Uncoupling protein, aka thermogenin, are proteins found in the inner mitochondrial membrane of the cell. Protons generated in the Kreb cycle leave the mitochondria via the electron transport chain, and then re-enter the mitochondria via the ATPase enzyme for the synthesis of ATP. This is called coupled respiration. With uncoupled respiration, protons re-enter the mitochondria via the UCPs instead of ATPase, producing heat, instead of ATP.
Uncoupled respiration has a higher rate of oxygen consumption, a high rate of CO2 production and lower lactate formation. Uncoupling also increases whole body energy expenditure (thermogenesis), the synthesis of new mitochondria, improves insulin signalling, increases lipid metabolism, reduces adiposity, protects the mitochondria against oxidative damage (from polyunsaturated fatty acids by transporting them out of the cells), aids in reversing fatty liver and liver steatosis, reduces anxiety as well as cognitive impairment (1, 2).
Excessive uncoupling will reduce ATP, cause hyperthermia, excessive sweating, restlessness, etc. This is what easily happens with overdosing on unnatural uncouplers such as DNP. Luckily, under normal circumstances, elevated nucleotides, such as GTP, ATP, GDP, ADP, GMP and AMP, inhibit uncoupling. So when energy becomes low, uncoupling is inhibited.
Most cells produce 50% ATP through oxidative metabolism (coupled respiration), whereas the mitochondria of brown adipocytes are able to “waste” almost 90% of the oxidative energy, as thermogenesis, through uncoupling. (3)
Cold, overeating, sympathetic nervous activation (adrenaline/noradrenaline), leptin, free radicals, lipid peroxides and superoxides all stimulate UCP activity.
There are 5 different UCPs found to date, but we’re only going to be talking out 3 of them.
UCP1 is found in brown adipose tissue and is involved in non-shiver heat generation. UCP1 contributes the most to the thermogenic effect, whereas, UCP2 and UCP3 are as much as 1000 fold less expressed than UCP1.
UCP2 is mostly expressed in parenchymal cells of the brain, spleen, white adipose tissue and β-cells of the pancreas, as well as in macrophages in the brain, liver and lungs.
Its activation reduces reactive oxygen species (ROS) and cellular damage, restores cellular redox homeostasis, reduces inflammation, improves insulin signaling and sensitivity. It is neuroprotective (beneficial for Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), brain hypoxia and stroke), is protective against atherosclerosis, lowers hypertension, increases alcohol tolerance, and may extend lifespan. (4, 5, 6, 7, 8, 9)
UCP3 is primarily expressed in skeletal muscle and heart. UCP3 plays a role in mitochondrial fatty acid oxidation, and aids in the prevention of mitochondrial ROS-induced oxidative damage. A deficiency increases fat storage. ROS itself or ROS by-products can induce UCP3 uncoupling, which provides a negative feedback loop for mitochondrial ROS production. (10)
Before we dive into the uncouplers, you need to go check out my other article on how to speed up your metabolism and increase CO2 production, if you haven’t done so already, and then you can come back to this one, and read more on the uncouplers. Optimizing the metabolism is most important, by avoiding PUFAs, lowering stress hormones (serotonin, cortisol, estrogen, adrenaline and prolactin) and keeping the gut clean as well as eliminating inflammation.
Lets talk about a few uncouplers:
1) Caffeine (A) similarly increases metabolism, UCP and mitochondrial content compared with DNP. (11, 12) Start with what you are able to tolerate, and work up to 400mg x2-3 times a day. If you are prone to anxiety, I would recommend to take theanine with it.
2) Nicotine increases UCP1 in the body and reduces fat mass. (13)
3) Methylene blue stimulates oxidative metabolism, improves the NAD+/NADH ratio, is a electron acceptor and uncouples the mitochondria at higher dosages. (14) 15mg of methylene blue is enough to uncouple the mitochondria. Over time methylene blue builds up in the body, and less than 15mg is likely needed when used every day. If your urine starts turning green/blue, your tissue is saturated with methylene blue and the dose can be reduced, till it’s no longer visible.
4) Aspirin uncouples the mitochondria in a U-curve. (15) Meaning, too much or too little will not uncouple the mitochondria. Taking 500 every four hours will keep uncoupling in the sweet spot. When waking up in the morning, taking 1.5g to saturated tissue with aspirin and then take 500mg every 4 hours thereafter. Aspirin is prone to thin the blood, so I would advise taking it with vitamin K (as vitamin K helps to stabilize blood viscosity).
5) Ubiquinone (Coenzyme Q10), similar to methylene blue, are electron acceptors which help with energy production. CoQ10 levels also correlate with UCP1 activity, but is only activated by the oxidized form and not by the reduced CoQ form. (16, 17) As mentioned above, UCP is inhibited by nucleotides such as GTP, ATP, GDP, ADP, GMP and AMP, but this inhibition is alleviated when the ubiquinone redox state, high ubiquinone reduction level, exceeded 85-88%.
6) DHEA is able to significantly increase the levels of UCP1 and PGC-1, as well as increase the expression of UCP3 mRNA and β3-adrenergic receptor. (18) I would recommend starting with 5mg daily. More on DHEA here.
7) Vitamin D (A) and calcium (A). Vitamin D increases the absorption of calcium, and calcium increases uncoupling UCP2. (19, 20) Vitamin D with a calcium deficiency will reduce UCPs and have an anti-metabolic effect. Depending on your vitamin D levels and daily sun exposure, you can start with 1-2000IU daily, and 500mg-2g of calcium, also depending on your daily calcium intake. You want to consume approx 2g of calcium daily, from food and supplement sources. Just be sure to consume adequate magnesium as well to prevent an imbalancement.
8) Vitamin A (A) (retinoic acid) strongly increases proton transport by UCP1 in brown adipose tissue’s mitochondria, and is much more potent than fatty acids. (21, 22, 23, 24) Vitamin A works synergistically with vitamin D, and would prevent vitamin D’s hypercalcemia, and possibly its calcification effect when levels are too high. A good ratio for vitamin A:vitamin D would be 5:1. So for every 1000IU vitamin D, you’ll need 5000IU of vitamin A. Vitamin E also works synergistically with vitamin A, in preventing its oxidation, as well as protecting the body against any potential harmful effect that
vitamin A might have.
9) Vitamin E (A) is able to increase thermogensis through UCP. The α-tocopherol is responsible for this effect. (25) However, it would be silly to just use α-tocopherol on it’s own, as it’s much healthier and beneficial to use all 4 versions of tocopherol instead of just one. I advise to start with 200IU daily, depending on your PUFA intake. If you eat a moderate to high PUFA diet (>10g), take 400IU daily.
10) Thyroid hormones increase UCP3 in skeletal muscle and increase energy expenditure (26). If your thyroid is already optimal, there would be no need to take thyroid hormones, but most people are hypothyroid, and taking thyroid hormones would be most beneficial. If your taking synthetic thyroid hormones, as a basic guideline, it’s best to take it in a ratio of 1:3 for T3:T4, and to only take T3 for the rest of the day as needed. Or use 1 grain of desiccated thyroid upon waking.
- TyroMax – 1 grain per serving, 90 serving (raw desiccated thyroid from bovine origin)
11) Progesterone increases oxygen consumption, reduces ATP production, which indicates an increase in uncoupling. It also increases uncoupling mRNA.
Progesterone is also potent anti-cortisol and is an aromatase inhibitor, which works synergistically with DHEA. (28, 29)
- Progestene – 1.66mg progesterone per drop, 500 drops per container
(highly advised to start with 1 drop).
12) Berberine is known to increase UCP. (30) However, despite all its health benefits, I would personally not use it because it activates 5-HT2A and increases 17β-HSD1 mRNA. Which will increase the release and synthesis of cortisol and estrogen respectively (31, 32).
- Berberine – (Amazon)
13) Forskolin increases UCP1 and thermogenesis (33). It is an effective fat loss agent, and it also increases free testosterone and dopamine receptors.
A few other supplements which are not uncouplers themselves, but will boost the effectiveness of the above-listed uncouplers.
1) Vitamin B1 (A) increases glucose oxidation, reduces lactate and increases CO2 production.
Recommended dosage: 50-100mg x3 daily.
2) Vitamin B3 (A), niacinamide, inhibits lipolysis and fatty acid oxidation.
It also improves the redox status (NAD+:NADH ratio) of the cells and is involved in energy metabolism.
Recommended dosage: >100mg x3 times daily.
3) Biotin is involved in glucose oxidation and increases CO2 production. Use >1mg daily.
5) Vitamin K2 (A), methylene blue and β-lapachone are also electron acceptors, and can be used with, or instead of CoQ10, as vitamin K2 and methylene blue are also much cheaper than CoQ10.
6) Magnesium (A) is indispensable for ATP production and health.
Foods you should be eating
- Fructose increases UCP2 (35). Fructose also increases glucose oxidation, can enter muscle cells via GLUT5 transporter, doesn’t spike insulin like glucose does, generates more CO2 than glucose, and is just more rapidly used than glucose. Glucose enters the circulation and travels around in the blood, whereas fructose immediately goes to the liver, where it is used as energy. I advise fruits (dried, fresh, juice), honey and sugar for fructose. Don’t drink or eat high fructose corn syrup, which is not the same as fructose found in natural sources.
- Quercetin is a bioflavonoid present in citrus and apples, in high amounts, and it increases uncoupling. (36)
- You can make yourself dates blended with desiccated coconut for a perfect candy snack on the run.
2) Saturated fats. Fats (lauric, myristic, palmitic, stearic acid) and ketones increase uncoupling and inhibit mitochondrial recoupling (37). I don’t advise to eat a low carb diet to achieve this, but rather use MCT oil which can create ketones even in the presence of large amounts of carbs.
Recommended usage: Start with 1-2tsp MCT per meal. For other fat sources, beef, bison, lamb, goat and dairy fat as well as coconut oil, cocoa butter, stearyl alcohol ((for stearic acid) is converted to palmitic and stearic acid in the body) are great sources.
4) Brassica oleracea (cabbage, broccoli, cauliflower, kale, Brussels sprouts, collard greens, savoy, kohlrabi, and gai lan) are shown to increase UCP2 via the AMPK/SIRT1/PGC1α/PPARα/UCP2 axis (40). However, I would rather stay away from cruciferous vegetables as they also contain anti-thyroid substances.
- Caffeine – (Amazon)(iHerb) (200-400mg, x3 daily)
- Methylene blue – (Amazon) (15mg when used alone / 5mg (12-13 drops)
- Aspirin – (Amazon) (1-1.5g on waking, 500mg every 4-6 hours thereafter)
- Calcium – (Amazon)(iHerb)
- vitamin D – (Amazon)(iHerb) (1g + 1-2000IU depending on sun exposure, only once daily)
- Vitamin E – (Amazon)(iHerb) (200IU, x1 daily)
- DHEA – (Amazon)(iHerb) (5mg in the morning)
- Progesterone (Progestene) (1 drop before bed)
- Thyroid (TyroMax) (1 grain upon waking)
- Vitamin K2 – (Amazon)(iHerb) (3-15mg)
- Thiamine – (Amazon)(iHerb) (100mg x3 daily)
- Niacinamide – (Amazon)(iHerb) (100mg x3 daily)
- Magnesium – (Amazon)(iHerb) (200mg x2 daily)