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High Dose of Dietary Nicotinamide Riboside Induces Glucose Intolerance and White Adipose Tissue Dysfunction in Mice

nad in vivo

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#1 malbecman

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Posted 23 October 2019 - 09:53 PM


 Perhaps there is a U shaped curve where too much NR can be harmful.....

 

 

Nutrients. 2019 Oct 13;11(10). pii: E2439. doi: 10.3390/nu11102439.
High Dose of Dietary Nicotinamide Riboside Induces Glucose Intolerance and White Adipose Tissue Dysfunction in Mice Fed a Mildly Obesogenic Diet.
Author information
1 Human and Animal Physiology, Wageningen University, PO Box 338, 6700 AH Wageningen, The Netherlands. ws456@cornell.edu. 2 Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA. ws456@cornell.edu. 3 Human and Animal Physiology, Wageningen University, PO Box 338, 6700 AH Wageningen, The Netherlands. m.a.hegeman@uu.nl. 4 Educational Consultancy & Professional Development, Faculty of Social and Behavioral Sciences, Utrecht University, 3508 TC Utrecht, The Netherlands. m.a.hegeman@uu.nl. 5 Human and Animal Physiology, Wageningen University, PO Box 338, 6700 AH Wageningen, The Netherlands. atanaska.doncheva@outlook.com. 6 Human and Animal Physiology, Wageningen University, PO Box 338, 6700 AH Wageningen, The Netherlands. melissa.bekkenkamp-grovenstein@wur.nl. 7 Human and Animal Physiology, Wageningen University, PO Box 338, 6700 AH Wageningen, The Netherlands. 8 Human and Animal Physiology, Wageningen University, PO Box 338, 6700 AH Wageningen, The Netherlands. jaap.keijer@wur.nl.
Abstract

Nicotinamide riboside (NR) is a nicotinamide adenine dinucleotide (NAD+) precursor vitamin. The scarce reports on the adverse effects on metabolic health of supplementation with high-dose NR warrant substantiation. Here, we aimed to examine the physiological responses to high-dose NR supplementation in the context of a mildly obesogenic diet and to substantiate this with molecular data. An 18-week dietary intervention was conducted in male C57BL/6JRccHsd mice, in which a diet with 9000 mg NR per kg diet (high NR) was compared to a diet with NR at the recommended vitamin B3 level (control NR). Both diets were mildly obesogenic (40 en% fat). Metabolic flexibility and glucose tolerance were analyzed and immunoblotting, qRT-PCR and histology of epididymal white adipose tissue (eWAT) were performed. Mice fed with high NR showed a reduced metabolic flexibility, a lower glucose clearance rate and aggravated systemic insulin resistance. This was consistent with molecular and morphological changes in eWAT, including sirtuin 1 (SIRT1)-mediated PPARγ (proliferator-activated receptor γ) repression, downregulated AKT/glucose transporter type 4 (GLUT4) signaling, an increased number of crown-like structures and macrophages, and an upregulation of pro-inflammatory gene markers. In conclusion, high-dose NR induces the onset of WAT dysfunction, which may in part explain the deterioration of metabolic health.

KEYWORDS:

NAD+; Nnt; adipose tissue; glucose tolerance; supplementation; vitamin B3

PMID: 31614949
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#2 Oakman

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Posted 24 October 2019 - 12:41 AM

Those mice get 9 grams NR per kg? Those are some rich mice! The H.E.D from mice to men gives about 730 mgs/kg for a human.  So for a 70 kg person, something over 51 grams.seems a bit excessive to think humans will get to that level.  

 

These scientist will do anything, including torturing mice with NR, to get a catchy headline.


Edited by Oakman, 24 October 2019 - 12:42 AM.

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#3 joesixpack

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Posted 24 October 2019 - 02:35 AM

That is how I read it as well. The NR probably weighed more than the mouse. The mouse probably died from suffocation after having that much NR stuffed down it's throat. Surprised they did not say: "high dose of NR causes death in mice". I am sure I will get "time wasting", "unfriendly" and "needs references" emojis for this post.



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#4 Hebbeh

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Posted 24 October 2019 - 02:45 AM

It's not 9 grams NR per Kg of body weight, it's 9 grams of NR per Kg of food.  How long does it take for a mouse to eat a Kg of chow?  I doubt any single mouse ate a Kg of mouse food by themselves in the 18 week trial.  I'm sure the 9 grams of NR in the Kg of chow was shared by many mice in the trial.  Again, I believe people are misreading what they did.  Read it again... "a diet with 9000 mg NR per kg diet".  It clearly says per kg diet where diet refers to food... not per kg body weight.

 

edit:  I don't have the time to research it, but I vaguely remember reading in a similar study that mice eat something like 4 or 5 mg of food per day..  which would be like 650 mg of food per mouse total over the 18 weeks.. which would be 30 mg NR per day.


Edited by Hebbeh, 24 October 2019 - 02:50 AM.

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#5 Oakman

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Posted 24 October 2019 - 03:33 AM

It's not 9 grams NR per Kg of body weight, it's 9 grams of NR per Kg of food.  How long does it take for a mouse to eat a Kg of chow?  I doubt any single mouse ate a Kg of mouse food by themselves in the 18 week trial.  I'm sure the 9 grams of NR in the Kg of chow was shared by many mice in the trial.  Again, I believe people are misreading what they did.  Read it again... "a diet with 9000 mg NR per kg diet".  It clearly says per kg diet where diet refers to food... not per kg body weight.

 

edit:  I don't have the time to research it, but I vaguely remember reading in a similar study that mice eat something like 4 or 5 mg of food per day..  which would be like 650 mg of food per mouse total over the 18 weeks.. which would be 30 mg NR per day.

 

Of course you are correct. What is problematic in these mouse studies, is that they regularly use what I'll call 'defective' mice, or strains of mice with certain characteristics, rather than "normal" mice, whatever they are(?). As I read the study they used these, best I could tell:

 

"C57BL/6J mice are resistant to audiogenic seizures, have a relatively low bone density, and develop age related hearing loss. They are also susceptible to diet-induced obesity, type 2 diabetes, and atherosclerosis. Macrophages from this strain are resistant to the effects of anthrax lethal toxin."

 

Those results are skewed (and I don't understand how the results are affected) by their gene characteristic, at least to me, reading from a layperson's understanding.


Edited by Oakman, 24 October 2019 - 03:34 AM.

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#6 Harkijn

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Posted 24 October 2019 - 04:06 PM

If you ever had 1 mouse in your house you'd know that they eat a lot more than 5mgs per day. The average mouse is said to eat between 3 to 5 grams of food per day. Frankenmice leaning to obesity and then fed a mildly obesogenic diet might even eat more? I don't know.

I have to prioritize other reading but if the authors' point is that a phenotype in a very bad state is worsened by giving them NR, well they just might be right....


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#7 orion22

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Posted 24 October 2019 - 04:39 PM

when i  become a millionaire im going to have to worry about this  



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#8 aribadabar

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Posted 05 November 2019 - 06:43 PM

OK, after the clarifications made above (3-5g of average daily food intake containing 9g/kg NR) we are talking about 45mg max NR per day.

An average C57BL/6J mouse weighs about 20g so the dose is 2250mg/kg which translates to HED  of 183mg/kg or 12.8g NR for a 70kg human - a monstrous dose still.


Edited by aribadabar, 05 November 2019 - 06:49 PM.

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