Effect Of Taurine And N-acetylcysteine On Methionine Restriction-mediated Adiposity Resistance

[Terma]

So I was slowly embarking on MR, but planned to use NAC from time to time.

Turns out it's a great way to sabotage MR:

http://www.metabolismjournal.com/article/S0026-0495(12)00387-3/abstract

Objectives
Methionine-restricted (MR) rats, which are lean and insulin sensitive, have low serum total cysteine (tCys) and taurine and decreased hepatic expression and activity indices of stearoyl-coenzyme A desaturase-1 (SCD1). These effects are partly or completely reversed by cysteine supplementation. We investigated whether reversal of MR phenotypes can be achieved by other sulfur compounds, namely taurine or N-acetylcysteine (NAC).

Methods
MR and control-fed (CF) rats were supplemented with taurine (0.5%) or NAC (0.5%) for 12 weeks. Adiposity, serum sulfur amino acids (SAA), Scd1 gene expression in liver and white adipose tissue, and SCD1 activity indices (calculated from serum fatty acid profile) were monitored.

Results
Taurine supplementation of MR rats did not restore weight gain or hepatic Scd1 expression or indices to CF levels, but further decreased adiposity. Taurine supplementation of CF rats did not affect adiposity, but lowered triglyceridemia. NAC supplementation in MR rats raised tCys and partly or completely reversed MR effects on weight, fat %, Scd1 expression in liver and white adipose tissue, and estimated SCD1 activity. In CF rats, NAC decreased body fat % and lowered SCD1-18 activity index (P<0.001). Serum triglycerides and leptin were over 40% lower in CF+NAC relative to CF rats (P≤0.003 for both). In all groups, change in tCys correlated with change in SCD1-16 index (partial r=0.60, P<0.001) independent of other SAA.

Conclusion
The results rule out taurine as a mediator of increased adiposity produced by cysteine in MR, and show that NAC, similar to L-cysteine, blocks anti-obesity effects of MR. Our data show that dietary SAA can influence adiposity in part through mechanisms that converge on SCD1 function. This may have implications for understanding and preventing human obesity.

Which is because of:
Cysteine supplementation reverses methionine restriction effects on rat adiposity: significance of stearoyl-coenzyme A desaturase

Stearoyl-CoA desaturase-1 (SCD1) is a key enzyme in fatty acid and energy metabolism, but little is known about its nutritional regulation. Dietary methionine restriction in rats decreases hepatic Scd1 mRNA and protein, increases energy expenditure, and decreases fat-pad mass/body-weight% (FM/BW%). In humans, plasma concentrations of the methionine product, cysteine, are associated with obesity. To determine which consequences of methionine-restriction are mediated by decreased cysteine availability, we monitored obesity-related variables in 4 dietary groups for 12 weeks: control-fed (CF), methionine-restricted (MR), MR supplemented with 0.5% l-cysteine (MR+Cys) and CF+Cys rats. MR lowered weight gain and FM/BW% despite higher food intake/weight than CF, and lowered serum cysteine. Hepatic Scd1 expression was decreased, with decreased serum SCD1 activity indices (calculated from serum fatty acid profile), decreased serum insulin, leptin and triglycerides, and higher adiponectin. Cysteine supplementation (MR+Cys) essentially reversed all these phenotypes and raised serum cysteine but not methionine to CF levels. Adding extra cysteine to control diet (CF+Cys) increased serum taurine but did not affect serum cysteine, lipids, proteins, or total weight gain. FM/BW% and serum leptin were modestly decreased. Our results indicate that anti-obesity effects of MR are caused by low cysteine and that dietary sulfur amino acid composition contributes to SCD1 regulation.

I don't know if this has been posted, I only saw one poster mention something of the sort, but seemed worth it.

 

[brix]

So, assuming one is lean, supplementing NAC, l cysteine, or l methionine could help with weight gain?

 

[Such_Saturation]

@Travis does this have to do with glutathione and polyamines

 

[Terma]

So, assuming one is lean, supplementing NAC, l cysteine, or l methionine could help with weight gain?

Not cysteine: [edit: this is misleading, see next post]

However, cysteine supplementation of a control diet did not promote further fat mass gain, and in fact, tended to decrease adiposity.

Methionine still could through other means.

 

[Terma]

Ok, correction, sorry:

Cysteine supplementation in CF+Cys rats neither increased tCys nor adiposity above CF levels, and thus failed to replicate the elevated plasma tCys that is linked to human obesity (17, 18). This may result from the role of the liver, demonstrated in rodents (54), in disposing of excess dietary cysteine via conversion to taurine, as shown by raised serum taurine in CF+Cys rats.

Cysteine didn't increase weight in the second study above, but it's because the blood levels stayed too low. In some other studies where cysteine remained high there was weight gain. So depends on clearance.

Further, in the present study the effect of dietary cysteine on SCD1 function and fat mass accretion clearly showed a ceiling effect that stopped at control values for these parameters. This is at odds with human findings of a linear dose-response relation between tCys and body fat extending well into the obese range of BMI and fat mass (17, 18). The discrepancy could reflect a species difference in body weight response to excess dietary cysteine

 

[Terma]

Here's an interesting tidbit (I'll let Travis fill in the glutathione question since I can't hope to fill in for Travis):

In contrast to liver, adipose tissue showed enhanced Scd1 expression in MR rats, an effect that was reversed by cysteine supplementation.

So apparently SCD1 in WAT doesn't matter too much in weight gain compared to total EE and liver SCD1, for whatever reason...

 

[Travis]

@Travis does this have to do with glutathione and polyamines

I think so, but this author did not:

'Our results indicate that anti-obesity effects of MR are caused by low cysteine and that dietary sulfur amino acid composition contributes to SCD1 regulation.'​

Nothing causes cell proliferation like polyamines; androgens and prostaglandind E₂ cause proliferation and growth, but they also transcribe for ornithine decarboxylase—which makes polyamines. Let's see that quote one more time, with the acronym expanded:

'Our results indicate that anti-obesity effects of methionine restriction are caused by low cysteine and that dietary sulfur amino acid composition contributes to SCD1 regulation.'
​

But what does cysteine restriction do? By their logic, cysteine restriction would have an even greater effect—but it don't!

Only in Lewis Carroll books is such logic taken seriously.

 

[Terma]

Anyhow, I'm going to go on a tangent because I took 5 grams of phenibut today and I feel like writing something. I might have to stop suddenly.

This is almost all conjecture, but I wonder if the lipogenic potential of Fructose - through SCD1 - doesn't lie in methionine, cysteine and maybe related aminos like serine?

Since fructose experimentally appears to potently increase SCD1 in liver - e.g. Stearoyl-CoA desaturase 1 gene expression is necessary for fructose-mediated induction of lipogenic gene expression by sterol regulatory element-bi... - PubMed - NCBI and should end up producing mostly intracellular oleate the more fructose you chuck at the liver. (note this is not necessarily technically de novo lipogenesis)

I doubt I need to link this, but regularly glycine is given to mitigate the negative effects of fructose in liver. This is usually ascribed to TNF-alpha and the glycine receptor, which surely matter, but what if part of it were even simpler - glycine's effects via GNMT and one-carbon metabolism?

This is where it gets the most interesting but also more muddy:
Fructose Alters Intermediary Metabolism of Glucose in Human Adipocytes and Diverts Glucose to Serine Oxidation in the One–Carbon Cycle Energy Producing Pathway

Collectively, these results suggest that fructose preferentially drives glucose through serine oxidation glycine cleavage (SOGC pathway) one-carbon cycle for NAD+/NADP+ production that is utilized in fructose-induced lipogenesis and storage in adipocytes.

This was very in-vitro (so large grains of salt required) but showed that fructose overdose doesn't necessarily increase mitochondrial respiration, but instead feed one-carbon metabolism, or basically serine [see attached picture]. This also showed the oleate increases but that's not as novel.

What the study fails to do is give any hint as to the mechanism for oleate and SCD1 increasing. But, it happens concomitantly with the one-carbon serine pathway. I find this highly suggestive.

It would be awesome to know exactly what detailed mechanism leads to SCD1 increases, to see if methionine and cysteine might somehow tie together with fructose's effect on the one-carbon/serine pathway or any other way.

I'm not sure that made that much sense, but I'll just click post cause I have nothing to lose. If the site lets me.

 

[Andman]

5g of phenibut? :O

 

[Kunder]

Translation anyone?

 

[Terma]

If you mean Travis's post, honestly I'm not sure what he meant. He seems to not approve.

The original article is mostly just: taurine is great, doing MR without restricting cysteine is pointless. It would be better if it was in humans but it probably holds. There's a quirk about SCD1 actually going higher during MR in white adipose tissue, I guess it's not significant but would like to know why.

If you mean my poorly reasoned thing on fructose, I'm trying to find a basis for the idea that methionine+cysteine restriction [plus just a little glycine; plus choline and uridine, see other topic] might be enough to offset any issues from fructose, only stronger, I wonder if their effects could be directly related. I really don't want to cut it out. But at this point if you accept information from a guy still on high dose phenibut, it's at your own peril.

 

[Travis]

If you mean Travis's post, honestly I'm not sure what he meant. He seems to not approve.

The original article is mostly just: taurine is great, doing MR without restricting cysteine is pointless. It would be better if it was in humans but it probably holds. There's a quirk about SCD1 actually going higher during MR in white adipose tissue, I guess it's not significant but would like to know why.

If you mean my poorly reasoned thing on fructose, I'm trying to find a basis for the idea that methionine+cysteine restriction [plus just a little glycine; plus choline and uridine, see other topic] might be enough to offset any issues from fructose, only stronger, I wonder if their effects could be directly related. I really don't want to cut it out. But at this point if you accept information from a guy still on high dose phenibut, it's at your own peril.

It's just that these authors had explained the effect of a high‐methionine diet and its attenuation by cysteine completely without mentioning even once the word 'polyamine' throughout the entire article. The effects of methionine are profound, and high‐cysteine diets do not cause massive weight gain and 44% lifespan reductions. The next most fatal is tryptophan; small increases in this amino acid can cause a reduction of lifespan around 10–20%, ostensibly by increasing serotonin which releases growth hormone. But explanations on how methionine reduces lifespan have always been manifold, ranging from the usual ones to the more extreme:

I. Free radical explanations are used to explain the functions of thousands of molecules when the author is too lazy to find a more realistic explanation. While it's true that free radicals cause lipid peroxidaton, they don't greatly contribute to growth or cancer. In the cell's nucleus is a corepressor and transcription factor called p53; this protein has a redox‐active disulfide domain which senses oxidative stress, leading to its release upon activation. This event causes death of the entire cell, and is why p53 is called the 'tumor suppressor protein.' Considering this nuclear factor, one can get the impression that free radicals could actually cure cancer. Free radical explanations have been used to explain the life‐shortening effects of methionine—through glutathione—but fortunately nobody even attempts to explain weight gain in this manner. Antioxidant capacities of molecules do not correlate with anti‐cancer of anti‐obesity effects, and they never will.

II. The nucleic acid scientists, not to be outdone, have attempted to explain this shortened longevity observed in methionine‐fed rats on account of DNA methylation. These explanations can always be made to 'make sense,' because they can willy‐nilly silence whatever gene they feel like with an imaginary methyl‐group on paper. However, these explanations fail for a number of reasons: (1) DNA methylation is not strongly correlated with anything at all, and so perhaps shouldn't be considered a very powerful cellular control mechanism. (2) Methylators such as betaine, choline, folate, and creatine don't shorten or prolong life to any great extent—nor do they greatly effect growth.

III. Glutathione has other effects besides, and methionine can become glutathione. People have historically tried to explain the effects of methione through other glutathione functions, which basically would revolve around cysteine. Glutathione is created more efficiently from cytsteine itself, yet cysteine‐feeding does not have these effects. So all explanations centering around glutathione fail for this reason, being excluded from serious consideration due to cysteine's inability to reproduce the effect.

IV. Homocysteine is sometimes considered. As a free radical, this overlaps a bit with the 'free radical explanations.' True that homocysteine is very strongly correlated with brain lipid peroxidation, but this can't exactly be said to be conducive to growth (i.e. cancer). Homocysteine is epidemiologically correlated with low IQ, dementia, and cardiovascular disease—but not obesity or cancer. Vegans generally have a slightly higher homocysteine concentration despite low methionine—despite greater intakes of folate and pyroxidal—mostly because of lower cobalamin, choline, and creatine intakes. Vegans don't generally have reduced lifespans, and rarely overweight.

V. Polyamines can explain everything: the plumpening of the rats, their reduction of lifespan, and the low concentration of methionine needed for this. Polyamines interact with DNA directly, induce the Z‐DNA configuration, and accelerate the replication rate during routine PCR. Cancer cells are often found with increased ornithine decarboxylase mRNA, SAM decarboxylase mRNA, and those enzymes themselves. Both prostaglandin E₂ and androgens increase ornithine decarboxylase, and their growth‐stimulating effects can be explained—at least partially—in this manner. What follows from the induction of these enzymes are increased polyamine concentrations, a concomitant shift in the cell cycle, and higher mitosis rates—what a person would expect from increased polyamine concentrations. Methionine is necessary for all polyamines, more so than ornithine (which can be replaced by lysine, forming less‐active polyamines barely capable of keeping the cell alive), so polyamine concentrations greatly depend on this amino acid more than any other. Selenomethionine is a natural amino acid found in plants; this can do everything methionine can besides forming polyamines. It should then be no surprise that selenomethionine supplementation increases prostate cancer survival threefold.

 

[Terma]

I would probably agree about methionine excess. By default (article indirectly brings out this problem, in screwup above) I'm now viewing restriction and excess as possibly working through different pathways, though some are no doubt the same. So I won't comment on the excess.