SLU-PP-332 vs O-304 is a fun comparison, because both get called “exercise mimetics” and they get there by completely different roads. SLU-PP-332 switches on a family of nuclear receptors called ERRs. O-304 nudges AMPK, the cell’s fuel gauge. One has only ever been studied in animals and cells, the other made it into a small trial in people with type 2 diabetes. We went back to the primary papers so you can see what was actually measured, and what wasn’t.
Key findings
- SLU-PP-332 is a pan-ERR agonist (ERRα, β and γ) with its highest potency at ERRα (Billon 2023).
- In mice it raised type IIa oxidative fibers and running endurance, and that endurance effect depended on ERRα.
- In obese mice it increased energy expenditure and fatty acid oxidation and cut fat mass (Billon 2024).
- O-304 is a pan-AMPK activator that lowered fasting glucose and HOMA-IR in a phase IIa trial in type 2 diabetes patients already on metformin (Steneberg 2018).
- A 2025 study found O-304 also behaves as a mitochondrial uncoupler in cells.
- Nobody has compared the two compounds head to head. Every comparison here is across separate papers.
Two compounds, two very different starting points
SLU-PP-332 came out of a structure-based design effort by Thomas Burris, John Walker and colleagues. Their problem was simple to state: ERRβ and ERRγ agonists existed, but nobody had a decent ERRα agonist that worked in a living animal. SLU-PP-332 hits all three ERRs, leans toward ERRα, and had good enough pharmacokinetics to serve as an in vivo tool [1].
O-304 has Swedish roots, from Helena Edlund’s group in Umeå and the biotech company Betagenon. It was introduced as a “PAN-AMPK activator,” meaning it isn’t picky about AMPK subunit combinations [2]. You’ll sometimes see it called ATX-304 in industry material. We stuck to O304 or O-304, since that’s what the papers use.
Quick note so nobody gets confused: Loti carries SLU-PP-332. We don’t carry O-304. It’s here purely as a point of comparison.
How each one works
Here’s the cleanest way we can put it. SLU-PP-332 acts in the nucleus. ERRs are orphan nuclear receptors that sit on DNA and drive genes for mitochondrial biogenesis and fat burning. Turn them up and the cell behaves, at least at the gene level, a bit like it just went for a run. Billon’s team saw exactly that: an ERRα-dependent “acute aerobic exercise” gene program in muscle [1].
O-304 works upstream, in the cytoplasm. AMPK fires when energy runs low, during exercise or calorie restriction. Once it’s on, it pushes glucose uptake and fuel oxidation. The Edlund papers framed O-304 as a way to get that signal without the energy deficit [2].
There’s a twist, though. A 2025 paper from China Pharmaceutical University reported that O-304 also acts as a mitochondrial uncoupler. In vascular smooth muscle cells and HepG2 cells it raised oxygen consumption and dropped mitochondrial membrane potential at low micromolar concentrations [3]. The authors note earlier work tying its AMPK activation to inhibition of protein phosphatase 2C. So “AMPK activator” may be only part of the story. Worth keeping in mind if you’re reading older O-304 data.
| SLU-PP-332 | O-304 | |
|---|---|---|
| Primary target | ERRα, ERRβ, ERRγ (nuclear receptors) | AMPK (kinase), plus uncoupling reported |
| Where it acts | Gene transcription in the nucleus | Energy-sensing signaling in the cytoplasm and mitochondria |
| Highest stage of research | Mouse and cell studies | Phase IIa trial in type 2 diabetes |
| Carried by Loti | Yes | No |
What the SLU-PP-332 studies found
The 2023 ACS Chemical Biology paper is the one everybody cites. In a skeletal muscle cell line, SLU-PP-332 boosted mitochondrial function and cellular respiration. In mice, it shifted muscle toward type IIa oxidative fibers and improved endurance on a treadmill. And when ERRα was taken out of the picture, the endurance boost went away [1]. That genetic check is why we take the mechanism seriously.
The follow-up in 2024 moved to obesity models. Diet-induced obese mice and ob/ob mice given SLU-PP-332 burned more energy, oxidized more fat, and put on less fat mass. Insulin sensitivity improved too [4].
Then there’s the heart. In a pressure overload model of heart failure in mice, both SLU-PP-332 and a sister compound, SLU-PP-915, improved ejection fraction, reduced fibrosis and increased survival without changing cardiac hypertrophy. Interestingly, the cardiac effect ran mostly through ERRγ, not ERRα [5].
One thing the papers don’t give you: any human data. None. Some blog posts float claims about resting heart rate or long-term safety in people. We couldn’t find a primary source for those, so we left them out.
What the O-304 studies found
O-304’s headline paper (JCI Insight, 2018) covers mice and people. In diet-induced obese mice it increased glucose uptake in skeletal muscle and reduced beta cell stress. In a proof-of-concept phase IIa trial in type 2 diabetes patients on metformin, it lowered fasting plasma glucose and HOMA-IR, improved peripheral microvascular perfusion and reduced blood pressure [2]. In mice it activated AMPK in the heart and improved left ventricular stroke volume without increasing heart weight.
A 2021 Communications Biology study looked at aged mice. O-304 prevented and reversed age-associated hyperinsulinemia and insulin resistance, and improved cardiac function and exercise capacity [6]. The authors described it as well tolerated in humans, which refers to their own trial work.
Another 2021 paper zoomed in on pancreatic islets. In high-fat-fed mice, O-304 largely prevented diet-driven gene expression changes and blocked the rise of a beta cell stress marker, Aldh1a3 [7].
A fair caveat: most O-304 papers come from the same group, and several authors hold shares in Betagenon. That’s disclosed in the papers. It doesn’t make the data wrong, but independent replication is thin.
So which one fits a given study?
It depends on the question you’re asking. If you want to probe ERR biology, mitochondrial gene programs, or fiber-type switching in muscle, SLU-PP-332 is the more targeted tool, and the ERRα knockout data give you a clean way to check on-target effects. If your question is about AMPK signaling, glucose handling or beta cell stress, O-304 has the longer paper trail, plus a small human dataset.
Honestly, the biggest gap is that nobody has run them side by side. Different labs, different models, different endpoints. So any “which is stronger” claim you read online is a guess. We’d love to see the comparison done properly.
If you want more on our side of the pair, see the SLU-PP-332 compound profile, or read how it compares with a different mitochondrial tool in our BAM15 and SLU-PP-332 research overview.
References
- Billon C, Sitaula S, Banerjee S, et al. Synthetic ERRα/β/γ Agonist Induces an ERRα-Dependent Acute Aerobic Exercise Response and Enhances Exercise Capacity. ACS Chem Biol. 2023. PMID: 36988910
- Steneberg P, Lindahl E, Dahl U, et al. PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients. JCI Insight. 2018. PMID: 29925691
- Li WF, Zeng Y, Zhang YD, et al. O304 is a mitochondrial uncoupler which extends C. elegans lifespan and induces vasorelaxation of rat mesenteric arteries. Chem Biol Interact. 2025. PMID: 41130350
- Billon C, Schoepke E, Avdagic A, et al. A Synthetic ERR Agonist Alleviates Metabolic Syndrome. J Pharmacol Exp Ther. 2024. PMID: 37739806
- Xu W, Billon C, Li H, et al. Novel Pan-ERR Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism and Mitochondrial Function. Circulation. 2024. PMID: 37961903
- Ericsson M, Steneberg P, Nyrén R, Edlund H. AMPK activator O304 improves metabolic and cardiac function, and exercise capacity in aged mice. Commun Biol. 2021. PMID: 34795407
- López-Pérez A, Norlin S, Steneberg P, et al. Pan-AMPK activator O304 prevents gene expression changes and remobilisation of histone marks in islets of diet-induced obese mice. Sci Rep. 2021. PMID: 34949756
Disclaimer: This content is intended for research purposes only and is not meant to constitute medical advice.
This educational material discusses laboratory research concepts only. Loti Labs products are intended strictly for research and development use and are not for human consumption.
