Could Weekly, Not Daily Prednisone Represent A New Approach to Obesity Therapy?

It’s recognized that daily prednisone promotes obesity, but a new preclinical study by Northwestern Medicine researchers has shown that once-weekly prednisone has very different results, promoting nutrient uptake into muscles and improving lean body mass. The team’s research showed that obese mice fed a high-fat diet (HFD) and receiving the glucocorticoid steroid prednisone just once per week had improved exercise endurance, became stronger, lost weight, and demonstrated increased lean body mass. The treated animals also exhibited increased muscle metabolism, and increased levels of adiponectin, a fat-derived hormone that appears to play an important role in protecting against diabetes and insulin resistance.

“Daily prednisone is known to promote obesity and even metabolic syndrome—a disorder with elevated blood lipids and blood sugar and weight gain,” said Elizabeth McNally, MD, PhD, director of the Center for Genetic Medicine at Northwestern University Feinberg School of Medicine. “So, these results, in which we intermittently ‘pulse’ the animals with once-weekly prednisone, are strikingly different. Obesity is a major problem, and the idea that once-weekly prednisone could promote nutrient uptake into muscle might be an approach to treating obesity.”

McNally and colleagues reported on their findings in the Journal of Experimental Medicine, in a paper titled, “Intermittent prednisone treatment in mice promotes exercise tolerance in obesity through adiponectin.” In their paper the researchers concluded, “Our study demonstrates that intermittent glucocorticoids produce healthful metabolic remodeling in diet-induced obesity.” McNally is a Northwestern Medicine physician and the Elizabeth J. Ward professor of genetic medicine.

Fat–muscle communication regulates metabolism and involves circulating signals like adiponectin, the author explained. “Modulation of this cross-talk could benefit muscle bioenergetics and exercise tolerance in conditions like obesity.” Many patients take prednisone daily for different immune conditions. Known side effects of daily prednisone include weight gain and even muscle atrophy with weakness. The authors noted, “Glucocorticoid steroids such as prednisone are widely used immune suppressants and their chronic daily intake promotes metabolic stress and obesity.”

The team had been interested in finding out whether patients can get the same immune benefit with intermittent prednisone dosing, which could be much more beneficial to the muscle. In previously published research, McNally’s team discovered that giving prednisone intermittently was helpful for muscular dystrophy, and they demonstrated that once-weekly prednisone improved strength. The group also recently reported findings from a pilot clinical trial in individuals with muscular dystrophy, in which one weekly dose of prednisone improved lean mass.

The newly reported research in mice with dietary obesity showed that intermittent once-weekly prednisone increased adiponectin levels and improved exercise tolerance and energy expenditure. The effects were dependent on adiponectin, as adiponectin gene knockout (Adipoq-KO) mice failed to benefit from weekly prednisone therapy. “Intermittent prednisone promoted muscle metabolism and exercise tolerance through adiponectin,” the team commented, and added, “…treatment failed to improve adiposity, exercise tolerance, and insulin tolerance with HFD in Adipoq-KO mice.”

The scientists also showed that the benefits of once-weekly prednisone therapy also extended to mice that were already obese from eating a high-fat diet, with treated animals experiencing increased strength, running capacity, and lower blood glucose. “Opposite to daily dosing, intermittent prednisone blunted weight accrual and improved strength, treadmill endurance, and glucose homeostasis in mice with pre-established obesity,” the investigators stated. The studies confirmed that “…the favorable metabolic effects of prednisone were specific to the intermittent dosing even in mice already obese before treatment.”

Most of what has previously been known about steroids such as prednisone has resulted from studies investigating the effects of taking prednisone every day. “We see a very different outcome when it is taken once a week,” said McNally. “We need to fine-tune dosing to figure out the right amount to make this work in humans, but knowing adiponectin might be one marker could provide a hint at determining what the right human dose is.”

McNally described the weekly dose as “a bolus, or spike, of nutrients going into your muscle.” She said, “We think there is something special about promoting this spike of nutrients into muscle intermittently, and that it may be an efficient way to improve lean body mass.”

Corresponding author, Mattia Quattrocelli, PhD, added, “What is exciting to me about this work is the finding that a simple change in the dosing frequency can transform glucocorticoid drugs from inducers to preventers of obesity. Chronic once-daily intake of these drugs is known to promote obesity. Here we show that dosing the same type of drug intermittently—in this case, once weekly—reverses this effect, promotes muscle metabolism and energy expenditure, and curtails the metabolic stress induced by a fat-rich diet.” Quattrocelli, who initiated the research while at Northwestern, is now assistant professor at Cincinnati Children’s Hospital Medical Center and department of pediatrics at the University of Cincinnati.

People have different responses to prednisone dosing so McNally wants to determine which biomarkers are most critical to mark having a beneficial response to prednisone. “If we can determine how to choose the right dose of prednisone that minimizes atrophy factors and maximizes positive markers like adiponectin, then we can really personalize the dosing of prednisone,” she said.

The group also recently showed that weekly prednisone uses strikingly different molecular pathways to strengthening the muscle in male versus female mice, based on a recently published study by Isabella Salamone, a graduate student in McNally’s lab.

The benefits of weekly prednisone are linked to circadian rhythms, reported another recent study from Northwestern and University of Cincinnati. Human cortisol and steroid levels spike early in the morning before you wake up. “If you don’t give the drug at the right time of day, you don’t get the response,” Quattrocelli said. “In mice, we obtained good effects with intermittent prednisone in muscle mass and function when we dose them at the beginning of their daytime. Mice have a circadian rhythm inverted to us, as they generally sleep during the daytime and are active at night. This could mean that the optimal dosing time for humans during the day could be in the late afternoon/early evening, but this needs to be appropriately tested.”

McNally remains cautious about making inferences on the potential clinical applications of intermittent prednisone. “These studies were done in mice,” she acknowledged. “However, if these same pathways hold true in humans, then once-weekly prednisone could benefit obesity.”

She further noted, “While we are encouraged by the pilot study in humans with muscular dystrophy, mouse muscles have more fast-twitch fibers than humans, and slow-twitch muscle could be different. More studies are needed to try to better understand whether these same mechanisms work in human muscles.” Nevertheless, the authors stated in their newly released paper, “In conclusion, our study reported that intermittent prednisone promoted a virtuous fat-muscle communication through adiponectin. These findings pave the way for adjuvant drug strategies to restore adiponectin sensitivity and exercise tolerance in conditions of metabolic stress.”


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