US Pharm. 2024;49(6):41-44.
New Window Into How Men and Women Burn Fat
Vigorous exercise burns fat more in males than in females, an unexpected finding from the largest study to date to explore how exercise affects the body. “Everyone knows that exercise is good for you, but no one knows exactly why,” said Joshua Adkins, a scientist at the Department of Energy’s Pacific Northwest National Laboratory (PNNL) and a corresponding author of a study published online in Nature Metabolism. “We don’t know what’s happening in the body that creates such great benefits.”
The results come from the Molecular Transducers of Physical Activity Consortium (MoTrPAC), a years-long study investigating the molecular actions that translate vigorous movement into a glut of health benefits. The collaboration stretches across more than two dozen sites around the country, involving more than 100 scientists. The group found that the effects of exercise are extensive, affecting more than 35,000 molecules.
The study subjects were rats, which share much of their basic physiology with people. The scientists are now studying more than 1,500 people, using the findings from the rodents as a starting point to investigate what happens in humans.
Overall, the MoTrPAC team looked at 18 tissue types as well as blood. They found molecular signals in both males and females that demonstrated extensive benefits of exercise: enhanced liver function, stronger heart muscle, enriched immunity, and reduced inflammation in the lungs and gut. Throughout the body, mitochondria become healthier after exercise, they discovered. The most remarkable difference between the sexes was in the fat tissue.
“We found that fat tissue between males and females is very different even in sedentary animals,” said Christopher Newgard, director of the Duke Molecular Physiology Institute. “But then I was truly gobsmacked with how amazingly different the sex-dependent responses to exercise are. Males burn fat for energy while females preserve their fat mass. This is brought about by many differences in molecular responses lurking beneath the surface in fat from male compared to female rats. The dichotomy is truly striking.”
The results are based on an analysis of tissues and blood samples from rats that ran on treadmills in a research laboratory at the University of Iowa. The team made thousands of measurements of proteins, molecular messengers known as transcripts, and chemical compounds called metabolites. Those measurements give scientists clues about what is actually happening in the body. Behind every breath, thought, movement, or step on a treadmill, there is a cascade of molecular actions.
The samples were sent to several laboratories for analysis. Scientists at PNNL analyzed the proteins in the fat samples, a challenging task because fat has few proteins relative to lipids. The team looked at white adipose tissue, by far the most prevalent form of fat in the body. Scientists studied rats that ran 5 days a week for 1, 2, 4, or 8 weeks, comparing them to sedentary rats. The team studied healthy, lean animals.
The difference in fat characteristics was remarkable even between sedentary male and female rats. More than 20,000 molecular measures were different. Overall, the fat in female rats was healthier both before and after training.
Male and female sedentary rats did have one characteristic in common: They all gained weight throughout the study. The differences in rats that ran the treadmill were even more noteworthy. Males burned fat and kept it off. Females initially burned fat, but by the end of 8 weeks, their fat stores were back to where they were when they started. Male rats that exercised lost fat. Female rats that exercised did not lose fat, but they did not gain fat as their sedentary counterparts did.
Exercise did make the fat stores of both sexes healthier—more metabolically active and energetic, with fewer signals like those involved in obesity. This was more noteworthy in the male rats, whose fat was less healthy to start with.
“We saw both sexes mobilize their metabolism to get the energy they need,” said first author Gina Many. “But they get their energy in different ways. Females do so without drawing much from their fat stores, likely because those are critical to reproductive health.”
Urine-Based Test Detects High-Grade Prostate Cancer
Researchers at the University of Michigan (U-M) Rogel Cancer Center have developed a urine-based test that addresses a major problem in prostate cancer: how to separate the slow-growing form of the disease that is unlikely to cause harm from more aggressive cancer that needs immediate treatment. The results were published in JAMA Oncology.
The test, called MyProstateScore 2.0 (MPS2), looks at 18 different genes linked to high-grade prostate cancer. In multiple tests using urine and tissue samples from men with prostate cancer, it successfully identified cancers classified as Gleason 7, Grade Group 2 (GG2), or higher. These cancers are more likely to grow and spread compared with Gleason 6 or Grade Group 1 prostate cancers, which are unlikely to spread or cause other impact. More than one-third of prostate cancer diagnoses are the low-grade form. Gleason and Grade Group are both used to classify how aggressive prostate cancer is.
“Our standard test is lacking in terms of its ability to clearly pick out those who have significant cancer. Twenty years ago, we were looking for any kind of cancer. Now we realize that slow-growing cancer doesn’t need to be treated. All of a sudden, the game changed. We went from having to find any cancer to finding only significant cancer,” said cosenior study author John T. Wei, MD, David A. Bloom Professor of Urology at Michigan Medicine.
Prostate-specific antigen (PSA) remains the linchpin of prostate cancer detection. MPS2 improves upon a urine-based test developed by the same U-M team nearly a decade ago following a landmark discovery of two genes that fuse to cause prostate cancer. The original MPS test, which is used today, looked at PSA, the gene fusion TMPRSS2::ERG, and another marker called PCA3.
“There was still an unmet need with the MyProstatescore test and other commercial tests currently available. They were detecting prostate cancer, but in general they were not doing as good a job in detecting high-grade or clinically significant prostate cancer. The impetus for this new test is to address this unmet need,” said cosenior author Arul M. Chinnaiyan, MD, PhD, director of the Michigan Center for Translational Pathology. Dr. Chinnaiyan’s laboratory discovered the T2::ERG gene fusion and developed the initial MPS test.
To make MyProstateScore even stronger at identifying high-grade cancers, researchers used RNA sequencing of more than 58,000 genes and narrowed it to 54 candidates that are uniquely overexpressed in higher-grade cancers. They tested the biomarkers against urine samples collected and stored at U-M through another major study, the National Cancer Institute’s Early Detection Research Network (NCI-EDRN). This included about 700 patients from 2008 to 2020 who came for a prostate biopsy due to an elevated PSA level.
This first step narrowed the field to 18 markers that consistently correlated with higher grade disease. The test still includes the original MPS markers plus 16 additional biomarkers to complement them.
From there, the team reached out to the larger EDRN, a consortium of more than 30 laboratories across the country that are similarly collecting samples. This ensured a diverse, national sampling. Knowing no specific details about the samples, the U-M team performed MPS2 testing on more than 800 urine samples and sent the results back to collaborators at the NCI-EDRN. The NCI-EDRN team assessed MPS2 results against the patient records. MPS2 was shown to be better at identifying GG2 or higher cancers. More importantly, it was nearly 100% correct at ruling out GG1 cancer.
“If you’re negative on this test, it’s almost certain that you don’t have aggressive prostate cancer,” said Dr. Chinnaiyan.
Surprising Connection Between Male Infertility and Family Cancer Risk
Researchers at the Huntsman Cancer Institute at the University of Utah (the U) found a surprising trend in families with male infertility: an increased risk of certain cancers. This discovery could lead to a more personalized approach to cancer risk assessments, making cancer prevention more effective.
According to the National Institutes of Health, around 9% of men of reproductive age have experienced fertility problems.
“We know that men who experience infertility tend to have more health issues like cardiovascular disease, autoimmune conditions, earlier mortality, chronic health conditions, and cancer,” said Joemy Ramsay, PhD, the study’s lead investigator, researcher at Huntsman Cancer Institute, and assistant professor in the Division of Urology at the U. “We wanted to look at whether the family members of these men were at higher risk for these conditions.”
This study represents the first step in determining family members’ correlated risk levels to diseases, such as cancer. Dr. Ramsay explained that since family members share similar genetic factors, environments, and lifestyles, it would be easier to identify other things impacting their cancer risk. Once general risk has been assessed, etiological factors can be more accurately evaluated in determining the part they play in a diagnosis.
Using the Utah Population Database, Dr. Ramsay and her team, which included Heidi Hanson, MS, PhD, Nicola Camp, PhD, and Myke Madsen, looked at parents, siblings, children, and even aunts, uncles, and cousins of men who have been diagnosed with infertility.
By observing several types of cancer at once, the team was able to develop an algorithm that clusters similar things together. This algorithm made it possible to identify roughly 13 characteristic patterns based on families possessing similar multicancer risks, instead of looking at only one cancer type at a time.
“Both cancer and subfertility are complex diseases and processes,” said Dr. Ramsay. “This method helps create similar family groups, making it easier to uncover the reason behind a family being at high risk for certain diseases over others.”
Common Hair Loss and Prostate Drug May Cut Heart Disease Risk in Men
The drug finasteride treats male pattern baldness and enlarged prostate in millions of men worldwide. But a new University of Illinois (U of I) Urbana-Champaign study suggests that the drug may also provide a surprising and lifesaving benefit: lowering cholesterol and cutting the overall risk of cardiovascular disease.
The study, published in the Journal of Lipid Research, found significant correlations between finasteride use and lower cholesterol levels in men taking part in the National Health and Nutrition Examination Survey between 2009 and 2016. In mice taking high finasteride doses, the researchers found reductions in total plasma cholesterol, delayed atherosclerosis progression, lower inflammation in the liver, and related benefits.
“When we looked at the men taking finasteride in the survey, their cholesterol levels averaged 30 points lower than men not taking the drug. I thought we’d see the opposite pattern, so it was very interesting,” said lead study author Jaume Amengual, assistant professor in the Department of Food Science and Human Nutrition and the Division of Nutritional Sciences, both part of the College of Agricultural, Consumer and Environmental Sciences at U of I.
The survey results had limitations, however. Of nearly 4,800 survey respondents meeting general health criteria for inclusion in the analysis, only 155, all men aged older than 50 years, reported using finasteride. Moreover, the researchers could not tell how much or how long men in the survey had taken the drug.
“This was not a clinical study in which you can control everything perfectly,” Dr. Amengual said. “It was more of an observation that led us to say, ‘Okay, now we’ve seen this in people. Let’s see what happens in mice.’”
Because atherosclerosis is far more common in men than in premenopausal women, scientists have long suspected that the sex hormone testosterone is important in atherosclerosis, although its role is not entirely clear. Finasteride works by blocking a protein found in hair follicles and the prostate gland that activates testosterone. The common thread, testosterone, was enough to pique Dr. Amengual’s interest.
“I was reading about this medication one day, and I started to notice that there were not many long-term studies of the implications of the drug. Initially, it was just my own curiosity, based on the fact that hormone levels are known to have an effect on atherosclerosis, hair loss, and prostate issues,” he said. “So, we decided to dig into it.”
After documenting the first-ever link, albeit observational, between finasteride and lower cholesterol in men, Dr. Amengual asked doctoral student Donald Molina Chaves to see if the pattern held in mice.
Mr. Molina Chaves tested four levels of finasteride—0, 10, 100, and 1,000 milligrams per kilogram of food—in male mice that were genetically predisposed to atherosclerosis. The mice consumed the drug, along with a high-fat, high-cholesterol Western diet, for 12 weeks. After the experiment, he analyzed the levels of cholesterol and other lipids in the mice, along with evidence of atherosclerotic plaques. He also tested gene expression in the liver, looked at bile acid metabolism, and analyzed steroids, triglycerides, immune activity, and more.
“Mice that were given a high dose of finasteride showed lower cholesterol levels within the plasma as well as in the arteries,” Mr. Molina Chaves said. “There were also fewer lipids and inflammatory markers in the liver.”
Although the effects were only significant at the highest dose, a level that Dr. Amengual calls “outrageous” for humans, he explained that mice metabolize finasteride differently than people. “It’s an incredibly high level of the drug. But we use mice as a model, and they are extremely resistant to things that would kill any of us,” he said. “So it is not that crazy when you think about it that way.”
Humans take 1-milligram or 5-milligram doses of finasteride daily for hair loss and enlarged prostate, respectively. The fact that a clear pattern showed up in a survey of men likely taking one of these doses suggests that the drug may be lowering cholesterol without the megadoses tested in mice.
The next step is for physicians to start tracking cholesterol in finasteride patients or conduct a clinical trial to verify the effect. Dr. Amengual says that it may be especially important to understand how finasteride affects transgender individuals.
“Over the past decade, doctors have started prescribing this drug for individuals transitioning either from male to female or female to male. In both cases, the hormonal changes can trigger hair loss,” he said. “The interesting thing is that transgender people are also at a higher risk of cardiovascular diseases. So this drug could have a potential beneficial effect to prevent cardiovascular disease not only in cis men, but also in transgender individuals.”
Dr. Amengual noted, like any medication, finasteride is not without risk, and individiuals should consult their doctors to learn more.
Men Born to Obese Mothers More Likely to Suffer Health Issues as Adults
Males born to obese women are more likely to be overweight at birth and develop metabolic complications in later life, including liver disease and diabetes. The way that male sex hormones activate pathways in the developing liver is partly to blame.
That was the finding from a study led by University of South Australia (UniSA) researchers examining the impact of maternal obesity on fetal liver androgen signaling.
Male fetuses of obese pregnant women have different signals that are activated by male sex hormones in the liver, which encourages them to prioritize growth at the expense of their health. UniSA researcher Ashley Meakin said that androgens give men their male characteristics and are crucial in their development, but if there are too many, male fetuses grow too large, not only causing problems at birth, but impacting liver function as an adult.
Female fetuses that are exposed to excess testosterone from an obese pregnancy are wired to switch off the androgen pathway in the liver, restricting their growth and lowering the risks of metabolic disorders in adulthood.
“We know there are sex differences in metabolic disorders in later life in response to maternal obesity,” Dr. Meakin said. “Men are more prone to nonalcoholic fatty liver diseases and diabetes as an adult if their mother was obese during pregnancy and their birth weight was above 4 kg (9 lb 15 oz). They are genetically wired to prioritize androgens because it supports the development of male characteristics, including size, but too much androgen is bad.”
Study lead author Janna Morrison, head of the Early Origins of Adult Health Research Group at UniSA, says it is a fine balance for women getting the right nutrition in pregnancy to ensure optimal conditions for their unborn child to flourish.
“There are also risks for offspring being malnourished during pregnancy,” she said. “If you are too little, too big, born too early, or a male, you are more vulnerable to negative outcomes later in life. You need the Goldilocks pregnancy: You must be the right size, born at the right time.”
Dr. Morrison said that unless society changes its approach to nutrition, it will be an uphill battle to reduce obesity and associated health issues, from the womb into adulthood. “As a society, we urgently need to address obesity. If children were taught early on about the importance of healthy eating, it would carry through into adulthood, including during pregnancy, where the right nutrition is so important.”
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