Diet and Exercise in a Pill Are Real: How Mimetics Work (Medscape)

If couch-potato lab mice had beach-body dreams and if they could speak, they might tell you they’re thrilled by advances in the science of exercise and calorie-restriction (CR) mimetics.

In recent studies conducted at research centers across the United States, mice have chowed down, fattened up, exercised only if they felt like it, and still managed to lose body fat, improve their blood lipids, increase muscle power, avoid blood sugar problems, and boost heart function.

How did these mice get so lucky? They were given mimetics, experimental drugs that “mimic” the effects of exercise and calorie reduction in the body without the need to break a sweat or eat less.

“The mice looked like they’d done endurance training,” said Thomas Burris, PhD, a University of Florida pharmacodynamics professor and coauthor of a September 2023 study of the exercise mimetic SLU-PP-332, published in the Journal of Pharmacology and Experimental Therapeutics.

Enter the exercise mimetics. Unlike CR mimetics, exercise mimetics affect mitochondria — the tiny power plants in muscle and every other cell in the body. They switch on genes that encourage the growth of more mitochondria and encourage them to burn fatty acids, not just glucose, for fuel.

In mice, this can keep them from gaining weight, increase insulin sensitivity, and boost exercise endurance. “We can use a drug to activate the same networks that are activated by physical activity,” said Ronald Evans, PhD, professor and director of the Gene Expression Laboratory at the Salk Institute for Biological Studies in La Jolla, California.

Among notable mimetics moving into human studies is ASP0367, a drug in a class called PPAR delta modulators first developed in Evans’ lab. ASP0367 was licensed to the pharmaceutical company Mitobridge, later acquired by Astellas. Astellas is currently running a phase 2/3 human trial of the investigational drug in people with the rare genetic disorder primary mitochondrial myopathy.

“We can use a drug to activate the same networks that are activated by physical activity.”

At the University of Florida, Burris and team hope to soon move the exercise mimetic SLU-PP-332 into human studies. “It targets a receptor called ERR that I’ve been working on since the 1980s,” Burris said. “We knew from genetic studies that ERR has a role in exercise’s effects on mitochondrial function in muscle.” The calorie mimetics he’s studying also activate genes for making more mitochondria and driving them to burn fatty acids. “This generates a lot of energy,” he said. In a January 2024 study in Circulation, Burris found the drug restores heart function in mice experiencing heart failure. “Very little heart function was lost,” he said. It’s had no serious side effects.

The field has hit some bumps. Some feel inevitable — such as otherwise healthy people misusing the drugs. GW1516, an early experimental exercise mimetic studied by Evans and abandoned because it triggered tumor growth in lab studies, is used illegally by elite athletes as a performance-enhancing drug despite warnings from the US Anti-Doping Agency. Burris worries that future CR mimetics could be misused the same way.

Full story:

Related thread: Much discussion about Exercise and Caloric Restriction Mimetics, What about Sleep Mimetics?

Details on the Exercise and Caloric Restriction Mimetics mentioned in the story:

A brand-new kind of drug, tested in mice, shows promising new results that could lead to the development of a new weight-loss drug that mimics exercise.

The new compound, developed and tested by a University of Florida professor of pharmacy and his colleagues, leads obese mice to lose weight by convincing the body’s muscles that they are exercising more than they really are, boosting the animals’ metabolism.

It also increases endurance, helping mice run nearly 50% further than they could before. All without the mice lifting a paw.


A Synthetic ERR Agonist Alleviates Metabolic Syndrome

Physical exercise induces physiologic adaptations and is effective at reducing the risk of premature death from all causes. Pharmacological exercise mimetics may be effective in the treatment of a range of diseases including obesity and metabolic syndrome. Previously, we described the development of SLU-PP-332, an agonist for the estrogen-related receptor (ERR)α , β, and γ nuclear receptors that activates an acute aerobic exercise program. Here we examine the effects of this exercise mimetic in mouse models of obesity and metabolic syndrome. Diet-induced obese or ob/ob mice were administered SLU-PP-332, and the effects on a range of metabolic parameters were assessed. SLU-PP-332 administration mimics exercise-induced benefits on whole-body metabolism in mice including increased energy expenditure and fatty acid oxidation. These effects were accompanied by decreased fat mass accumulation. Additionally, the ERR agonist effectively reduced obesity and improved insulin sensitivity in models of metabolic syndrome. Pharmacological activation of ERR may be an effective method to treat metabolic syndrome and obesity. SIGNIFICANCE STATEMENT: An estrogen receptor-related orphan receptor agonist, SLU-PP-332, with exercise mimetic activity, holds promise as a therapeutic to treat metabolic diseases by decreasing fat mass in mouse models of obesity.

Paywalled Paper: A Synthetic ERR Agonist Alleviates Metabolic Syndrome - PubMed


Open Access Papers:

An Avocado Extract Enriched in Mannoheptulose Prevents the Negative Effects of a High-Fat Diet in Mice

Glycolytic inhibition: an effective strategy for developing calorie restriction mimetics

Calorie restriction mimetics encompass a growing research field directed toward developing treatments that mimic the anti-aging effects of long-term calorie restriction without requiring a change in eating habits. A wide range of approaches have been identified that include (1) intestinal inhibitors of fat and carbohydrate metabolism; (2) inhibitors of intracellular glycolysis; (3) stimulators of the AMPK pathway; (4) sirtuin activators; (5) inhibitors of the mTOR pathway, and (6) polyamines. Several biotech companies have been formed to pursue several of these strategies. The objective of this review is to describe the approaches directed toward glycolytic inhibition. This upstream strategy is considered an effective means to invoke a wide range of anti-aging mechanisms induced by CR. Anti-cancer and anti-obesity effects are important considerations in early development efforts. Although many dozens of candidates could be discussed, the compounds selected to be reviewed are the following: 2-deoxyglucose, 3-bromopyruvate, chrysin, genistein, astragalin, resveratrol, glucosamine, mannoheptulose, and d-allulose. Some candidates have been investigated extensively with both positive and negative results, while others are only beginning to be studied.

Caloric Restriction Mimetics in Nutrition and Clinical Trials


When I read this article yesterday, I recall wondering what the larger, perhaps the largest, picture might look like as mimetics are refined to the point that they become widely employed as a substitute for exercise, quality sleep, eating well, and even for developing the human bonds, culture, and social systems associated to these basic functions. We exist in an ecology the complexity of which lies beyond anyone’s grasp. I can see countless ways that the fabric of society can be altered with unpredictable consequences. A very old piece of science in which devices generated artificial meaning and enjoyment for the masses came to mind. We live in interesting times.


I would argue (with only a hint of sarcasm) that we’ve already widely deployed diabetes mimetics in the form of Highly Processed, High Fructose Corn syrup infused packaged consumer products, and we have seen the impact.

Perhaps the diabetes mimetics will finally start losing the battle in the near future… Life Expectancy in the USA (Bad and Getting Worse)


All too true @RapAdmin and at least one other consideration seems worth considering, Ozempic presenting a recent example. The drug underwent Phase III clinical trials from January 2016 to May 2017 and was approved shortly thereafter. Given its mechanism of action, we have no basis for inferring lifetime or even long term impacts. Essentially, we are running a large scale experiment on the public with the theoretical risk judged to be offset by the known short term biochemical benefits. This decision may turn out to have been a wise gamble but we have not positioned it as such to patients or to the public.

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The alternative is leaving tens of millions of people obese for decades.


Big Pharma vs. Big Food, who will win?


There is no competition there… its a symbiotic relationship. They help each other… the more KFC / McDonalds, the more the GLP1 agonists that are needed.


The Big Food intelligence services are already on the case:

Recent reports from Numerator indicate that GLP-1 households are decreasing food and alcohol purchases more significantly than households without GLP-1 users and, particularly those with individuals using the drug for weight loss. GLP-1 households decreased food spending by -1.6% in the first nine months of the year versus a year ago—three times faster than non-GLP-1 households (-0.5%). Declines were even more pronounced among households with GLP-1 weight loss users, who decreased food spending six times faster than non-GLP-1 households (-3%).
How GLP-1 Prescriptions are Reshaping Food and Beverage Trends | C+R

I am still betting on Big Pharma, at least they are in the lead, for now. Hopefully the diet gurus don’t ruin the party because they want everyone to keep failing.


Indeed. I am one of those people. I was at relatively healthy weight and quite strong for my age before catching a stomach bug that landed me in the ICU within 3 days. By the time I left the hospital, my gut microbiome was destroyed but my life was saved. However, I gained 40 lbs, lost years worth of powerlifting strength (muscle), and developed a pre-diabetic HbA1c within 6 months, maybe 4. Caloric restriction wouldn’t work and my appetite was simultaneously insatiable like never before. I felt like I was starving all the time.

The weight gain caused my testosterone to plunge and I became depressed. I was constantly anxious, I couldn’t think straight and I was worried about not being able to function in my mentally taxing job. I was a mess.

Then I finally got on tirzepatide and testosterone, dropped a lot of weight, gained muscle back, watched my lipids fall through the floor (ApoB tested 52-62, triglycerides below 35) and saw my blood sugar correct (HbA1c at 4.9). HOMA-IR looks great, NMR Lipoprofile could not be more insulin sensitive. Cardio IQ says inflammation is very low.

There are many thousands (more?) with similar stories - I’m on forums with them. I felt like I was dying, and now I feel fantastic. I’m glad I got to be a part of this massive experiment, though I acknowledge the long term risks are unknown. For now, I regard the new obesity drugs as modern miracles. Time will tell.


I hope it “SLU-PP-332” comes to market soon as I am very bored of going to the gym :laughing: