The Case Against High Dose Slu
I’ve talked about this a few times before, but I know there are still plenty of questions around it so I wanted to take another shot at clearly explaining the reasoning behind my answer. The case against higher doses of SLU-PP-332 starts with first principles: this compound works as a signaling cue, not a substrate to be “pushed” toward saturation. In cell systems and animal models, SLU-PP-332 appears to activate the estrogen-related receptor (ERR) program with PGC-1α coactivation, shifting transcription toward fatty-acid oxidation, oxidative phosphorylation, and mitochondrial quality control. That kind of pathway is amplifier biology: a small receptor-level nudge fans out into many downstream genes and post-translational switches. In such networks, more ligand does not linearly equal more benefit; it often crosses into different biology entirely, including compensatory braking and desensitization. Think of it like tapping a conductor’s baton to set tempo versus throwing a bigger baton at the orchestra. The first coordinates; the second creates noise and reflexes you didn’t intend. A key downstream branch of the ERR/PGC-1α program is modulation of uncoupling proteins. Mild, context-appropriate uncoupling in UCP2 and UCP3 can lower electron pressure, trim reactive oxygen species, and improve metabolic flexibility under load. But pushing the axis hard increases the probability of off-site expression and activity in UCP4 and UCP5, which are enriched in neurons and glia. Excess uncoupling in those tissues risks local ATP shortfall where energy security is non-negotiable. In brain and autonomic circuits, too much leak across the inner mitochondrial membrane can force compensatory hypermetabolism to maintain voltage, distort calcium handling, and disturb neurotransmission timing. At the organism level, that looks like brain fog, dysautonomia, sleep fragmentation, and reduced stress tolerance exactly the systems you don’t want to pay for marginal fat-loss gains. Mechanistically, high-dose signaling also raises the odds of maladaptive redox and substrate partitioning. ERR/PGC-1α drive beta-oxidation and electron delivery to the respiratory chain. If you layer that on top of exercise, fasting, thyroid augmentation, or catecholamine tone, you can overshoot electron influx relative to complex-level throughput, increasing retrograde signaling and forcing the cell to dump potential as heat via uncoupling. At low dose this can be hormetic and helpful. At high dose, it can flatten the ATP/ADP ratio, trigger AMPK hard, suppress mTORC1 anabolics, and blunt hypertrophy. In muscle, that shifts toward more oxidative phenotype at the expense of contractile remodeling; in the heart, it risks energetics imbalance that the sinoatrial node and conduction system must buffer beat-to-beat.