Mitochondrial & metabolic reprogramming
One of 6 mechanistic pathways to 🔥 Lose fat · 25 options
This is the pathway Cam means when he says stretch and extrapolate. Instead of eating less, you change how much energy the cell burns and how efficiently it burns it — mitochondrial biogenesis, uncoupling, NAD+ availability, PGC-1α. Almost nothing here has a human fat-loss trial. The mechanisms are well characterised and the rodent data is often striking. That gap is the opportunity and the risk in one.
There is no direct 'mitochondrial function' blood test, which is worth saying plainly. What you can check is whether the cofactors that machinery needs are present — carnitine, CoQ10, thiamine, magnesium. Deficiency here explains fatigue-with-normal-labs, and correcting it is cheaper and better evidenced than anything else in this pathway.
Carnitine, Total and FreeCoenzyme Q10Vitamin B1 (Thiamine)Magnesium, RBCHbA1c (Hemoglobin A1c)🍭 Metabolic Health & Prediabetes covers these in one panel →
What engages this pathway
Ordered by how directly each one acts on the mechanism above — never by how much trial evidence exists. Each links to its full breakdown with dosing, half-life and vendor.
💉 MOTS-c
A mitochondrially-encoded peptide that activates AMPK and shifts the cell toward fat oxidation and glucose uptake. In mice it prevents diet-induced obesity and reverses age-dependent insulin resistance. Human trials for fat loss do not exist — but the mechanism is exactly what you'd design if you wanted metabolic flexibility back.
💉 SLU-PP-332
An ERRα agonist — an exercise mimetic. Rodents given it increase fat oxidation and running capacity without training. Rodent-stage, and the honest read is that nobody knows the human dose, kinetics or safety. The mechanistic case is genuinely excellent.
💉 SLU-PP-915
A more selective ERRα analog from the same programme, tuned to reduce off-target activity. Even earlier than SLU-PP-332 — the argument is entirely by analogy.
💉 Bam15
A mitochondrial uncoupler that dissipates the proton gradient as heat rather than capturing it as ATP. Unlike DNP it has a wide therapeutic window in rodents and does not raise body temperature dangerously. In mice it drops fat mass while sparing muscle and without touching food intake — which is the whole appeal. Rodent-stage.
💉 5-Amino-1MQ
Inhibits NNMT, an enzyme that clears nicotinamide out of the salvage pathway. Block it and the adipocyte's NAD+ pool rises, SIRT1 activity increases, and stored lipid gets mobilised. Mouse data shows fat loss without appetite change; the human trial hasn't run.
💉 AICAR
A direct AMPK activator — the master fuel-sensing switch. Cells behave as though they've just trained. Endurance and glucose disposal improve in rodents; the human obstacle is that it is poorly bioavailable and expensive at any dose that would matter.
💉 ATX-304
A newer, more drug-like pan-AMPK activator built to fix AICAR's bioavailability problem. Early human safety work exists; fat-loss efficacy does not.
💉 SR-9009
A REV-ERB agonist that increases mitochondrial content and shifts the circadian metabolic programme. Famous rodent endurance data. Its oral bioavailability is close to nil, so most of what people report is unlikely to be the mechanism.
💉 Cardarine (oral/inj) Gw-501516
PPARδ agonism — upregulates the fat-oxidation gene programme in muscle and shifts substrate use away from glucose. The rodent carcinogenicity signal at high chronic doses is why it carries a flag, and it is a real one worth understanding before deciding.
💉 Nad+
Raising the NAD+ pool restores sirtuin and PARP activity that declines with age; the downstream prediction is better mitochondrial function and substrate handling. IV NAD+ has poor evidence for fat loss specifically — the mechanism is upstream of it, not aimed at it.
🧬 NMN
An NAD+ precursor one step from NAD+. Human trials show the pool rises; whether that translates into fat loss is unestablished and probably depends on how depleted you were.
💉 NR
Nicotinamide riboside, the better-characterised precursor. Raises NAD+ reliably in humans. Metabolic endpoints in trials have been underwhelming, which is worth knowing before you build a stack on it.
💉 SS-31
Binds cardiolipin in the inner mitochondrial membrane and restores cristae architecture — repair rather than stimulation. In clinical development for mitochondrial myopathy, not for fat loss; the extrapolation is that a repaired mitochondrion oxidises substrate better.
💉 Humanin
Another mitochondrially-derived peptide, cytoprotective and insulin-sensitising in animals. Very early, very interesting, and essentially no human work.
💉 Meldonium
Inhibits carnitine biosynthesis, which paradoxically shifts the heart and muscle toward glucose oxidation and away from fat. That is the opposite of what a fat-loss stack wants — it's here so you understand why it doesn't belong.
💉 Methylene Blue
At low doses acts as an alternative electron carrier, bypassing damaged complexes in the electron transport chain. The prediction is better ATP yield and modestly raised metabolic rate. Serotonin-syndrome risk with SSRIs is the real constraint.
🧬 Urolithin A
Induces mitophagy — clearing damaged mitochondria so the surviving pool works properly. Human trials show improved muscle endurance and mitochondrial gene expression; body-composition change is not the endpoint that moved.
🧬 Berberine
Activates AMPK through mild complex-I inhibition. Human trials show meaningful glucose and lipid improvement; the weight effect is smaller than the internet claims and is downstream of the metabolic change.
🧬 Dihydroberberine
Reduced berberine with substantially better absorption, so a lower dose reaches the same plasma exposure. The efficacy argument is entirely pharmacokinetic.
🧬 NR (Nicotinamide Riboside)
NiaCel — the NR form with the most human pharmacokinetic data. Raises NAD+ reliably. What that buys you metabolically is the open question.
🧬 PQQ
Stimulates mitochondrial biogenesis via PGC-1α signalling in cell and animal work. More mitochondria should mean more oxidative capacity; the human body-composition trial doesn't exist.
🧬 CoQ10
Essential electron carrier in the respiratory chain. Deficiency impairs oxidative metabolism, so repletion matters — but supplementing a replete person is unlikely to change substrate handling.
🧬 Alpha Lipoic Acid
Mitochondrial cofactor and AMPK modulator. Meta-analyses show a small but consistent weight reduction, plus genuine insulin-sensitivity benefit.
🧬 Acetyl-L-Carnitine
Shuttles fatty acids into the mitochondrion for β-oxidation. The catch: carnitine is rarely the rate-limiting step in a healthy person, which is why supplementation underperforms the mechanism.
🧬 Calcium AKG
A TCA-cycle intermediate with rodent lifespan and body-composition data. Mechanistically upstream of everything metabolic; human evidence is thin.
The other 5 routes to lose fat
Pick the pathway that matches where you are actually stuck. An appetite drug does nothing for someone who already undereats.
Want the protocols behind these?
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Frequently asked questions
This is the pathway Cam means when he says stretch and extrapolate. Instead of eating less, you change how much energy the cell burns and how efficiently it burns it — mitochondrial biogenesis, uncoupling, NAD+ availability, PGC-1α. Almost nothing here has a human fat-loss trial. The mechanisms are well characterised and the rodent data is often striking. That gap is the opportunity and the risk in one.
25 options are mapped to this pathway in the Vault, including MOTS-c, SLU-PP-332, SLU-PP-915, Bam15. They are grouped by the mechanism they act through rather than ranked by how much trial evidence exists — 4 carry clinical validation and 20 are mechanistic predictions.
There is no direct 'mitochondrial function' blood test, which is worth saying plainly. What you can check is whether the cofactors that machinery needs are present — carnitine, CoQ10, thiamine, magnesium. Deficiency here explains fatigue-with-normal-labs, and correcting it is cheaper and better evidenced than anything else in this pathway. The markers worth checking are Carnitine, Total and Free, Coenzyme Q10, Vitamin B1 (Thiamine), Magnesium, RBC.
Unproven is not the same as ineffective. Of the 25 options on this pathway, 4 have clinical validation and 20 are graded theoretical — meaning the mechanism is sound but the specific human trial has not been run, which is true of a great deal of what works in this space. Nothing on this page is ordered by evidence tier, because sorting by trial count would bury the compounds you came looking for.