 65 people, in three balanced groups of healthy patients and among those with early-stage and late-stage fibrosis. This was determined using the Enhanced Liver Fibrosis (ELF) test, the existing benchmark for liver fibrosis detection. They found that the sensor identified different protein-level patterns in the blood of people in the three groups. The ELF test requires samples to be sent away to a lab.

Co-author William Peveler, a chemist now at the University of Glasgow, adds, “By comparing the different samples, the sensor array identified a ‘fingerprint’ of liver damage. It’s the first time this approach has been validated in something as complex as blood, to detect something as important as liver disease.”

The investigators report that the test distinguished fibrotic samples from healthy blood 80 percent of the time, reaching the standard threshold of clinical relevance on a widely-used metric and comparable to existing methods of diagnosing and monitoring fibrosis. The test distinguished between mild-moderate fibrosis and severe fibrosis 60 percent of the time. The researchers plan further tests with larger samples to refine the method’s effectiveness.

Peter Reinhart, director of UMass Amherst’s IALS says, “These exciting findings epitomize the mission of IALS to translate excellent basic science into diagnostics, therapeutic candidates and personalized health monitoring devices to improve human health and well-being.”

Peveler adds, “This may open the door to a cost-effective regular screening program thanks to its simplicity, low cost and robustness. We’re addressing a vital need for point-of-care diagnostics and monitoring, which could help millions of people access the care they need to prevent fatal liver disease.”

Rotello explains that the sensing strategy uses a “signature-based” approach that is highly versatile and should be useful in other areas. “A key feature of this sensing strategy is that it is not disease-specific, so it is applicable to a wide spectrum of conditions, which opens up the possibility of diagnostic systems that can track health status, providing both disease detection and monitoring wellness.”

In addition to UMass Amherst, UCL and the University of Glasgow, the U.K.-based research and development firm iQur Ltd. took part in the study. The work was supported by the U.K. Royal Society, the U.K. Engineering and Physical Sciences Research Council, the U.S. National Institutes of Health and the U.K. National Institute for Health Research UCLH Biomedical Research Centre.

Liver hormone discovered to drive sugar consumption

A recent study has shown that fibroblast growth factor 21 (FGF21), a liver-generated hormone, suppresses the FGF21 is produced in response to high carbohydrate levels, in which it enters the bloodstream and signals the brain to suppress the preference for sweets. Matthew Potthoff, assistant professor of pharmacology in the University of Iowa Carver College of Medicine, noted that this is the “first liver-derived hormone that regulates sugar intake specifically.”consumption of simple sugars.

Earlier studies have shown how some hormones affect appetite. However, these do not regulate any specific macronutrient (eg, carbohydrate, protein, fat) and are produced in organs other than the liver. FGF21 has been known to boost insulin sensitivity but the new findings “can help people who might not be able to sense when they’ve had enough sugar, which may contribute to diabetes,” said Lucas BonDurant, a doctoral student and co-first author in the study.

Researchers used genetically-engineered mouse models and pharmacological approaches to study FGF21 in regulating sugar cravings. Normal mice were injected with FGF21 and were given a choice between a normal diet and a sugar-enriched diet. These mice did not completely stop eating sugar but consumed 7 times less than normal. The team also looked at mice that either did not produce FGF21 at all or overproduced FGF21 (>500 times more than normal mice). When presented with the same two diets as the normal mice, researchers saw that the mice that didn’t produce FGF21 all consumed more sugar whereas the mice that overproduced FGF21 consumed less sugar.

Study findings support the conclusion that FGF21 decreased appetite and sugar intake. It did not, however, decrease intake of all sugars (eg, sucrose, fructose, glucose) nor did it affect the intake of complex carboydrates. The new data may help patients who are obese or have diabetes, researchers noted. More studies are needed to see if other hormones exist to regulate appetite for specific macronutrients comparable to the effects of FGF21 on carbohydrate intake.