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.

Monday, March 17, 2008

Two urges to eat

As a biologist, in a lifetime attempt to lose weight, I have always wondered about the fascinating nature of eating. I will begin with a general overview on eating and later discuss our conscious part in it.
To physically live, we need two major ingredients - food and breath. Comparing the utilization of these two assets seems different; the eating appears to be volitional while continuous breathing feels essential. However, more accurate observation reveals that they are in principle rather similar; both have a volitional aspect and an essential aspect. However, they differ in their proportions. If we decide to stop breathing it will take at most a few minutes before we are naturally forced to restart breathing. When we decide to stop eating it takes much longer before we finally eat, regardless of our decision. The evolutionary rationale for this type of behavior is easy to understand. Oxygen is almost always present in our surrounding air and it is unnecessary to develop oxygen reserves in our body, therefore we need to breath continuously. Food on the other hand has not always been available, making it crucial to develop fat reserves and making it unnecessary to eat all the time.
It is interesting to watch dolphins who, like us, breathe air but live in the sea where air is not available. They manage air more like we manage food, dolphins decide when to breath and they can also hold their breath for long periods of time.
It is no wonder that dolphin models are useful in yoga, as yoga is based greatly on breathing.
It is not coincidental that I have introduced yoga here. Evolution has led us to develop both eating and breathing with major autonomous (non-voluntary) regulators. It can therefore be concluded that if we wish to control our eating, we need to develop “yoga type” dexterities.
This also explains why most diets fail, as well as diet pills usage (after 2-3 years). Note that the mammalian energy interface (regulating our eating) is related to about 25% (in mice) of the genes, thus trying to skirt it is pointless. Genes are associated with the lean component of our body mass as well. The main issue is that obesity is a very complex disposition, e.g. a core network module in humans and mice was identified that is enriched for genes involved in the inflammatory and immune response and has been found to be causally associated to obesity-related traits.

I will clarify, how long term effects on our nutrition, requires taking into account the bodily holistic physiological goals as well as its intricacy. Furthermore, affecting these goals intelligently (e.g. good night sleep preferably without headaches, or via physical activity, preferably with music) can lead automatically to smart eating habits and weight loss, without too many struggles. Overeating, rather than the obesity it causes, is the trigger for developing metabolic syndrome.
Note that these special efforts are essential only at our wealthy times, e.g. when Cuba was hit with serious food shortage and people had to walk or cycle wherever they needed to go, health was drastically improved...(today, with better economics it is worse again).

The major point I want to emphasize here is that the need to eat, as well as our satiety, are regulated by two unrelated urges. One is our daily energy expenditure and the other is the need to accumulate energy for the future (our bodily worry).
Which urge we choose to fill, depends on our genetics and condition.
If our body feels that there is no need to worry, we will be satiated once we eat approximately the averaged total energy that we expend daily. This was nicely demonstrated when healthy people were asked to drink various caloric shakes and they drank more or less to reach the same caloric total regardless of the shake.
Recently, scientists from Chicago have demonstrated how the brain integrate information from multiple domains and assesses hunger or satiety. We also have mechanisms to evaluate the caloric value of our foods. Scientists from Duke university have shown that calorie-rich nutrients can directly influence brain reward circuits that control food intake independently of palatability or functional taste transduction. Recently it was shown that the ghrelin hormone can change how we see and smell food, there is no doubt that multiple factors affect our satiety.

On the other hand, if our body feels “worried” (economically not emotionally), the second urge to eat will be initiated, an urge that will subside only when the worry disappears.
Note the multiple reasons for this bodily worry (detailed later); if indeed a quarter of the genes are associated with our weight, it is no wonder that so many reasons are relevant.
The obesity related second urge is manifested not only via the unending urge to eat, but also via bodily "saving policy" [see the top sketch, no water (=calories) is wasted]. Is obesity associated with lower body temperatures?
This obesity related policy prohibits dealing with health issues, promotes no-exercise and leads as much energy as possible to the fat storage. It naturally explains why obesity is associated with so many maladies (e.g. The stress cytokine IL-6, induces obesity related insulin resistance). At old age this "saving policy" is manifested via sarcopenia (loss of muscle mass) which is frequently associated with fat accumulation and varoius disorderly conditions (via renin-angiotensin system?).
What was once a smart temporary strategy to overcome food deficiency, more recently has become a steady limiting strategy that causes the fat to become fatter and sicker. Even obese children find food more reinforcing than do nonoverweight children.
It is, therefore, easy to conclude why obese people can/want to consistently eat more, why they eat quickly (to eat more per time), why satiation is impaired, why they stop eating only when they are full, why they eat more on weekends or when served with smaller bags of potato chips , why they behave differently at buffets, why they stop eating due to technical reasons (e.g. no food left on the table), why there is no relationship between eating pattern and sensations of hunger or fullness and thus why recommending healthy eating is usually futile.

A note for the non-obese reader - It will be difficult for the non-obese to empathize with the obesity behaviors as he is mainly acquainted with the first eating urge. It is not a problem for the non-obese to meet his energy needs and thus to follow healthy nutrition guidelines . The obese, in comparison, is eating due to the second urge and thus is rarely satiated or filling his energy needs as most energy is reffered to storage. For a laugh (and to better understand) see this "getting fat" youtube.

Some of the reasons for bodily worry (besides the trivial reason of lack of food):
* Lack of physical activity (or muscles...) - it raises the question of why didn’t we move (not enough energy?) and possibly assumes that eating might supplement the energy required for movements. Note that exercising reduces the urge to eat... or also another study from well as affects our mitochondrial coupling. Indeed muscular strength is inversely and independently associated with death in men.
* Overeating - Digestion of the eaten food, requires abundance of efforts. Thus overeating will cause temporary lack of attention from most other bodily functions (we might feel tired). This evolutionary smart mechanism that was ideal when dealing with sporadic food abundance, is hazardous today when food abundance is constant. It also may explains why fasting is healthy; all the digestive effort can be forwarded to other essential functions. This btw gives a sense of abundance and I will speculate and suggest that thus it does not promote bodily worry. It is no wonder that fasting has become a "hot" issue, e.g. Fasting-Induced Hormone FGF21. Note that in contrast to fasting, diet foods lead to obesity as they promote its economic Saving policy.
See also how energy restriction induces extension of life span in obese but not in lean mice.
* "Thinner" fat cells metabolism (results of diets). Fat cells that have lost their stored fat, induce “catch-up” processes which promote the second urge of eating. Note how manipulating fat cells can increase the body’s metabolism. Also known, visceral adipose tissue promotes obesity.
* Stress, ADHD (attention deficit hyperactivity disorder) and other psychological disturbances (e.g. depression) are associated with obesity. Note that stress is a complex issue, I have tried to define "muscle/body worry" vs. "emotional worry" as different stress "shippers" and to which we do not respond equally. e.g., “muscle/body worry” promotes eating while “emotional worry” represses eating.
I propose to interpret the association between emotional stress and overeating as a decreasing ability to control overeating and not as if the emotional-stress promotes overeating. Indeed, obesity (initial increased overeating) is associates with the emotional-stress over eating, while leanness is more likely to be associates with eating reluctance under stress.
* Lack of sleep is also associated with obesity... btw, singing could help a silent night...
and not to mention (here, as the article is already too long...) lack of love , body image or mind-body attitude.
and of course other reasons that you might want to add…

Final words
Be smart if you wish to lose weight… rid yourself of your bodily worry ...

Don’t Muscle Worry, Be Happy. aps Observer, 21(4), April, 2008
visit the CURE TOGETHER site:

Thursday, January 10, 2008

Is nitric oxide an archaic communication signal?

Do you think of our primordial language? or, not even a language just an initial communication system…in those early days with groups of cells launching the transition from unicellular to multicellular organisms ~ a giga years ago…
Contemplating for a long time on the nitric oxide (NO) netting system, has led me to suggest that maybe it was compounds like NO which enabled such initial communication. The advantage of a radical NO net as a communication tool is its simplicity and availability, and its drawback is its vulnerability and reactivity.
What triggered this blog was the study published by the Geobiology Research Group of the Virginia Tech. They have discussed the 2 explosive evolutionary events which shaped the early history of multicellular life, and I thought whether it was gases like NO or CO which enabled the communication and organization of multicellularity. Such compounds are major signals at our times and they were even more predominant in the prehistoric days when life forms were simpler and less diverse.
The presence and functions of NO in the animal, vegetative or microbial kingdoms are well documented. In an historical review, it was shown that NO is indeed an archaic molecule, biologically functioning in every living organism. It is not difficult to understand its abundance and essentiality, especially prior to the evolution of the biological nitrogen fixation. Nitrogen is an essential element for life and is often a limiting nutrient. As most nitrogen is locked in the stable form, N2, in the atmosphere, processes that can fix N2 into biologically available forms control the supply of nitrogen for organisms. On the early Earth, nitrogen is thought to have been fixed abiotically, as NO was formed during lightning discharge.
In a recent study, the functions of NO in the developing circulatory system were expanded, NO is also important for vessel formation and tone.
While discussing these issues with Prof. Xiao from the Virginia Tech, he has suggested that the modern analogs for the early multicellular organisms would be sponges and cnidarians, and I guess it would be very illuminating to study the effects of NO on their social behavior. Any suggestions?
If indeed the NO net is so ancient, it was functioning before the evolution of the brain and senses. This opens a novel point of view for a current communication system, operating unrelated to emotions or mind, pls read the Viagra blog. Is it part of what we attribute to alternative communication routes? mysticism? holism?

On nitric oxide signaling, metamorphosis, and the evolution of biphasic life cycles
Evol Dev., 2003 Sep-Oct;5(5):542-50

A hypothesis about cellular signaling with nitric oxide in the earliest life forms in evolution
Free Radic Biol Med. 2009 May 9.