I wasn't kidding. Your antioxidants are trying to kill you.

So you've got this creature. It's a weird thing. It doesn't make vitamin c. It lacks uricase, so instead of peeing allantoin, the oxidized form of uric acid, it pees uric acid itself. This leaves the creature susceptible to a number of things. The vitamin c, scurvy. The high levels of uric acid can make gout a problem, if the diet isn't right.
One thing a creature with low levels of vitamin c needs, besides vitamin c; a system to preserve vitamin c. Linus Pauling observed that sick or wounded animals have elevated levels of vitamin c. Scar tissue has high levels of collagen; vitamin c is needed for the maintenance of collagen. One of the lovely consequences of scurvy is old wounds opening up; broken bones that have long healed will even separate. The tough collagen, an adaptation that should improve the strength of the repair, has become a weakness. So, Pauling's theory was that Lp(a), a lipoprotein that is increased in people in heart disease (and also, according to Peter, in very young infants) is a surrogate for vitamin-c collagen formation. So heart disease is a form of low-grade, prolonged scurvy caused by excessive dependence on the Lp(a) patch to repair arteries. So eating lots of vitamin C (and other nutrients, like lysine, of which collagen is composed) should prevent and reverse heart disease.

How to preserve vitamin c? Well, there's these glut-doohickeys which I understand are somehow involved in the uptake of both glucose and vitamin c, and our doohickeys seem to be set up to keep vitamin c in the system. I direct you to the world wide web if you want to know more about those.

Here's another way; healing demands collagen formation, which demands vitamin c. Even uses it up. When vitamin c is in short supply, it's awfully valuable, you don't want to waste it. Maybe you use up your vitamin c healing a major wound, you wind up with scurvy. Trying to heal is killing you. So you need a way to ration your resources so that the tissues under the most repeat stress (artery branches, etc.) get the collagen they need to toughen up, while avoiding scurvy in the whole body.

Enter uric acid, allantoin, lp(a) and maybe Neu5Gc.



Here's how I see it; "

Edit; how I see it is largely my understanding of what Peter (Hyperlipid) has been explaining it on his blog. The uric acid thing is my fixation.

An artery is wounded. Lipoproteins (ldl "bad" cholesterol) is drawn to the injury site. Ldl cholesterol is a lipoprotein that delivers fat and cholesterol to places where it's needed.

Artery endothelial cells (the cells that make up the inner lining of arteries) have receptors for ldl.
Endothelial cells have mitochondria, which help the cells produce energy from fatty acids or glucose. When mitochondria are happily chomping away on fats, they start spewing out reactive oxygen species, free radicals. The thing about reactive oxygen species is, they tend to oxidize things. Like, for instance, uric acid. Which produces allantoin. Which is, um, permissive of endothelial cell proliferation. Which is, um, pretty obviously a healing process.

What kind of fat do you want fed into your endothelial mitochondria when it's time for some healing?

Well, here's an interesting bit about fish oil vs corn oil;

An increase in reactive oxygen species by dietary fish oil coupled with the attenuation of antioxidant defenses by dietary pectin enhances rat colonocyte apoptosis
Auteur(s) / Author(s)SANDERS Lisa M. (1) ;
HENDERSON Cara E. (1) ; MEE YOUNG HONG (1) ; BARHOUMI Rola (2) ;
BURGHARDT Robert C. (2) ; NAISYIN WANG (3) ; SPINKA Christine M. (3) ;
CARROLL Raymond J. (1 3) ; TURNER Nancy D. (1) ; CHAPKIN Robert
S. (1) ; LUPTON Joanne R. (1) ;
Affiliation(s) du ou des auteurs /
Author(s) Affiliation(s)(1) Faculty of Nutrition, Texas A&M University,
College Station, TX 77843, ETATS-UNIS(2) Department of Veterinary Anatomy and
Public Health, Texas A&M University, College Station, TX 77843,
ETATS-UNIS(3) Department of Statistics, Texas A&M University, College
Station, TX 77843, ETATS-UNIS
Résumé / AbstractWe showed previously that the dietary combination of fish oil, rich in (n-3) fatty acids, and the fermentable fiber pectin enhances colonocyte apoptosis in a rat model of experimentally induced colon cancer. In this study, we propose that the mechanism by which this dietary combination heightens apoptosis is via modulation of the colonocyte redox environment. Male Sprague-Dawley rats (n = 60) were fed 1 of 2 fats (corn oil or fish oil) and 1 of 2 fibers (cellulose or pectin) for 2 wk before determination of reactive oxygen species (ROS), oxidative DNA damage, antioxidant enzyme activity [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx)] and apoptosis in isolated colonocytes.

Fish oil enhanced ROS,

whereas the combination of fish oil and pectin suppressed SOD and CAT and enhanced the SOD/CAT ratio compared with a corn oil and cellulose diet. Despite this modulation to a seemingly prooxidant environment, oxidative DNA damage was inversely related to ROS in the fish oil and pectin diet, and apoptosis was enhanced relative to other diets. Furthermore, apoptosis increased exponentially as ROS increased. These results suggest that the enhancement of apoptosis associated with fish oil and pectin feeding may be due to a modulation of the redox environment that promotes ROS-mediated apoptosis.

Do not eat corn oil; beware plant fats high in omega-6 fatty acids in general. Fish oil seems like a very good idea, if you're depending on your blood lipids to ensure that your arteries are healed properly.

Pectin works as an anti-anti-oxidant (pro-oxidant) in the colon? Pretty freakin' cool. Those studies with anti-oxidants, the disappointing ones where vitamin c led to carotid artery thickening, where beta-carotene supplemented smokers got more cancer. Here's what Health Canada has to say about the dangers of vitamin e supplementation;

Recently published studies have suggested that vitamin E supplements not only fail to prevent heart disease and cancer, but may actually harm people who take high doses over a long term. However, these studies are limited by the fact that they involved: people 55 years or older who already had heart disease or diabetes; people with cancer or who previously had cancer; and people who may be at higher risk of developing these diseases.
One study found that patients with heart disease or diabetes who took 400 IU of vitamin E daily for an average of seven years were at a significantly increased risk of
heart failure compared to patients who were not taking vitamin E supplements. This study concluded that high-dose vitamin E supplements (400 IU or greater) should not be taken by patients with heart disease or diabetes.
In another study, daily doses of 400 IU of vitamin E were given to patients receiving
radiation therapy for cancers of the head and neck. The theory was that the antioxidant treatment might reduce the incidence of additional cancers of the same type among these patients. However, it was found that those who received vitamin E supplements were significantly more likely to develop other similar cancers during the supplementation period than those receiving a placebo.

ApoE is a lipoprotein tingy that carries certain fat soluble nutrients around in the blood stream. Antioxidants all. These have a place in the healing and maintenance of the body. But there's a time to oxidize, and then there's a time to anti-oxidize. The ApoE-4 genotype is more prone to heart disease, alzheimers, various cancers, etc. Misdelivery of these vital antioxidants could pretty obviously be dangerous, in light of the importance of reactive oxygen species to the healing and to the cancer-fighting processes.

Vitamin k is an antioxidant. Human atherosclerotic plaque is generally calcified, at least in Western populations. Vitamin k is important to calcium homeostasis-- including the removal of calcium from soft tissues, artery walls, etc. Maybe a bit of a catch-22 there.

You Anti-Oxidants are trying to Kill You

Maybe we lack uricase because we developed in a high ROS environment?http://www.springerlink.com/content/47q5376hv0507243/

Birds lack uricase, and are also high-energy producers. Exercise increases oxidation of uric acid to allantoin. Not enough to keep uric acid from being high in the urine, but maybe enough to interfere with crystal formation?
http://resources.metapress.com/pdf-preview.axd?code=g6x348hx14737518&size=largest

These guys compare allantoin to vitamin c. I don't have access to the article, but just the preview itself is interesting.

The similarity of energy characteristics of reactions of hydroxylation of allantoin and vitamin C should determine the similarity of their biological effects in model systems in vitro and in vivo. In view of this, we performed comparative evaluation of the ability of allantoin, ascorbic acid, and p-aminobenzoic acid (PABA) to quench free-radical processes and inactivate genotoxicity of hydrogen peroxide."

I wonder if this stuff shortens the lives of glucose-blocked nematode worms? And whether uric acid would have the same effect, or not.

Wikipedia on allantoin;

Manufacturers cite several beneficial effects for allantoin as an active ingredient in over-the-counter cosmetics: a moisturizing and keratolytic effect, increasing the water content of the extracellular matrix and enhancing the desquamation of upper layers of dead skin cells, increasing the smoothness of the skin; promotion of cell proliferation and wound healing

That worm study did mention something about collagen... Calorie restricted mice live longer (the ones that don't die younger, anyways) and heal slower.


Uric acid as a precursor for allantoin, allantoin perhaps a tool in the repair kit. Uric acid increases blood pressure.
http://jama.ama-assn.org/cgi/content/full/300/8/924

"Interestingly, raising uric acid levels in rats resulted in increased BP and the development of microvascular disease (resembling arteriolosclerosis) in the kidneys.17-18 The mechanism of hypertension was shown to be caused by a uric acid–mediated reduction in endothelial nitric oxide levels19-20 and stimulation of renin expression.18 Studies in humans have also correlated uric acid levels with both endothelial dysfunction21-22 and elevated plasma renin activity"

http://ajprenal.physiology.org/cgi/content/full/282/6/F991?ijkey=e1d892d3fa02232b64fca5fcd893d456749cfa4e

Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism

The previous experiments were performed under low-salt-diet conditions, because the effect of hyperuricemia on blood pressure is most pronounced under these dietary conditions

Huh. In this study, they show uric acid as increasing smooth muscle cell proliferation in isolated cells from rats. Uric acid levels were increased by adding uric acid in this part of the study. I wonder if any of it oxidized? (Rhetorical question. Of course it did.

Then they show arteriosclerosis in rat kidneys. The rat's uric acid levels are increased by blocking the oxidation of uric acid. They don't show what happens to the elevated uric acid once it reaches the kidney. The kidney would be a major site for uric acid oxidation, which is also allantoin synthesis. How come the elevated uric acid levels didn't cause arteriosclerosis outside of the kidneys?

Maybe an unresolved healing process could lead to an elevation of uric acid, and high blood pressure?

Taking lots of anti-oxidants to prevent oxidative stress might not be a good idea if you depend on reactive oxygen species formation to oxidize uric acid into allantoin to somehow facilitate smooth muscle proliferation and arterial healing.

Most of this post came from some comments I made at Peter's blog (Hyperlipid.) It's what led me to make yesterdays post, and it sort of leads in to the next post, so I thought I'd work it in here.

Your Sialic Acid is Trying to Kill You

Sialic acid content of human low density lipoproteins affects their
interaction with cell receptors and intracellular lipid accumulation.

Low density lipoproteins (LDL) isolated from the plasma of patients with angiographically demonstrable coronary heart disease (CHD) induced accumulation of triglycerides, free cholesterol, and cholesteryl esters in cultured macrophages, smooth muscle cells, and endothelial cells derived from uninvolved intima of human aorta, but not in skin fibroblasts or hepatoma cells. The sialic acid content of LDL from CHD patients was 40-75% lower than that from healthy donors. There was a negative correlation between LDL sialic acid content and the LDL-induced accumulation of total intracellular cholesterol. Neuraminidase treatment of LDL from normal healthy donors produced sialic acid-depleted LDL (Ds-LDL) which was able to stimulate intracellular lipid accumulation. Neuraminidase treatment of LDL from CHD patients further increased its capacity to induce intracellular lipid accumulation. Sialic acid-poor LDL isolated by affinity chromatography of LDL from CHD patients induced a 2- to 4-fold increase of free and esterified cholesterol in human intimal smooth muscle cells. Binding, uptake, and degradation of 125I-labeled Ds-LDL by macrophages and endothelial cells were 1.5- to 2-fold higher than for native LDL. Binding and uptake of Ds-LDL was inhibited 64-93% by the addition of 20-fold excess acetylated LDL (Ac-LDL); in the inverse experiment, the level of inhibition was 35-54%. These data indicate that a sialic acid-poor form of LDL isolated from CHD patients can interact with both native and scavenger LDL receptors. A sialic acid-poor form of LDL may be a naturally occurring ligand that interacts with the scavenger receptor(s) on macrophages and endothelial cells.

http://www.ncbi.nlm.nih.gov/pubmed/1512508?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_SingleItemSupl.Pubmed_Discovery_RA&linkpos=2&log$=relatedarticles&logdbfrom=pubmed

Peter at Hyperlipid has gone into this subject, I'm having trouble finding the link. This study was in a list of studies related to a study he posted about sialic acid lack on the other side of the equation, in lesions in the artery wall, leading to the delivery of fat and cholesterol to the wound area.

So what depletes the sialic acid?

Thus, in the blood of over 95% of the CHD patients examined, we found a modified, sialic acid-poor form of LDL that determines the potential of a patient's plasma to cause lipid accumulation in arterial cells. Additional evidence indicating the presence of sialic acid-depleted LDL in the blood of CHD patients has recently been obtained. In these patients, we have found anti-LDL autoantibodies with much greater affinity for sialic acid depleted LDL than for native LDL or chemically modified LDL (28). This observation strongly suggests that desialylation is a significant LDL modification that occurs in vivo.

A vegan blogger might use this to peg red meat as the cause of heart disease. I am not a vegan blogger.

Most mammals make a type of sialic acid called Neu5gc. Humans can only make a precursor of Neu5gc called Neu5AC. Sialic acid is used as a marker-molecule in the immune system. The body develops anti-bodies to the Neu5GC.

http://www.telegraph.co.uk/science/science-news/3346666/Mystery-of-the-meat-eaters-molecule.html

Humans are weird. We don't make vitamin c; important to collagen formation. We don't make allantoin; which is oxidized from uric acid, (I'll post about that sometime) which is also important to collagen formation, both are important to healing, including broken arteries. One more weirdness; we don't make Neu5Gc, instead we have an immune reaction to it. Could all three of these be related?

The Neu5gc concentration is very low in most human tissue. The few places where it is high, the fetus, tumours, the gut-- are also the tissues with the most growth or turnover. So, if our mother eats red meat, we have lots of Neu5gc initially, but over time general maintenance weeds that out and replaces it with the stuff we make ourselves, the Neu5Ac.

A vegan blogger might tell you the Neu5gc finds its way into the tumour because meat causes cancer. I'm not going to tell you that. Maybe red meat also causes babies and intestines. But there are implications of that Neu5gc. If you're fighting cancer, for instance, cancer cells conveniently tagged with foreign sialic acid might come in handy to the immune response, especially if doctors find a way to take advantage of this.

Now, here's the question;

Is there something about Neu5Ac that makes it more prone to the degradation of its sialic acid? That isn't the question I thought I was going to ask. I'll go ahead and ask that question anyways; Is there something about the Neu5Gc that makes it prone to the degradation of its sialic acid? Or is there something about it that changes it's general distribution?

Given the known differences in sialic acid biology between humans and great apes (Varki 2008), we also stained normal-appearing myocardial sections from humans
and apes with two lectins that bind sialic acids: Sambucus nigra agglutinin (SNA) which recognizes terminal Siaa2-6Galb1-4GlcNAcb- units on N-linked glycan chains of glycoproteins, and Maackia Amurensis hemagglutinin (MAH), which recognizes Siaa2-3Gal termini on various glycoconjugates (Martin et al. 2002; Varki and Varki 2007). Both SNA and MAH strongly stained large areas of heart sections from chimpanzees, gorillas and orangutans, with MAH staining again showing evidence of encircling ‘bundles’ that were not seen in human heart sections (Fig. 4). These differences with SNA and MAH lectin staining imply that terminal sialic acids are much denser in the great ape heart.

http://cmm.ucsd.edu/varki/varkilab/A173.pdf

Varki should maybe read Hyperlipid. He (Varki) seems to think the purpose of the healing process in chimpanzees and in humans is to kill the subject. Chimpanzees and humans don't heal the same. So although both get heart disease, which is basically a mis-healing, it looks different.

Paraffin sections of hearts from humans, chimpanzees, gorillas, and orangutans were stained using the Masson-Trichrome stain for collagen. As shown in Fig. 3, otherwise normal heart sections from all three great apes showed collagen bundles that appeared to divide the heart muscle along the planes where the larger blood vessels were situated. This pattern was not observed in the human heart sections.

Okay. Another anomaly; missing collagen bundles. Humans are collagen-challenged. We can't make vitamin c or allantoin (not on purpose. uric acid can still oxidize into allantoin, but we lack the specific enzyme.)

Just in case I didn't actually say what I meant to say, here it is; unable to make vitamin c or allantoin on purpose, our collagen making ability is compromised. We need to somehow live in spite of this; something about our metabolism of sialic acid causes our damaged arteries to use material and energy from ldl cholesterol for repair. This keeps us from being dead.

Pre-inflammatory?

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC108207/

Lipoproteins can bind lipopolysaccharide (LPS) and decrease LPS-stimulated
cytokine production. Lipoprotein(a) [Lp(a)] was as potent as low-density
lipoproteins (LDL) in inhibiting LPS-stimulated tumor necrosis factor synthesis
by human mononuclear cells. The kinetics of LPS inhibition by Lp(a) was similar
to that of LDL. This suggests that circulating Lp(a) may be an important factor
determining the amplitude of the response to LPS in humans.

The systemic toxicity of gram-negative sepsis is largely due to endotoxin,
a lipopolysaccharide (LPS) component of the outer membrane of gram-negative
bacteria. LPS stimulates the production of proinflammatory cytokines such as
tumor necrosis factor alpha (TNF) and interleukin-1, which in turn may induce
disseminated intravascular coagulation, hypotension, and renal, hepatic, and
cerebral damage

These guys were looking for a reason for lp(a) to be in the human body besides the obvious benefit of increased risk of heart disease. Peter at Hyperlipid makes a good argument for lp(a) being useful as sort of an emergency artery-repair patch. So maybe it's an anti-bacterial, anti-fungal artery-repair patch. The anti-endotoxin effect is attributed specifically to the lipoprotein fraction; the body might fail to clear small, dense ldl from circulation in a high carb, low fat diet in order to preserve the ability to counter endotoxin.

According to wikipedia, blocking tnf can increase danger of opportunistic infection from already present fungus, causing diseases like tuberculosis.

http://www.ncbi.nlm.nih.gov/pubmed/8662983

Tumor necrosis factor (TNF)-alpha inhibits insulin signaling through
stimulation of the p55 TNF receptor and activation of sphingomyelinase.

Tumor necrosis factor (TNF)-alpha plays a central role in the state of insulin resistance associated with obesity. It has previously been shown that one important mechanism by which TNF-alpha interferes with insulin signaling is through the serine phosphorylation of insulin receptor substrate-1 (IRS-1), which can then function as an inhibitor of the tyrosine kinase activity of the insulin receptor (IR). However, the receptors and the signaling pathway used by TNF-alpha that mediate the inhibition of IR activity are unknown. We show here that human TNF-alpha, which binds only to the murine p55 TNF receptor (TNFR), is as effective at inhibiting insulin-dependent tyrosine phosphorylation of IR and IRS-1 in adipocytes and myeloid 32D cells as murine TNF-alpha, which binds to both p55 TNFR and p75 TNFR. Likewise, antibodies that are specific agonists for p55 TNFR or p75 TNFR demonstrate that stimulation of p55 TNFR is sufficient to inhibit insulin signaling, though a small effect can also be seen with antibodies to p75 TNFR. Exogenous sphingomyelinase and ceramides, known to be formed by activation of p55 TNFR, inhibit IR and IRS-1 tyrosine phosphorylation and convert IRS-1 into an inhibitor of IR tyrosine kinase in vitro. Myeloid 32D cells expressing IR and IRS-1 are sensitive to this inhibition, but cells expressing IR and IRS-2 are resistant, pointing to an important difference in the biological function between IRS-1 and IRS-2. These data strongly suggest that TNF-alpha inhibits insulin signaling via stimulation of p55 TNFR and sphingomyelinase activity, which results in the production of an inhibitory form of IRS-1.

TNF seems to impair wound healing. A decrease in insulin signalling fits into that.

http://autoimmunenews.blogspot.com/2009/09/broken-bones-blame-it-on-autoimmune.html


Let's see; impairs wound healing. Fights infection (endotoxin)... doesn't sound like TNF is trying to hurt us. When does rheumatoid arthritis seem like a good idea? When the alternative is tuberculosis? Or some other infection?

Anti-inflammatory might not be the right word. Blocking TNF does that. Pre-inflammatory? Before TNF becomes necessary. Glycine, taurine, vitamin d, fish oil.

And pay attention to this guy;

http://coolinginflammation.blogspot.com/2009/03/enteroviruses-autoimmunity-diabetes.html

Glutamic acid and bones

http://www.ismni.org/jmni/pdf/32/09SKERRY.pdf

T. M. Skerry

Abstract
Communication between the cells in bone underlies the way that the tissue functions physiologically, and in nearly all pathologies, the pathogenesis of skeletal diseases. The number of molecules involved in intercellular signalling in bone grows constantly and it is perhaps unsurprising that the list includes many with functions in other tissues. In recent years, evidence has accumulated to show that molecules involved in neurotransmission have paracrine roles in the skeleton. The focus of this review is the excitatory amino acid glutamate and its role in regulating bone formation and resorption. Specifically, this article will concentrate on the functional role of the system, and the reasons why mechanisms like synaptic transmission are relevant to what might appear to be a slow responding tissue, as the sites of expression of glutamate signalling components in bone have been reviewed already. While there is strong evidence for a regulatory role for glutamate in osteoblast and osteoclast differentiation and function in vitro, in vivo data is less advanced.
Preliminary data from in vivo systems does however suggest that glutamate has a
physiological function in the skeleton.

The whole leptin/brain-derived serotonin, umami/sweet, glutamic acid/carbohydrate appetite see-saw seems to be pretty important. Would glutamic acid intake--satisfying the "protein" appetite induced by excess leptin or brain serotonin blockade-- prevent the deleterious effects of these treatments on bone?

And does all this relate to the bone-ification of arteries?

Is saturated fat (beef tallow) a leptin analog?

Check it out;

The effect of dietary fat on diet selection may involve central
serotonin.
Mullen BJ, Martin RJ.
Department of Foods and Nutrition, University of
Georgia, Athens 30602.
Rats consuming a diet of 34% tallow select more protein and less carbohydrate than rats fed either 5% corn oil or tallow or 34% corn oil (25). To examine potential mechanism(s) of this phenomenon, we fed rats diets containing either tallow or corn oil at levels of 5 or 34% for 2 days. Sera were analyzed, and rats fed 34% tallow had higher serum insulin compared with those fed 34% corn oil. In a second experiment, rats were fed either 34% corn oil or tallow for 2 days. Brain tissues were analyzed, and rats fed 34% tallow had elevated serotonin in the raphe area compared with those fed 34% corn oil. In a third experiment, rats were fed either 34% corn oil or tallow for 2 days and then given dl-fenfluramine before diet selection. Fenfluramine depressed food intake to a greater degree in rats fed 34% tallow compared with those fed corn oil. These findings suggest that the diet selection behavior observed in tallow-fed rats may be mediated by a central serotonin system.

http://www.ncbi.nlm.nih.gov/pubmed/2600660?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_SingleItemSupl.Pubmed_Discovery_RA&linkpos=4&log$=relatedarticles&logdbfrom=pubmed


I'm kind of dorky when it comes to re-naming links. Anyways, that second link is a full study showing the effect of tallow vs corn oil on food selection. Tallow fed rats choose more protein, less carbs-- which is similar to the effects of centrally-administered leptin.


That first study mentioned fenfluramine (the fen from phen-fen.)

Look what wikipedia says;

The drug was withdrawn from the U.S. market in 1997 after reports of heart
valve disease,[2][3] and pulmonary hypertension, including a condition known as cardiac fibrosis. After the US withdrawal of fenfluramine, it was also withdrawn from other markets around the world.
The distinctive valvular abnormality seen with fenfluramine is a thickening of the leaflet and chordae tendineae. One mechanisms used to explain this phenomenon involves heart valve serotonin receptors, which are thought to help regulate growth. Since fenfluramine and its active metabolite norfenfluramine stimulate serotonin receptors 5-hydroxytryptamine (5-HT) this may have led to the valvular abnormalities found in patients using fenfluramine. In particular norfenfluramine is a potent agonist of 5-HT2B receptors, which are plentiful in human cardiac valves. The suggested mechanism by which fenfluramine causes damage is through over or inappropriate stimulation of these receptors leading to inappropriate valve cell division. Supporting this idea, is the fact that this valve abnormality has also occurred in patients using other drugs that act on 5-HT2B receptors. [4].

I really haven't done enough homework to say this; but I'm gonna say it anyways. Heart disease is a disease of energy homeostasis; largely mediated by serotonin. Overgrowth, thickening of the arteries perhaps caused by overactive serotonin receptors; or undergrowth, leaky artery disease not all that far removed from leaky gut disease, since the gut is also dependent on serotonin for the mediation of its upkeep.

Edit; make that involving serotonin. Then toss that whole last paragraph over your shoulder.

Back on topic. Or as close as I'm capable.

http://www.ncbi.nlm.nih.gov/pubmed/11540865

d-Fenfluramine selectively suppresses carbohydrate snacking by obese
subjects.
Wurtman J, Wurtman R, Mark S, Tsay R, Gilbert W, Growdon J.
Department of Applied Biology, MIT, Cambridge, MA
02139, USA.
Twenty obese inpatients who claimed to crave carbohydrate-rich foods were given d-fenfluramine (15 mg p.o., twice daily) or its placebo, double-blind, for two consecutive eight-day periods. Food choices were measured on treatment days 1, 7, and 8 by giving the subjects access to unlimited portions of six isocaloric meal foods (three high in carbohydrate and three high in protein) and of 10 isocaloric snack foods (five high in protein and five high in carbohydrate) available 24 hours a day in a computerized vending machine. d-fenfluramine reduced mealtime calorie intake by only 16% (from 1940 +/- 94 to 1630 +/- 92; p < .001), mealtime carbohydrate by 22%, and had no significant effect on mealtime protein consumption; in contrast, snack calorie intake was reduced by 41% (from 707 +/- 97 to 414 +/- 46; p < .001), and snack carbohydrate intake by the same proportion. The mean number of carbohydrate-rich snacks consumed per day decreased from 5.8 +/- 0.8 to 3.4 +/-0.4 (p < .01), while that of protein-rich snacks failed to change signficantly (i.e., from 0.7 +/- 0.2 to 0.5 +/- 0.2).

Tallow-fed rats already had blunted carbohydrate appetites. Fenfluramine "satisfies" carbohydrate appetite, perhaps by sending the false signal that carbohydrates have already been eaten; so fenfluramine ends up more effective for tallow fed than for corn oil fed rats. A false signal of nourishment might not be a good idea.

A fellow commenter (Westie) on Peter's Hyperlipid Blog told me this;

Glutamine decreases the amount of glucose carbon directed to Krebs cycle. That
is connected to increased UCP-2 expression which is also related to insulin
resistance.

This single sentence explains quite a bit of the stuff I've been reading about leptin. I might as well start here, it's as good as anywhere;
http://cmbi.bjmu.edu.cn/news/report/2009/pdf/med09_09_1.pdf

Leptin inhibition of bone mass accrual requires the integrity of specific hypothalamic neurons but not expression of its receptor on these neurons. The same is true for its regulation of appetite and energy expenditure. This suggests that leptin acts elsewhere in the brain to achieve these three functions.We show here that brainstem-derived serotonin (BDS) favors bone mass accrual following its binding to Htr2creceptors on ventromedial hypothalamic neurons and appetite via Htr1a and 2b receptors on arcuate neurons. Leptin inhibits these functions and increases energy expenditure because it reduces serotonin synthesis and firing of serotonergic neurons. Accordingly,while abrogating BDS synthesis corrects the bone, appetite and energy expenditure phenotypes caused by leptin deficiency,inactivation of the leptin receptor in serotonergic neurons recapitulatesthem fully. This study modifies the map of leptin signaling in the brain andidentifies a molecular basis for the common regulation of bone and energymetabolisms.

The authors mention later on that leptin shows up with skeletons, so it makes sense that it is involved in proper bone mass maintenance. So leptin has a very close relationship to serotonin. I'm going to skip over serotonin for now, mostly because while I know that serotonin is involved in appetite and metabolism etc., all over the body, that's about all I know, and I came here to talk about leptin.
Okay, into the meat of the thing.
http://endo.endojournals.org/cgi/content/full/145/2/839
Leptin decreases the preference for the taste of sweet.
http://ajpregu.physiology.org/cgi/content/full/293/4/R1468

Leptin reduces body fat selectively, sparing body protein. Accordingly, during chronic leptin administration, food intake is suppressed, and body weight is
reduced until body fat is depleted. Body weight then stabilizes at this fat-depleted nadir, while food intake returns to normal caloric levels, presumably in defense of energy and nutritional homeostasis. This model of leptin treatment offers the opportunity to examine controls of food intake that are independent of leptin's actions, and provides a window for examining the nature of feeding controls in a "fatless" animal. Here we evaluate macronutrient selection during this fat-depleted phase of leptin treatment. Adult, male Sprague-Dawley rats were maintained on standard pelleted rodent chow and given daily lateral ventricular injections of leptin or vehicle solution until body weight reached the nadir point and food intake returned to normal levels. Injections were then continued for 8 days, during which rats self-selected their daily diet from separate sources of carbohydrate, protein, and fat. Macronutrient choice differed profoundly in leptin and control rats. Leptin rats exhibited a dramatic increase in protein intake, whereas controls exhibited a strong carbohydrate preference. Fat intake did not differ between groups at any time during the 8-day test. Despite these dramatic differences in macronutrient selection, total daily caloric intake did not differ between groups except on day 2. Thus controls of food intake related to ongoing metabolic and nutritional requirements may supersede the negative feedback signals related to body fat stores.

This study has sort of confused me for a while; leptin decreases the appetite for carbohydrate. But, isn't the alternate fuel fat, not protein? But if you throw in this;

Glutamine decreases the amount of glucose carbon directed to Krebs cycle

Then gosh, glutamine becomes awfully important to the switch between glucose and fat as the major energy source.
We taste sweet, sour, bitter, salty, umami. Umami is the taste set off by mono-sodium glutamate. We taste glutamine, glutamic acid, etc. Out of all the proteins we have a particular sense of taste for that one protein.
Yeah, I know. MSG makes you fat, right? But... l glutamine is often recommended to fight carbohydrated addiction. Also alcohol addiction.
And there's this; http://www.ncbi.nlm.nih.gov/pubmed/18559279?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_SingleItemSupl.Pubmed_Discovery_RA&linkpos=2&log$=relatedarticles&logdbfrom=pubmed

Monosodium l-glutamate (MSG), an umami taste substance, may be a key molecule coupled to a food intake signaling pathway, possibly mediated through a specific l-glutamate (GLU) sensing mechanism in the gastrointestinal tract. Here we investigated the effect of the spontaneous ingestion of a 1% MSG solution and water on food intake and body weight in male Sprague-Dawley rats fed diets of varying caloric density, fat and carbohydrate contents. Fat mass and lean mass in the abdomen, blood pressure, and several blood metabolic markers were also measured. Rats given free access to MSG and water showed a high preference (93-97%) for the MSG solution, regardless of the diet they consumed. Rats ingesting MSG had a significantly smaller weight gain, reduced abdominal fat mass, and lower plasma leptin levels, compared to rats ingesting water alone. Naso-anal length, lean mass, food and energy intakes, blood pressure, blood glucose, and plasma levels of insulin, triglyceride, total cholesterol, albumin, and GLU were not influenced by the ingestion of the MSG solution. These same effects were observed in a study of adult rats. Together, these results suggest that MSG ingestion reduces weight gain, body fat mass, and plasma leptin levels. Moreover, these changes are likely to be mediated by increased energy expenditure, not reduced energy intake or delayed development. Conceivably, these effects of MSG might be mediated via gut GLU receptors functionally linked to afferent branches of the vagus nerve in the gut, or the afferent sensory nerves in the oral cavity.

Pay special attention to those red letters. Looking for this study, I sorted through a someshort term studies in humans. One bowl of soup containing lots of msg, followed by a meal, failing to suppress appetite. That doesn't matter. Another important thing to note; the rats drank msg-water or msg-free water at will; the rat's natural appetites were in charge. MSG mixed into chow would be an entirely different experiment.

Of course, I'm not dismissing possible consequences of individual MSG sensitivities, I really don't know enough about that stuff to even comment.

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Okay. Leptin and fat accumulation.
http://ajpendo.physiology.org/cgi/content/full/285/3/E521

To test whether fatty acids play a messenger role between stimulation of lipolysis by norepinephrine and inhibition of leptin secretion, adipocytes were incubated with insulin (10 nM) in the presence of norepinephrine (1 µM) or palmitic acid (1 mM; Fig. 1). Because albumin strongly binds extracellular fatty acids (4), experiments were carried out at low (0.1%) and high (4%) albumin concentrations. Palmitic acid (1 mM) mimicked the inhibitory effects of norepinephrine (1 µM) on leptin secretion at low but not at high albumin concentrations (Fig. 1). This indicates that albumin, at high concentrations, effectively binds extracellular fatty acids and consequently inhibits their effects on leptin secretion. Therefore, subsequent experiments were carried out at low albumin concentrations. Concentration-response curves carried out in the presence of 0.1% albumin revealed that palmitic acid inhibited insulin (10 nM)-stimulated leptin secretion between 0.1 and 1 mM without significantly affecting basal values (Fig. 2). In fact, the palmitic acid effect critically depended on the ratio of the molar concentrations of palmitic acid over albumin with an IC50 of 4.5 (Fig. 3). This is consistent with the observation that one molecule of albumin has several low- and high-affinity binding sites for long-chain fatty acids

The fact that concentrations of albumin similar to those found in plasma (4%) inhibit the effects of palmitic acid (1 mM) indicates that circulating fatty acids (the concentration of which varies at the millimolar level) have little influence on leptin secretion, at least directly (Figs. 1 and 3). This is supported by several in vivo studies in humans, which failed to demonstrate any inhibitory effects of fatty acids on plasma leptin concentrations (35, 37). It is more likely that an intracellular increase in fatty acids, generated in consequence of activated lipolysis, causes the inhibition of leptin secretion

When the fat cell is awash in free fatty acids, particularly palmitic acid, but not in albumin, leptin secretion is suppressed. When would lipolysis be high? I'd assume that lipolysis is high inside the fat cell at the same times that it's high in other parts of the body, like the liver. When fat is being used for energy. When is fat being used for energy?
1) when carbs are low
2) when all the tools necessary to the efficient use of fat for energy are present.

Glutamine decreases the amount of glucose carbon directed to Krebs cycle. That
is connected to increased UCP-2 expression which is also related to insulin
resistance.

Here's an interesting thing;

http://ajpendo.physiology.org/cgi/content/full/289/1/E166

Amino acids are catabolized at the glycolysis and tricarboxylic acid cycle levels (Table 1). Interestingly, they exhibited the following four different types of effect on leptin secretion: 1) amino acids that stimulated poorly or did not stimulate leptin secretion (L-glycine, L-alanine, L-histidine, L-arginine and L-glutamine; Figs. 3 and 6), 2) an amino acid that increased leptin secretion only in the presence of glucose (L-leucine; Fig. 4), 3) an amino acid that mimicked and potentiated glucose action (L-aspartate, L-valine, L-methionine, and L-phenylalanine; Figs. 4 and 5), and 4) an amino acid that stimulatedleptin secretion in the absence of glucose or insulin (L-glutamate]; Fig. 4). Each of these is discussed below

Glutamic acid was special in this study in that it stimulated leptin secretion in the absence of glucose or insulin. Hunger for protein increases after fat depletion in leptin-treated Sprague-Dawley rats. Glutamic acid is the one protein we have specific taste-receptors for, the taste "umami."
Another interesting line in that study;

First, regarding the amino acids that did not show any or showed only small effects on leptin secretion, one hypothesis is that white adipocytes metabolize these amino acids poorly. For example, glutamine is known to be released rather than being oxidized in white adipose tissue.

What, the same adipose tissue that's famous for releasing leptin when glutamic acid is present, even in a low-insulin, low-glucose state? Could leptin help fat cells synthesize glutamine from glutamic acid?
Maybe.
http://www.nature.com/ijo/journal/v23/n11/abs/0801095a.html

However, in the presence of leptin, the production of glucose from glycerol (2 mM), L-lactate (2 mM). L-alanine (5 mM) and L-glutamine (5 mM) by the isolated hepatocytes was significantly reduced (30%, 30%, 23% and 25%, respectively).

Well, it looks like I was in the ballpark, anyways. The reduction of glucose production from L-glutamine would at least increase local glutamine levels. So glutamic acid increases leptin production, and leptin decreases attrition of glutamine to glucose synthesis.