Saturday, July 5, 2008

A novel obese therapy - reversed (reduced) NO production

The two major topics that attract my scientific interest are obesity and the routes of NO -nitric oxide (the above links summarise my previous studies).
NO, as I have suggested, enabled the initial physiological communication of multicellular organisms and serves now as a support communication system in all living organisms.
It was thus no wonder for me to read the recent Austrian study, which showed that obesity reduces the bioavailability of NO. The studied obese juveniles revealed highly significant alterations in the NO pathway. NOX and citrulline were decreased in obese compared to normal weight juveniles and negatively correlated with body weight. Arginine was increased in obese juveniles and positively correlated with body weight. Is the arginine accumulation related to the arginine paradox? Or mainly to the inhibition of NOX synthesis?
Int J Obes 2008 32: 826-831
I would like to suggest that the decrease in NO bioavailability in the obese (as well as in diabetics or others) is the result of a “savings” strategy…Resources are directed from activeness to accumulation (fat) and lowering the “primordial” communication system may be associated with this lower physiological tempo.
This might remind also aging… and indeed aging is also associated with an impaired bioactivity of NO. It is no wonder that obesity and aging have a lot in common… See also the effect of adipose tissue reduction on lifespan.

This article is meant to point a fault in the obesity strategy (e.g., see below how smart is the Sirt1 startegy). It is true that the obese are trying to accumulate a reservoir for the future, but is it essential that they also lower the NO communication system?
I would try to explain such an evolutionary logic by suggesting that obesity was in the past (before our century) rare and impermanent and maybe a transient lowered communication capacity was even helpful…
Today when obesity is permanent, such prolonged inhibited communication is hazardous and might be the reason for the numerous maladies associated with obesity.
We could thus assume that enhancement of the NO resources might contribute to the health of the fat person even when they do not lose weight.
This reminds me of the resveratrol, found in red wine, which keeps obese mice healthy, and of course the SirT1 which regulates energy metabolism and responds to caloric restriction in mice. It does so smartly, by repressing UCP2 , or via promoting fat mobilization ...see also the recent PNAS Sirt1 article... as well as the new data on the essential CLOCK protein that regulates the body's circadian rhythms and works in balance with the Sirt1...
Is NO signaling in the biological clock, impaired in the obese?
Recent data form Denmark indeed show that human adipose tissue contains Sirt1 and the expression of Sirt1 can be regulated by calorie restriction just as in other species. Interesting... lean women had more than twofold higher Sirt1 expression in subcutaneous adipose tissue compared to obese women...Is this related to NO?

So what can we do to improve wellness in spite of obesity? or in other words, how can we improve the NO availability?
L-arginine supplementation does indeed improve insulin sensitivity and endothelial function in obese type 2 diabetic patients…However I want to mention that it was associated with higher postinfarction mortality… and moreover, arginine was anyway increased in obese juveniles...

I would like to suggest a novel wellness therapy; induction of the reverse route - NO formation via nitrites and nitrates… or maybe through citrulline who is also decreased with obesity.

Nitrate and nitrite are important alternative source of NO to the classical L-arginine-NO-synthase pathway, in particular (but not only) under hypoxic states.
Note that intermittent hypoxia indeed improved glucose tolerance… nitrite therapy indeed augments ischemia-induced angiogenesis... and a role for mammalian nitrate reduction in regulation of nitrite and NO homeostasis as well as: Human endothelial cells bioactivate organic nitrates to nitric oxide.
Hypoxia can also assist wellness via preventing the producion of the toxic peroxynitrite...
It is interesting to note that documents (Dunhuang scrolls) dating to approximately 800 AD, suggested that nitrite and nitrate were used by the Chinese to relieve heart pains and cold in the hands.
I am a cautious person and thus I tend to recommend mainly wise nutrition (rather than food additives) and physical activity... please also consult your physician before applying any measure.
It is rather obvious that we should recommend nitrate-rich vegetables such as spinach, lettuce, radishes or beetroot or fruits like pomegranate.
Nitrate rich vegeatbles such as beetroot indeed reduces blood pressure ... in another experiment it was shown that green leafy vegetable consumption was linked to lower risk for diabetes in women and in another it was shown to decrease the oxygen demand during exercise.
We could also recommend Red wine, which (besides its other qualities, such as its antioxidants) was shown to promote the reduction of nitrite to NO.
Small amounts of polyphenol-rich dark chocolate improved formation of nitric oxide.
On Viagra we could talk as well, but please be moderate

As for physical activity, a rather hypoxic is the body building…I wonder if my usual recommendation for body building (obesity, diabetes or old age) contributes to this reverse NO formation as well and thus makes this type of physical activity a major contributor to wellness.


Anonymous said...

It doesn't matter how the obese is put on, as long as something is said.

Unknown said...

Aren’t nitrates/nitrites very toxic?

How do you rule out this toxicity?

Dina Ralt said...

nitrates/nitrites are toxic at concentrations much higher than those discussed here. e.g.
The highest positive nitrite effect was seen with 8.25 µg/kg....
Toxic water are those that contain over 50 mg/liter nitrates.

Unknown said...

Hi, Dina.
Fair enough. Still there might be a risk of exceeding these non-toxic levels when increasing the nitrates/nitrites in the diet. Curiously, the slightly toxic levels might indeed help reduce weight. This is probably a reason why smoking reduces weight. Cured tobacco is very rich in nitrates.

Hope to see you at our Bar-Ilan meeting on Thursday.

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