SLU-PP-332

SLU-PP-332 is a synthetic small-molecule agonist targeting estrogen-related receptors (ERRα, ERRβ, and ERRγ), orphan nuclear receptors that regulate energy metabolism and mitochondrial function. The compound demonstrates pan-ERR agonism with EC50 values of 98 nM (ERRα), 230 nM (ERRβ), and 430 nM (ERRγ), showing preferential activity toward ERRα. SLU-PP-332 activates transcriptional programs governing fatty acid oxidation, mitochondrial biogenesis, and oxidative metabolism, mimicking the molecular and physiological signatures of acute aerobic exercise. Preclinical research published 2023-2024 demonstrates that the compound produces exercise-like metabolic adaptations in mouse models including 25% increased fatty acid oxidation, 12% body weight reduction, 70% increased endurance capacity, and improved insulin sensitivity without changes in physical activity or food intake. Studies have shown therapeutic potential across multiple organ systems including metabolic syndrome treatment, cardiac function improvement in heart failure models, reversal of age-related kidney dysfunction, and skeletal muscle metabolic enhancement. While preclinical data suggests broad therapeutic applications, SLU-PP-332 remains experimental with no completed human clinical trials as of 2024, though researchers at the University of Florida aim to initiate human studies. The compound is available through gray market research chemical suppliers despite lacking FDA approval or established human safety profile.

Metabolic Effects and Fat Loss

• Body weight reduction: 12% decrease in body weight after 28 days in diet-induced obesity models, with fat mass gain limited to <0.5g versus ~5g in vehicle-treated controls ^[1]
• Fat mass reduction: Tenfold decrease in fat accumulation with smaller white adipocytes and reduced adiposity in both diet-induced obesity and ob/ob mouse models ^[1]
• Fatty acid oxidation: 25% enhancement in fatty acid oxidation rates compared to vehicle-treated animals, observable within 2 hours of first dose through reduced respiratory exchange ratio ^[1][2]
• Hepatic steatosis improvement: Reduced liver weight, decreased hepatic triglycerides, and improved liver fat content in obesity models ^[1]
• Energy expenditure elevation: Significantly elevated resting energy expenditure through activation of oxidative metabolism pathways without increased physical activity ^[1][2]

Exercise-Mimetic Properties

• Endurance capacity enhancement: 70% increase in running time and 45% increase in running distance in treated mice despite no increase in physical activity levels ^[1]
• Metabolic substrate shift: Reduced respiratory exchange ratio within 2 hours of first dose, indicating preferential shift from carbohydrate to lipid utilization ^[1]
• Exercise gene program activation: Induces ERRα-dependent acute aerobic exercise transcriptional program with hundreds of exercise-related genes upregulated ^[2]
• Mitochondrial function: Enhanced mitochondrial respiration and oxidative capacity in skeletal muscle cell lines with increased maximum mitochondrial respiration rates ^[2]
• Muscle fiber adaptation: Increased Type IIa oxidative muscle fibers, characteristic of endurance-trained muscle phenotype ^[2]

Glucose Metabolism and Insulin Sensitivity

• Glucose tolerance improvement: Enhanced glucose tolerance in high-fat diet mice with reduced fasting plasma glucose and insulin levels in context-dependent manner ^[1]
• Insulin sensitivity: Improved insulin sensitivity in metabolic syndrome models through enhanced metabolic flexibility ^[1]
• Muscle glucose uptake: Increased glucose uptake in skeletal muscle tissue ^[1]
• No hypoglycemia risk: No effects on glucose or insulin in chow-fed mice, suggesting glucose-lowering effects are metabolically appropriate and context-dependent ^[1]

Cardiovascular Benefits

• Heart failure improvement: Significantly improved ejection fraction in pressure overload-induced heart failure models, ameliorated cardiac fibrosis, and increased survival rates ^[4]
• Cardiac metabolism enhancement: Normalized metabolic profiles in fatty acid/lipid and tricarboxylic acid/oxidative phosphorylation pathways without triggering pathological cardiac hypertrophy ^[4]
• Mitochondrial function: Enhanced cardiac mitochondrial oxidative metabolism and fatty acid utilization through ERRγ-mediated cardioprotective effects ^[4]

Renal Protection (Age-Related)

• Albuminuria reduction: 8-week treatment reversed age-related increases in albuminuria in 21-month-old mice ^[3]
• Podocyte preservation: Reduced podocyte loss associated with aging kidney damage ^[3]
• Mitochondrial dysfunction reversal: Restored mitochondrial function in aged kidneys comparable to caloric restriction effects ^[3]
• Inflammatory modulation: Decreased inflammatory cytokines and markers of kidney inflammation ^[3]

Safety and Tolerability (Preclinical)

• No food intake changes: No alterations in feeding behavior or caloric consumption across all studies ^[1][2]
• Preserved lean mass: No changes in lean body mass, maintaining muscle while selectively reducing fat ^[1]
• Minimal organ toxicity: Minimal changes in plasma cholesterol/liver enzymes in normal-weight animals ^[1]
• No pancreatic pathology: No adverse pancreatic changes observed in extended treatment studies ^[1]
• ERRα selectivity advantage: Preferential ERRα activity may mitigate potential gluconeogenic side effects while maintaining metabolic benefits ^[1]

Preclinical Safety Profile

Animal Studies (Mice - Multiple Studies):

• Well-tolerated in 28-day studies at 50 mg/kg twice daily intraperitoneal injection ^[1]
• 8-week studies in aged mice showed no adverse effects on vital organs ^[3]
• No significant adverse effects on food intake, lean mass, or organ function ^[1][2][4]
• Minimal changes in liver enzymes or plasma lipids in normal-weight animals ^[1]
• No pancreatic pathology, cardiac hypertrophy, or skeletal muscle damage observed ^[1][4]

Pharmacokinetics (Mouse Data):

• Plasma exposure: 0.2 μM at 6 hours post-injection (30 mg/kg dose) ^[1]
• Muscle tissue exposure: 0.6 μM at 6 hours post-injection ^[1]
• Sufficient bioavailability for in vivo use as pharmacological tool ^[2]

Important Limitations:

• No human clinical trials: As of 2024, SLU-PP-332 has not been tested in humans despite researchers planning to initiate human studies
• Unknown human safety profile: Toxicity, pharmacokinetics, adverse effects, and appropriate dosing in humans are completely uncharacterized
• Regulatory status: Not FDA-approved; classified as research chemical only
• Quality control concerns: Gray market products may contain unknown purity levels, contaminants, or incorrect concentrations

Theoretical Concerns:

• ERR activation may affect hepatic gluconeogenesis, though ERRα selectivity may mitigate this risk ^[1]
• Long-term effects on metabolic hormones and endocrine function unknown
• Potential drug interactions with metabolic medications uncharacterized
• Reproductive/developmental effects not studied in animal models
• Chronic administration effects beyond 8 weeks not established

Clinical Context:
SLU-PP-332 should be considered an experimental research compound with significant unknowns regarding human use. All available efficacy and safety data derives exclusively from mouse studies. No human dosing protocols, safety parameters, maximum tolerated doses, or regulatory approvals exist. Use carries inherent risks due to complete absence of human safety data.