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Uncoupling increases T3

Mauritio

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Feb 26, 2018
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4,592
It has long been shown that T3 increases uncoupling ,but this study shows that it also works vice versa :
Uncoupling (through BAT activation) increases deiodinase type 2 ,which catalyzes T4 toT3 conversion .
This should create a positive feedback loop. If you uncouple your metabolism with aspirin for example ...

Salicylic Acid Is an Uncoupler and Inhibitor of Mitochondrial Electron Transport

...this will increase deiodinase type 2 ,which will increase T3 ,which will increase UCP1 ,which will increase uncoupling,...

"Vice versa, sympathetic stimulation of BAT triggers the expression of deiodinase type II, an enzyme that enhances local thyroid hormone availability and signaling"
Thyroid hormones in the regulation of brown adipose tissue thermogenesis - PubMed



This might be important as T3 has other ways of increasing glucose consumption and thermogenesis that are not related to uncoupling:

"Consequently, the metabolic and thermogenic effects of systemic hyperthyroidism were maintained in UCP1 knockout mice, demonstrating that neither beige nor brown fat contributes to the TH-induced hyperthermia and elevated glucose consumption, and underlining that the mere presence of UCP1 is insufficient to draw conclusions on the therapeutic potential of browning agents."
(Thyroid-Hormone-Induced Browning of White Adipose Tissue Does Not Contribute to Thermogenesis and Glucose Consumption - PubMed)

Interestingly T3 and UCP1 don't raise free radicals . Which has to with their increase in autophagy . They both help to get rid of old mitochondria and create new ones .
This study shows that blocking autophagy leads to an increase in free radicals and a decrease in metabolism by T3 .

"T3 increased fatty acid oxidation and mitochondrial respiration as well as autophagic flux, mitophagy, and mitochondrial biogenesis. Interestingly, there was no significant induction of intracellular reactive oxygen species (ROS) despite high mitochondrial respiration and UCP1 induction by T3. However, when cells were treated with Atg5 siRNA to block autophagy, induction of mitochondrial respiration by T3 decreased, and was accompanied by ROS accumulation, demonstrating a critical role for autophagic mitochondrial turnover."
(Thyroid hormone (T 3) stimulates brown adipose tissue activation via mitochondrial biogenesis and MTOR-mediated mitophagy - PubMed)
 
Last edited:

Guacamayo

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Mar 4, 2018
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Are there any uncouplers other than aspirin you can think of?

This is a huge issue for me since my body cannot convert T4 to T3 properly and I need to take massive doses of T3 - 100mcg per day.
 

Korven

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May 4, 2019
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936
Are there any uncouplers other than aspirin you can think of?

This is a huge issue for me since my body cannot convert T4 to T3 properly and I need to take massive doses of T3 - 100mcg per day.

Have you tried stacking pro-metabolic things like caffeine + 100-300 mg thiamine HCL + 500-1000 mg niacinamide? Maybe also throwing in a quinone like black cumin seeds, methylene blue, vitamin k2, Pau d arco, etc.

Increasing NAD+ levels seems to be an effective way of increasing uncoupling and body temperature, at least according to this study Nicotinamide riboside induces a thermogenic response in lean mice - PubMed
 

Guacamayo

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I've tried all of those things except methylene blue and niacinamide in such huge doses.

I am thinking of trying methylene blue seeing as Haidut is such a huge fan.
 

Korven

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I've tried all of those things except methylene blue and niacinamide in such huge doses.

I am thinking of trying methylene blue seeing as Haidut is such a huge fan.

Methylene blue could definitely be worth a shot!

I just bought lots of niacinamide, am curious what happens with the 1-2 g doses. Seems to have a way different effect vs the 30-50 mg in your standard B complex.

Another thing for mitochondrial support/boosting oxidative metabolism is beef heart: lots of CoQ10 and copper for ETC, riboflavin, selenium for T4 to T3 conversion, maybe even androgens (?).
 
Last edited:

MidBicep

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Dec 12, 2020
Messages
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Are there any uncouplers other than aspirin you can think of?

This is a huge issue for me since my body cannot convert T4 to T3 properly and I need to take massive doses of T3 - 100mcg per day.
Caffeine, sugar, salt, protein, calcium and saturated fat. Supplements like aspirin, NDT, vitamin D3 or K2 don't do anything for me aside from making me feel bad. Good food has been enough for me.
 

Mauritio

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Feb 26, 2018
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Are there any uncouplers other than aspirin you can think of?

This is a huge issue for me since my body cannot convert T4 to T3 properly and I need to take massive doses of T3 - 100mcg per day.
Caffeine, lauric acid ,stearic acid .
T4 toT3 conversion in usually a liver task ,so I'd look there...
 

Hans

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Aug 24, 2017
Messages
5,259
It has long been shown that T3 increases uncoupling ,but this study shows that it also works vice versa :
Uncoupling (through BAT activation) increases deiodinase type 2 ,which catalyzes T4 toT3 conversion .
This should create a positive feedback loop. If you uncouple your metabolism with aspirin for example ...

Salicylic Acid Is an Uncoupler and Inhibitor of Mitochondrial Electron Transport

...this will increase deiodinase type 2 ,which will increase T3 ,which will increase UCP1 ,which will increase uncoupling,...

"Vice versa, sympathetic stimulation of BAT triggers the expression of deiodinase type II, an enzyme that enhances local thyroid hormone availability and signaling"
Thyroid hormones in the regulation of brown adipose tissue thermogenesis - PubMed



This might be important as T3 has other ways of increasing glucose consumption and thermogenesis that are not related to uncoupling:

"Consequently, the metabolic and thermogenic effects of systemic hyperthyroidism were maintained in UCP1 knockout mice, demonstrating that neither beige nor brown fat contributes to the TH-induced hyperthermia and elevated glucose consumption, and underlining that the mere presence of UCP1 is insufficient to draw conclusions on the therapeutic potential of browning agents."
(Thyroid-Hormone-Induced Browning of White Adipose Tissue Does Not Contribute to Thermogenesis and Glucose Consumption - PubMed)

Interestingly T3 and UCP1 don't raise free radicals . Which has to with their increase in autophagy . They both help to get rid of old mitochondria and create new ones .
This study shows that blocking autophagy leads to an increase in free radicals and a decrease in metabolism by T3 .

"T3 increased fatty acid oxidation and mitochondrial respiration as well as autophagic flux, mitophagy, and mitochondrial biogenesis. Interestingly, there was no significant induction of intracellular reactive oxygen species (ROS) despite high mitochondrial respiration and UCP1 induction by T3. However, when cells were treated with Atg5 siRNA to block autophagy, induction of mitochondrial respiration by T3 decreased, and was accompanied by ROS accumulation, demonstrating a critical role for autophagic mitochondrial turnover."
(Thyroid hormone (T 3) stimulates brown adipose tissue activation via mitochondrial biogenesis and MTOR-mediated mitophagy - PubMed)
I posted about this in last Friday's newsletter so nice synergy haha.
Important here is that thyroid promotes autophagy and thermogenesis, which people think you can only get with fasting and cold water exposure, which is not the case. If you optimize thyroid function and sleep, then you're good to go.
Actually, one of the reasons why people get benefits of cold water exposure is because it increases T3 as you pointed out. But a study actually found that hypothyroid people had less conversion of T4 into T3, so the cold is more likely to make them feel worse, than better. And many people have reported this.
 

Mauritio

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I posted about this in last Friday's newsletter so nice synergy haha.
Important here is that thyroid promotes autophagy and thermogenesis, which people think you can only get with fasting and cold water exposure, which is not the case. If you optimize thyroid function and sleep, then you're good to go.
Actually, one of the reasons why people get benefits of cold water exposure is because it increases T3 as you pointed out. But a study actually found that hypothyroid people had less conversion of T4 into T3, so the cold is more likely to make them feel worse, than better. And many people have reported this.
Nice didnt know you had a newsletter ! Which study did you cite?

Yeah very interesting , something that I want to look into is how thyroid and autophagy influence cellular senescence.

"Autophagy is originally thought to suppress cellular senescence by removing damaged macromolecules or organelles, yet recent studies also indicated that autophagy promotes cellular senescence by facilitating the synthesis of senescence-associated secretory proteins."
 

Hans

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Nice didnt know you had a newsletter ! Which study did you cite?

Yeah very interesting , something that I want to look into is how thyroid and autophagy influence cellular senescence.

"Autophagy is originally thought to suppress cellular senescence by removing damaged macromolecules or organelles, yet recent studies also indicated that autophagy promotes cellular senescence by facilitating the synthesis of senescence-associated secretory proteins."
Mainly the first 2, which I found interesting last week.
Keep us posted on what you find on autophagy in relation to thyroid.
 

Yucca

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Maybe using low doses oxandrolone ? It really helps converting T4->T3. It's not really liver toxic, and HPTA suppression is also not really a concern at 10mg or below...
 

Zoiros

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Jan 29, 2020
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Don't forget the 800 pound gorilla, DNP. I first read about it in one of Ray's articles, though I don't recall him elaborating on it. I've never tried it myself, but it seems to be quite a powerful uncoupler.


Uncoupling of Oxidative Phosphorylation​

DNP decreases the formation of high-energy phosphate bonds in mitochondria and at the same time stimulates systemic oxygen consumption [23]. This dissociative effect is known as uncoupling of oxidative phosphorylation. Adenosine triphosphate (ATP) production is the final product of the tricarboxylic acid (Krebs) cycle in mitocondria along with CO2 and H2O. During glycolysis, there is a net production of two ATP molecules, but the majority of energy-rich phosphate bonds (38 in total) are produced during the final oxidative phosphorylation process. During this final phase, ATP synthetase converts adenosinediphosphate to ATP with the addition of an inorganic phosphate molecule. DNP interferes with the final energy production pathway by preventing the uptake of inorganic phosphate molecules into the mitochondria [24, 25]. This results in the inhibition of all energy-requiring processes and the extra-mitochondrial accumulation of inorganic phosphate [26]. DNP also acts as a chemical ionophore, stopping the final energy conversion by exporting the proton ions (H+) needed for ATP production across the mitochondrial membrane by increasing the basal leak of protons [12]. This shift in the proton electrochemical gradient then results in potential energy dissipating as heat, instead of being converted to ATP, with rapid consumption of calories [27, 28]. The heat production represents a failure in thermoregulatory homeostasis, leading to uncontrolled hyperthermia [29].

 

Mauritio

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Don't forget the 800 pound gorilla, DNP. I first read about it in one of Ray's articles, though I don't recall him elaborating on it. I've never tried it myself, but it seems to be quite a powerful uncoupler.

That's an interesting one. It's actually beeing studied more again in the last years for chronic diseases .
If you mess up the dosing, you might die . That's a downside .
 

shine

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Sep 27, 2018
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Are there any uncouplers other than aspirin you can think of?

This is a huge issue for me since my body cannot convert T4 to T3 properly and I need to take massive doses of T3 - 100mcg per day.

I think policosanols increase UCP1.
 

Mauritio

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I think policosanols increase UCP1.
Yes . Dosage was very high though .
HED=400 mg daily

The Policosanols Thread

 

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