O-304 100mg 30 caps

O-304 is one of the best-characterised candidates for this role. A small molecule, a pan-AMPK activator (acting on all isoforms of the enzyme), developed by Professor Helena Edlund’s group at Umeå University (Sweden) and advanced by Betagenon AB. The key publication — Steneberg et al. 2018 in JCI Insight — describes results from animal models (db/db mouse, high-fat-diet mouse) and preliminary phase IIa data in type 2 diabetes patients: reduced fasting glycaemia, improved microvascular perfusion, lowered arterial blood pressure.

In terms of its action profile it sits in a research niche close to next-generation fat burners — acting on energy metabolism, not on adrenergic thermogenesis.

Regulatory status

O-304 is a small molecule, not a peptide — online it is often mistakenly classified as the “O-304 peptide”. In fact it is a thiadiazole-substituted compound from the group of direct AMPK activators, the ADaM class (allosteric drug- and metabolite-binding site activators). The substance is a clinical candidate in development — it holds no FDA, EMA or other regulatory authorisation. The Pro-Body O-304 reagent does not replace medical consultation and is not a substitute for registered diabetes pharmacotherapy (metformin, GLP-1 agonists, SGLT2 inhibitors).

Most of the research-chemicals market treats the term “O-304” loosely: the name turns up on forums next to BPC-157, TB-500 and CJC-1295, implying kinship with peptides. The actual chemical structure says otherwise.

O-304 is a small-molecule pan-AMPK activator with a rigid, non-peptide structure based on a thiadiazole core. No amino-acid sequence, no peptide bonds, no need for reconstitution in bacteriostatic water. The molecule is stable in the gastric environment and has oral bioavailability sufficient for per os administration — which fundamentally distinguishes it from research peptides such as BPC-157 or GLP-1, which require parenteral administration.

This distinction has three practical consequences for research protocols:

• Delivery format — hard HPMC capsules with a weighed 100 mg dose, ready for oral administration in animal models or for further dispersion in buffer
• Stability — capsules are stored at room conditions (15–25°C, in a dry place); no cold-chain requirement, no reconstitution, no risk of degradation in freeze/thaw cycles
• Receptor mechanism — O-304 binds allosterically to the ADaM site at the interface of the AMPK α and β subunits, rather than to a membrane receptor like a peptide; this is direct enzyme activation, not GPCR signalling

In this category, O-304 sits alongside PF-739, MK-8722, A-769662 and salicylate — all direct AMPK activators. Among them it stands out for the best cardiac safety profile (PF-739 and MK-8722 caused cardiac hypertrophy in preclinical models) and the strongest in vivo dataset involving humans. In the Pro-Body portfolio, a mechanistically complementary reagent is BAM-15 MAX — a mitochondrial uncoupler acting on the other side of the energy balance (oxidation instead of ATP conservation).

Chemical data — basics:

What AMPK is and why it matters

AMPK (5′-AMP-activated protein kinase) is a heterotrimeric serine/threonine kinase made up of three subunits: the catalytic α, the structural β and the regulatory γ. In the cell it acts as an energy sensor — it reads the AMP:ATP and ADP:ATP ratios that signal an energy-deficit state (intense exercise, hypoxia, fasting, caloric deficit).

Activation of AMPK triggers an adaptive cascade whose net effect is:

• Inhibition of anabolic processes (protein synthesis, lipogenesis, hepatic gluconeogenesis)
• Stimulation of catabolic processes (fatty-acid oxidation, glycolysis, autophagy)
• Mitochondrial biogenesis via PGC-1α activation
• GLUT4 transporter translocation to the cell membrane in muscle (insulin-independent glucose uptake) — a mechanism whose net effect converges with that of classic GDAs such as Sugar Shield in lowering postprandial glycaemia, though via a different receptor pathway
• Inhibition of the mTORC1 pathway (less protein synthesis, more autophagy)

This is the same set of responses triggered by endurance training, caloric deficit and metformin — which is why AMPK is called the “metabolic master switch”, and its direct activators are sometimes referred to as exercise mimetics.

How O-304 works — binding to the ADaM site (the α/β interface)

O-304 belongs to the ADaM class (Allosteric Drug and Metabolite site activators). It binds at a site on the boundary of the α and β subunits, close to the γ domain. Binding induces a conformational change that stabilises the active form of the enzyme, independently of the cellular AMP concentration.

Practical consequences of O-304 binding to AMPK (db/db mouse model and HFD mouse, Steneberg et al. 2018):

1. Activation of all AMPK isoforms — unlike A-769662 (selective for β1) and PF-739 (selective for α1), O-304 is a pan-activator — it acts on the α1β1γ1, α1β2γ1, α2β1γ1, α2β2γ1 and α2β2γ3 isoforms (the last being important in skeletal muscle)
2. GLUT4 translocation to the muscle membrane — insulin-independent glucose uptake in skeletal muscle; relevant in the insulin-resistance model
3. Reduced hepatic glucose production — phosphorylation of CRTC2 and SHP, inhibiting expression of gluconeogenic enzymes (G6Pase, PEPCK)
4. Increased fatty-acid oxidation — phosphorylation of ACC (acetyl-CoA carboxylase), a drop in malonyl-CoA, opening of the β-oxidation pathway; the same metabolic profile was observed in studies on Meldonium as a modulator of β-oxidation
5. Improved microvascular perfusion — eNOS activation in endothelial cells, increased NO bioavailability

Does O-304 replace training?

Endurance training activates AMPK in pulses (a peak during exercise, a return to baseline in the hours afterwards) — and it does so in parallel with activation of PGC-1α, CaMKII, MAPK, mTORC2 and mechanotransduction in muscle. O-304 activates AMPK tonically (a sustained elevation of activity during dosing), without the simultaneous activation of mechanotransduction pathways or CaMKII.

In practical terms: O-304 reproduces the metabolic signature of training (glucose homeostasis, mitochondria, lipid profile), but it does not reproduce the strength signature (hypertrophy, myoneurogenesis, mechanical-stimulus-dependent capillarisation). The term “exercise mimetic” is therefore apt in a narrow, metabolic sense — not in the full sense of replacing physical activity. A related molecule in the portfolio in this respect is the mitochondrial peptide MOTS-C, which also modulates a metabolic signature close to the training effect — but through an entirely different mechanism (a peptide encoded in mitochondrial DNA).

AN IMPORTANT DISTINCTION

“Exercise mimetic” in the context of this description means: in animal-model studies and preliminary human studies in T2D, pharmacological activation of the AMPK pathway was observed, with metabolic effects partly similar to those after endurance training. This does not imply a guarantee of equivalence to physical activity in a healthy person, nor any suggestion of using O-304 RUO for that purpose.

db/db mice (type 2 diabetes model) — Steneberg 2018

db/db mice with genetically induced insulin resistance and hyperglycaemia received O-304 orally for 8 weeks. Results:

• Fasting glycaemia: a significant drop vs vehicle
• HbA1c: reduced after 8 weeks of dosing
• Insulin sensitivity (OGTT): improved
• No increase in body weight
• No hypoglycaemia (a mechanism dependent on AMP availability — a physiological limit on activation)

High-fat-diet mice (HFD obesity model) — Steneberg 2018

Mice fed a high-fat diet (60% kcal from fat) for 12 weeks, then dosed with O-304 or placebo for a further 8 weeks. Results:

• Reduced body weight vs placebo
• Decreased visceral (white) adipose tissue
• Improved lipid profile (triglycerides, LDL)
• Increased UCP1 expression in brown adipose tissue (suggesting enhanced thermogenesis)
• Improved mitochondrial function in skeletal muscle

Phase IIa in type 2 diabetes patients — Steneberg 2018

In the first human study in T2D (n = small cohort, oral dosing, 14 days) the following were observed:

• Reduced fasting glycaemia
• Improved microvascular perfusion (laser Doppler skin perfusion)
• Reduced systolic arterial blood pressure
• No hypoglycaemia
• Good tolerability, no serious adverse events reported

This is the first direct AMPK activator to reach a clinical phase in humans while preserving a cardiac safety profile (PF-739 and MK-8722 caused left-ventricular hypertrophy in animal models — which ended their preclinical development).

AMPK in sport and physiology — an overview

Literature context beyond the individual O-304 studies: the role of AMPK in exercise adaptation is well documented (Mounier 2015, Spaulding 2022). AMPK participates in PGC-1α-dependent mitochondrial biogenesis (O’Neill 2013), regulates hepatic fat oxidation (Foretz 2018) and is responsible for the metabolic switch between the fed state and energy deficit (Hardie 2012, Garcia & Shaw 2017).

O-304 is used in research work in several directions:

• Insulin-resistance and T2D models — db/db mouse, HFD mouse, ZDF rat; studies of the GLUT4 translocation mechanism and the reduction of hepatic glucose production
• AMPK pharmacology — comparative studies of pan-activators (O-304 vs PF-739 vs MK-8722 vs A-769662) in the context of isoform selectivity and cardiac safety
• Dyslipidaemia and NAFLD models — the effect of AMPK activation on hepatic fatty-acid oxidation, triglyceride profiles
• Microcirculation and blood pressure — animal models of hypertension, endothelial dysfunction; a mechanism via eNOS and NO bioavailability
• Exercise-mimetic research — comparison of the transcriptional signatures of O-304 vs endurance training in skeletal muscle of rodent models; alongside, comparisons with ERRα agonists of the SLU-PP-332-PLUS type, which act on a different node of the mitochondrial network
• Co-experiments — synergies and antagonisms with metformin (an indirect AMPK activator via LKB1), GLP-1 agonists (a category represented in the portfolio by Tirzepatide 5mg), SGLT2 inhibitors, fibrates

Each of these directions requires rigorous RUO conditions — the reagent supplied by Pro-Body is intended solely for laboratory research in registered research units.

O-304 100 mg, 30 capsules is a small-molecule pan-AMPK activator of the ADaM class, delivered in oral format for precise research protocols. The best-documented candidate in the direct-AMPK-activator niche — with an in vivo dataset covering T2D, dyslipidaemia and microcirculation models, plus preliminary phase IIa data in humans (Steneberg et al. 2018, JCI Insight). Mechanism: allosteric binding to the γ-AMPK domain, activation of all enzyme isoforms, metabolic effects partly similar to endurance training (GLUT4 translocation, mitochondrial biogenesis, β-oxidation, reduced hepatic glucose production). HPLC purity ≥98%, MS confirmation, COA per batch, HPMC capsule format. Status: Research Use Only, WADA S4.4.

1. Steneberg P, Lindahl E, Dahl U, et al. (2018). PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients.
2. Hardie DG, Ross FA, Hawley SA. (2012). AMPK: a nutrient and energy sensor that maintains energy homeostasis.
3. Garcia D, Shaw RJ. (2017). AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance.
4. Mounier R, Theret M, Lantier L, Foretz M, Viollet B. (2015). Expanding roles for AMPK in skeletal muscle plasticity.
5. O’Neill HM, Holloway GP, Steinberg GR. (2013). AMPK regulation of fatty acid metabolism and mitochondrial biogenesis: implications for obesity.
6. Foretz M, Even PC, Viollet B. (2018). AMPK Activation Reduces Hepatic Lipid Content by Increasing Fat Oxidation In Vivo.
7. Spaulding HR, Yan Z. (2022). AMPK and the Adaptation to Exercise.