Archive for the ‘The Genetics of FCI?’ Category
Thanks to a yahoo group called TaubesTalk for the following news article and abstract:
SYDNEY (AFP) – Australian scientists may have discovered how to help people lose weight without cutting back on food, a breakthrough that could pave the way for fat-burning drugs.
Researchers in Melbourne found that by manipulating fat cells in mice they were able to speed up the animals’ metabolisms.
They found that when a particular enzyme, known as angiotensin converting enzyme (ACE), was removed, mice were able to eat the same amount as other mice but burn more calories and therefore gain less weight.
Animals without the enzyme were on average 20 percent lighter than normal mice and had 50 to 60 percent less body fat, senior researcher at the Howard Florey Institute Michael Mathai said.
“It is very clear that they do have less body fat,” he told AFP.
Mathai, who is also a lecturer in nutrition at Victoria University, said the slimmer mice also appeared to have less chance of developing diabetes because they processed sugar faster than normal mice.
He said the research, to be published Tuesday in the US-based Proceedings of the National Academy of Sciences, could be used to develop drugs to assist weight loss.
Drugs which impair the action of ACE already exist and are mostly used to combat high blood pressure.
“The drugs are out there because they are used for hypertension,” he said.
“So we know their safety and their tolerability. What we don’t know is whether or not they will work in humans. And we don’t know whether it will work in all obese humans.”
Mathai said it could be a question of finding the right dosage of hypertension medication, or developing a new type of drug of the same class, to be used as weight-loss pills.
“This might be one way in which you can increase metabolic rate in combination with managing nutrition to limit the intake of calories,” he said.
Mathai said the research, conducted at the Howard Florey Institute, Victoria University, La Trobe University, Deakin University, the Baker Institute and the University of Melbourne, was yet to pinpoint why the genetic manipulation led to weight loss.
“Because we deleted the gene, the gene is gone from the whole body, that means that it is gone from all tissues including the brain,” he said.
“And so we don’t know whether it’s a direct effect of the deficiency in the tissue or whether it’s something coming from the brain.” Australian scientists report weight loss breakthrough
And the abstract:
Angiotensin II (AII), acting via its G-protein linked receptor, is an important regulator of cardiac, vascular, and renal function. Following injection of AII into rats, we find that there is also a rapid tyrosine phosphorylation of the major insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) in the heart. This phenomenon appears to involve JAK2 tyrosine kinase, which associates with the AT1 receptor and IRS-1/IRS-2 after AII stimulation. AII-induced phosphorylation leads to binding of phosphatidylinositol 3-kinase (PI 3-kinase) to IRS-1 and IRS-2; however, in contrast to other ligands, AII injection results in an acute inhibition of both basal and insulin-stimulated PI 3-kinase activity. The latter occurs without any reduction in insulin receptor or IRS phosphorylation or in the interaction of the p85 and p110 subunits of PI 3-kinase with each other or with IRS-1/IRS-2. These effects of AII are inhibited by AT1 receptor antagonists. Thus, there is direct cross-talk between insulin and AII signaling pathways at the level of both tyrosine phosphorylation and PI 3-kinase activation. These interactions may play an important role in the association of insulin resistance, hypertension, and cardiovascular disease. Cross-talk between the insulin and angiotensin signaling systems
I think this may be why low carbohydrate diets help so many people with food chemical intolerance. Lower your insulin levels, and I bet you lower your ACE output.
ACE – it stands for angiotensin converting enzyme. People with a common deletion in their ACE gene secrete more angiotensin II and aldosterone than people with the common insertion variant.
Emotional upsets related to changes in ovarian hormones are highly prevalent and are responsible for psychiatric morbidity and mortality. Significant increases in acute psychiatric hospitalizations, suicidal activity, and other psychopathology occur during the premenstruum and during menstruation.
This paper reviews evidence indicating that menstrual cycle psychopathology may be mediated by the effects of estrogen, progesterone, and possibly the renin—angiotensin—aldosterone system on the brain monoamines, norepinephrine, dopamine, and serotonin.
During the menstrual cycle, psychopathology often begins with the onset of luteal estrogen—progesterone—angiotensin—aldosterone secretion and intensifies as these hormone levels later fall, prior to and during menstruation. Aldosterone is reported elevated in cases of premenstrual tension syndrome.
There are numerous reports of affective upsets occurring with the use of estrogen—progestin oral contraceptives and following their withdrawal. Contraceptives stimulate the renin—angiotensin—aldosterone system and are reported useful in alleviating premenstrual—menstrual emotional upsets and postpartum depressive episodes.
What a counter-intuitive conclusion – aldosterone increases PMT, but if you increase aldosterone even further whilst nuking the menstrual cycle, it ‘alleviates’ the problem. It certainly didn’t work that way for me. When I was on the pill my ‘premenstrual’ tension went away – I just had massive chronic tension all the time instead! My PMT always went away immediately that my period started.
Affective lability, prevalent at parturition, occurs when estrogen, progesterone, and aldosterone levels are first high and later falling. Exogenous estrogen and progesterone profoundly affect mating activity in castrated rhesus monkeys, and cyclic fluctuations in sexual activity in humans may occur during the menstrual cycle. Much information links manic and depressive reactions with alterations in brain monoamines. Lithium, monoamine oxidase inhibitors, and tricylic antidepressants, specifically used to treat affective disorders, are reported useful in treating ovarian hormone—linked upsets. Similarities exist between changes in animal behavior caused by drugs altering affective states and the effects of ovarian hormones.
Like certain antidepressants, estrogen induces hyperactivity in rats. Like reserpine, progesterone exhibits sedative and soporific effects. Sexual behavior in female rats is reported linked to changes in brain monoamines. Agents increasing brain monoamine levels and availability decrease mating responses, and monoamine depletors, such as reserpine may be substituted for progesterone in activating mating behavior.
Serotonin and dopamine appear to be important in the regulation of ovulation. Brain norepinephrine varies with the phases of the rat estrus cycle. Castration increases brain norepinephrine and decreases brain dopamine. Exogenous estrogen decreases rat brain norepinephrine content. The monoamine-destroying enzymes, monoamine oxidase, and catechol O-methyl transferase are affected by ovarian steroids and show fluctuating levels during the reproductive cycle. The effects of reserpine, monoamine oxidase inhibitors, tricyclic antidepressants, and lithium on monoamines in neurophysiological preparations have been used as evidence supporting theories linking monoamine changes with human affective disorders. Estrogen, progesterone, and angiotensin also exhibit effects on in vitromonoamine systems.
Like the tricyclic antidepressants, uptake of norepinephrine and dopamine by nerve endings is inhibited in the presence of estrogen, progesterone, and angiotensin. As with reserpine, the flow of these monoamines from nerve endings is increased by progesterone. Estrogen slows the flow of norepinephrine from nerve endings and decreases the electrically induced release of serotonin and norepinephrine from brain slices. The above information provides clues that ovarian hormone—linked psychopathology, like affective disorders in general, may be related to alterations in brain monoamines. Monoamines and ovarian hormone-linked sexual and emotional changes: A review
Aldosterone is also responsible for water retention, by acting on the central nervous system to release vasopressin, the hormone which tells the kidneys to conserve water.
Angiotensin I-converting enzyme (ACE) is a zinc metallopeptidase whose main known functions are to convert angiotensin I into the vasoactive and aldosterone-stimulating peptide angiotensin II, and to inactivate bradykinin. ACE is believed to have other physiological roles because of its wide enzymatic specificity and wide distrubution. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels.
Analysis of ACE genotypes reveal[s] that patients with the wild type ACE gene (ACE I/I) have normal angiotensin II levels, while patients with a deletion in both alleles (ACE D/D) have far higher levels, and those with a single allele deletion have intermediate levels. New Approaches to Heart Failure: From Pharmacogenomics to Drug Development
Mild quantitative changes in the expression of ACE do not affect plasma angiotensin II level or BP because of the concomitant changes in the level of angiotensin I. However, plasma [bradykinin] level changes with changes in ACE expression. Minireview: Computer Simulations of Blood Pressure Regulation by the Renin-Angiotensin System
D/D homozygotes have a 25% increase, and I/I homozygotes have a 25% decrease in plasma ACE activity relative to the I/D heterozygotes. In otherwords, feedback causes angiotensin I levels to lower to maintain correct angiotensin II levels. Examine Figure 3B in the minireview linked to above. It displays D/D types as having lower angiotensin I levels whilst maintaining relatively normal angiotensin II levels.
Now check out the interaction with monoamine oxidase:
It is concluded that diminished [angiotensin I] receptor stimulation decreases cardiac MAO activity, probably by regulating MAO expression, since ANG, ACE inhibitors, and AT(1) antagonists had no effect on MAO activity in vitro. Angiotensin I-converting enzyme inhibition increases cardiac catecholamine content and reduces monoamine oxidase activity via an angiotensin type 1 receptor-mediated mechanism.
Stressed all the time?
Angiotensin II increases thirst sensation[...] It also potentiates the release of norepinephrine by direct action on postganglionic sympathetic fibers. Angiotensin Wiki
Another interaction with COMT:
Angiotensin-converting enzyme (ACE) modulates dopamine turnover in the brain and catechol-O-methyltransferase (COMT) enzyme is an important agent in the metabolic inactivation of dopamine and norepinephrine. Functional polymorphism in the COMT and ACE genes causes variation in enzyme activities. We investigated the relationship of COMT and ACE gene polymorphism with response to conventional neuroleptic treatment in schizophrenia. In this study population we had earlier detected that COMT genotype is associated with unsatisfactory drug response. A total of 94 schizophrenic patients were evaluated either as responders (n=43) or non-responders (n=51). The responders had experienced a fair and steady response to conventional neuroleptics. The non-responders had failed to achieve an acceptable response to conventional neuroleptics. We also used a control population of 94 age- and gender-matched blood donors. Genotyping of the COMT and ACE genes was performed by polymerase chain reaction. The risk of having both low activity COMT and high activity ACE genotypes was over 10 times higher (odds RATIO=10.89, 95%CI 1.14–103.98, P=0.04) in the non-responders compared to responders. ACE genotype alone did not differ between any groups. This finding may suggest a possible interaction with low activity COMT and high activity ACE genotype in association with poor response to conventional neuroleptics. Interaction between angiotensin-converting enzyme and catechol-O-methyltransferase genotypes in schizophrenics with poor response to conventional neuroleptics
One interesting fact I stumbled upon recently is that a low sodium diet increases monoamine oxidase activity in rats, and this operates via an angiotensin II mechanism. So does a high sodium diet decrease monoamine oxidase activity?
And check out the interaction with vitamin D receptors:
Mice lacking the Vitamin D receptor (VDR) have elevated production of renin and angiotensin (Ang) II, leading to hypertension, cardiac hypertrophy and increased water intake. These abnormalities can be prevented by treatment with an ACE inhibitor or AT(1) receptor antagonist. Vitamin D: a negative endocrine regulator of the renin-angiotensin system and blood pressure
In fact the lower your vitamin D levels the higher your whole renin-angiotensin sytem. Vitamin D is an extremely effective way to lower your blood pressure.
To begin with, here is an overview of the frequency of CFS and the factors thought to be involved:
The US case definition of CFS (the CDC-definition) is most widespread in research and clinical practice. Estimates of prevalence vary from 0.2% to above 2%. The female-male ratio is approximately 3:1. [...] Present knowledge suggests that certain genetic polymorphisms and personality traits might be regarded as predisposing factors, some infections and severe psychosocial stress constitute precipitating factors, whereas disturbances of immunity, skeletal muscle, cognitive abilities, endocrine control and cardiovascular homeostasis are possible perpetuating factors. The chronic fatigue syndrome–an update
Angiotension converting enzyme (ACE) deletions are associated with Gulf War Syndrome:
Increased risk for CFS/ICF was associated with alterations of the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene within the Gulf War veteran sample only. [...] Veterans with the DD genotype were eight times more likely to develop CFS/ICF than were those with the II genotype. Association of medically unexplained fatigue with ACE insertion/deletion polymorphism in Gulf War veterans
Corticosteroid-binding globulin (CBG) polymorphisms are associated with CFS:
A trend toward relative hypocortisolism is described in CFS. Twin and family studies indicate a substantial genetic etiologic component to CFS. Recently, severe corticosteroid-binding globulin (CBG) gene mutations have been associated with CFS in isolated kindreds. Human leukocyte elastase, an enzyme important in CBG catabolism at inflammatory sites, is reported to be elevated in CFS. We hypothesized that CBG gene polymorphisms may act as a genetic risk factor for CFS. [...] Sequencing and restriction enzyme testing of the CBG gene coding region allowed detection of severe CBG gene mutations and a common exon 3 polymorphism (c.825G–>T, Ala-Ser224). Plasma CBG levels were measured in 125 CFS patients and 198 controls by radioimmunoassay. Total and free (calculated and measured) cortisol levels were ascertained in single samples between 8-10 a.m. The age of onset (mid 30s) and gender ratio (2.2:1, female:male) of the patients were similar to those reported in U.S. epidemiologic studies. A trend toward a preponderance of serine224 homozygosity among the CFS patients was noted, compared with controls [...] Despite higher CBG levels, there was a nonsignificant trend toward lower total and free plasma cortisol in serine allele positive patients [...] Homozygosity for the serine allele of the CBG gene may predispose to CFS, perhaps due to an effect on hypothalamic-pituitary-adrenal axis function related to altered CBG-cortisol transport function or immune-cortisol interactions. Association between chronic fatigue syndrome and the corticosteroid-binding globulin gene ALA SER224 polymorphism
Serotonin (5-hydroxy-tryptamine) transport protein (5-HTT, also known as SERT) polymorphisms are associated with CFS:
Interaction between the hypothalamo-pituitary-adrenal axis and the serotonergic system is thought to be disrupted in chronic fatigue syndrome (CFS) patients. We examined a serotonin transporter (5-HTT) gene promoter polymorphism, which affects the transcriptional efficiency of 5-HTT [...] A significant increase of longer (L and XL) alleic variants was found in the CFS patients compared to the controls [...] Attenuated concentration of extracellular serotonin due to longer variants may cause higher susceptibility to CFS. Association between serotonin transporter gene polymorphism and chronic fatigue syndrome
We have recently reported the association of serotonin transporter gene polymorphism in CFS. A significant increase of longer (L and XL) alleic variants was found in the CFS patients compared to the controls. Compared to S allele, the L allele is believed to retain higher transcriptional activity, which causes decreased concentration of serotonin in the extracellular space, namely, active serotonin in CFS. These results thus support the serotonin hypothesis in the pathogenesis of CFS. Genetic background of chronic fatigue syndrome
Having serotonin levels that are too low can be caused by genetics, or by a viral infection:
Attenuation of serotonin neurotransmission can be caused by increased expression of serotonin transporter, which results either from viral infection and subsequent production of interferon–alpha or from abnormal promoter for serotonin transporter gene. Chronic fatigue syndrome and neurotransmitters
Yes, you read that right. The production of interferon-alpha due to a viral infection actually interferes with the genetic transcription of SERT, causing it to overproduce. This downregulates serotonin neurotransmission. Salicylate stimulates serotonin synthesis (the cause of the flavour chemical intolerant’s familiar ‘happy high’), so I suspect it works on CFS in a similar manner, by causing short term rebound deficiencies in substrates due to overproduction, and long-term downregulation of production. I know of several people who have complained of SSRI-like withdrawal symptoms when they begin the failsafe diet.
Serotonin receptor (HTR) polymorphisms are also involved in CFS:
The pathophysiology of CFS remains elusive, although abnormalities in the central nervous system (CNS) have been implicated, particularly hyperactivity of the serotonergic (5-hydroxytryptamine; 5-HT) system and hypoactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Since alterations in 5-HT signaling can lead to physiologic and behavioral changes, a genetic evaluation of the 5-HT system was undertaken to identify serotonergic markers associated with CFS and potential mechanisms for CNS abnormality. A total of 77 polymorphisms in genes related to serotonin synthesis (TPH2), signaling (HTR1A, HTR1E, HTR2A, HTR2B, HTR2C, HTR3A, HTR3B, HTR4, HTR5A, HTR6, and HTR7), transport (SLC6A4), and catabolism (MAOA) were examined [...] Of the polymorphisms examined, three markers (-1438G/A, C102T, and rs1923884) all located in the 5-HT receptor subtype HTR2A were associated with CFS when compared to NF controls. Additionally, consistent associations were observed between HTR2A variants and quantitative measures of disability and fatigue in all subjects. The most compelling of these associations was with the A allele of -1438G/A (rs6311) which is suggested to have increased promoter activity in functional studies. Further, in silico analysis revealed that the -1438 A allele creates a consensus binding site for Th1/E47, a transcription factor implicated in the development of the nervous system. Electrophoretic mobility shift assay supports allele-specific binding of E47 to the A allele but not the G allele at this locus. These data indicate that sequence variation in HTR2A, potentially resulting in its enhanced activity, may be involved in the pathophysiology of CFS. Genetic evaluation of the serotonergic system in chronic fatigue syndrome
Proopiomelanocortin (POMC), nuclear receptor subfamily 3, group C, member 1 (NR3C1), monoamine oxidase A (MAOA), monoamine oxidase B (MAOB), and tryptophan hydroxylase 2 (TPH2) polymorphisms are all associated with CFS:
This study examined whether genetic differences underlie the individual subgroups of the latent class solution. Polymorphisms in 11 candidate genes related to both hypothalamic-pituitary-adrenal (HPA) axis function and mood-related neurotransmitter systems were evaluated. [...] Of the five classes of subjects with unexplained fatigue, three classes were distinguished by gene polymorphsims involved in either HPA axis function or neurotransmitter systems, including proopiomelanocortin (POMC), nuclear receptor subfamily 3, group C, member 1 (NR3C1), monoamine oxidase A (MAOA), monoamine oxidase B (MAOB), and tryptophan hydroxylase 2 (TPH2). These data support the hypothesis that medically unexplained chronic fatigue is heterogeneous and presents preliminary evidence of the genetic mechanisms underlying some of the putative conditions. Polymorphisms in genes regulating the HPA axis associated with empirically delineated classes of unexplained chronic fatigue
Catechol-O-methyltransferase (COMT) polymorphisms, along with some genes already listed above, are associated with CFS:
This paper asks whether the presence of chronic fatigue syndrome (CFS) can be more accurately predicted from single nucleotide polymorphism (SNP) profiles than would occur by chance. [...] The top three genes containing the SNPs accounting for the highest accumulated importances were neuronal tryptophan hydroxylase (TPH2), catechol-O-methyltransferase (COMT) and nuclear receptor subfamily 3, group C, member 1 glucocorticoid receptor (NR3C1). CONCLUSION: The fact that only 28 out of several million possible SNPs predict whether a person has CFS with 76% accuracy indicates that CFS has a genetic component that may help to explain some aspects of the illness. Combinations of single nucleotide polymorphisms in neuroendocrine effector and receptor genes predict chronic fatigue syndrome
Wait. Let’s read that again: only twenty eight out of several million genetic polymorphisms predict whether a person has CFS with a 76% accuracy.
Yasko tests for some of the common polymorphisms listed above: ACE, MAO-A, and COMT. She doesn’t test for CBG, 5-HTT/SERT, POMC, NR3C1, MAO-B or TPH2.
You know you’re on to something when you can predict the genes that are involved in particular illnesses. Though Yasko doesn’t test for POMC variants, we’ve actually been discussing POMC on FailsafeNT recently. It is probably one of the primary genetic components of opioid sensitivity and pain perception. Also, I’ve also been puzzled for a while as to why Yasko doesn’t test for SERT polymorphisms, particularly as serotonin promotes sociability and for this reason is thought to be lacking in some autistics.
Of course, fibromyalgia is very closely related to CFS:
The exposure of a genetically predisposed individual to a host of environmental stressors is presumed to lead to the development of FMS. Fibromyalgia overlaps with several related syndromes, collectively compromising the spectrum of the functional somatic disorder. FMS is characterized by a strong familial aggregation. Recent evidence suggests a role for polymorphisms of genes in the serotoninergic, dopaminergic and catecholaminergic systems in the etiopathogenesis of FMS. These polymorphisms are not specific for FMS and are similarly associated with additional comorbid conditions. The mode of inheritance in FMS is unknown, but it is most probably polygenic. Recognition of these gene polymorphisms may help to better subgroup FMS patients and to guide a more rational pharmacological approach. The genetics of fibromyalgia syndrome
Why are women more prone to depression and mood disorders than men? And why do more women than men seem to suffer from food chemical related disorders, especially fibromyalgia?
Depressive disorders in women are commonly associated with reproductive events. This association may be due in part to the changing balance between estrogen, progesterone, and other hormones that affect neurotransmitter function throughout a woman’s lifecycle. [...] Some data suggest that depression in women tends to respond differently to antidepressant treatment than depression in men, underscoring the need to examine the risk and treatment of depressive disorders in males and females separately. Women have benefited considerably from serotonin reuptake inhibitor anti-depressants that are currently available. These agents appear to be more effective than the older tricyclic antidepressants in treating various depressive disorders that occur commonly or exclusively in women. Additionally, serotonin reuptake inhibitors have increased tolerability in women, who generally experience more adverse effects from tricyclics and monoamine oxidase inhibitors than do men. Estrogen appears to enhance antidepressant response in postmenopausal women receiving estrogen replacement therapy. Special issues related to the treatment of depression in women.
Women have worse responses to monoamine oxidase inhibitors than men do? Why would that be? After all, it’s men who only have one copy of the MAO gene – which resides on the X chromosome.
Estrogen replacement treatment in menopausal women has been reported to have a positive effect on mood states. However, the addition of a progestin partially negates this positive effect in some women. The opposite effects of estrogen and progestin on mood may relate to their opposite effects on adrenergic and serotonergic neural function. In a double-blind, placebo-controlled, crossover study, 38 nondepressed menopausal women were cyclically treated with estrogen and estrogen plus progestin, or with placebo, for five 28-day cycles. This paper identifies the pretreatment attributes of women who do and do not have negative mood responses to progestin, and examines the relationship of these adverse side-effects to platelet monoamine oxidase (MAO), a marker of adrenergic and serotonergic functioning. Adverse mood responses to progestin occur in women with a long duration of menopause, low pretreatment serum estradiol and testosterone levels, high pretreatment serum FSH levels, low pretreatment platelet MAO activity, and pretreatment mood abnormalities. We conclude that adverse mood response to the addition of a progestin occurs in menopausal women who have low pretreatment gonadal hormone levels secondary to a long duration of menopause. Impaired central nervous system adrenergic and serotonergic functioning also may be a factor predisposing to a negative mood response to progestin. Individual differences in changes in mood and platelet monoamine oxidase (MAO) activity during hormonal replacement therapy in menopausal women.
In this case the above study finds that oestrogen decreases monoamine oxidase expression, and progesterone increases monoamine oxidase expression. Hence in these depressed women, decreasing monoamine oxidase activity with oestrogen (effectively giving them an MAOI), elevated their mood. More of the same:
the expression of several genes associated with embryo implantation (i.e. thrombomodulin, monoamine oxidase A, SPARC-like 1) can be induced by P[rogesterone] in vitro Progesterone regulation of implantation-related genes: new insights into the role of oestrogen.
It had previously been reported that estrogen treatment in menopausal women had a positive effect on mood, whereas the combination of estrogen plus a progestin had a negative effect on mood. We found that the women with a long duration of menopause and higher treatment serum estradiol levels had significantly more dysphoria when receiving a combination of estrogen plus progestin than did the women with a short duration of menopause and lower serum estradiol levels. However, both short and long duration menopausal groups showed improvement in mood when estrogen was administered alone. Platelet MAO levels, a marker of adrenergic and serotonergic function thought to relate to mood, were negatively correlated with serum estradiol levels during HRT. We suggest that these paradoxical findings may be secondary to a prolonged estrogen deficiency state in women with a long duration of menopause. Relationships of serum estradiol levels, menopausal duration, and mood during hormonal replacement therapy.
Of course if you have the kind of depressed monoamine oxidase activity that leads to food chemical intolerance, oestrogen is the last thing you need. When I first started to get more severe symptoms (during and shortly after coming off the pill), one of my theories was that I had ‘progesterone deficiency’ – a condition that exists only in alternative medicine. In mainstream medicine, you only have a deficiency or an excess of female hormones if your period has either stopped or your bleeding is abnormally heavy. So when I suggested progesterone deficiency to my (female) doctor at the time, she laughed at me and said hormonal problems were always caused by oestrogen deficiency, and the cure was the pill. Which fortunately I couldn’t take anymore as it had put me in hospital with deep vein thrombosis.
My cycle has always been as regular as clockwork. The pill did change my period – I never used to spot during the week before I was due. It’s only during the last few months that this after-effect of the pill has gone away and I stopped using the pill something like five years or more ago. Apparently some effects of the pill, including loss of sex drive and hormonal changes, can last up to ten years after the pill is discontinued. It’s no wonder so many women have problems getting pregnant these days!
Though I haven’t had my hormone levels tested, I’m fairly sure I have high oestrogen levels. I’m an hourglass shape and have a DD cup size, something that runs in my family. My grandmother had oestrogen-dependent breast cancer. At the time I started to get anxious about post-pill symptoms, progesterone deficiency fitted a lot of my symptoms. Of course I was on warfarin at the same time. Now it turns out that progesterone would have done me some good, by raising my MAO levels. I wonder how many other women with low MAO levels are out there thinking along the same lines as I did about progesterone deficiency?
But of course it’s always a bit more complicated than a simple inverse correlation between oestrogen and MAO:
The serotonin neural system plays a pivotal role in mood, affective regulation and integrative cognition, as well as numerous autonomic functions. We have shown that ovarian steroids alter the expression of several genes in the dorsal raphe of macaques, which may increase serotonin synthesis and decrease serotonin autoinhibition. Another control point in aminergic neurotransmission involves degradation by MAO. This enzyme occurs in two isoforms, A and B, which have different substrate preferences. [...] MAO-A and -B mRNAs were detected in the dorsal raphe nucleus (DRN) and in the hypothalamic suprachiasmatic nucleus (SCN), preoptic area (POA), paraventricular nucleus (PVN), supraoptic nucleus (SON), lateral hypothalamus (LH) and ventromedial nucleus (VMN). MAO-A mRNA optical density was significantly decreased by E, P, and E+P in the DRN and in the hypothalamic PVN, LH and VMN. Ovarian hormones had no effect on MAO-B mRNA expression in the DRN. However, there was a significant decrease in MAO-B optical density in the hypothalamic POA, LH and VMN with E, P or E+P treatment. Pixel area generally reflected optical density. CONCLUSIONS: Ovarian steroids decreased MAO-A, but not B, in the raphe nucleus. However, both MAO-A and B were decreased in discrete hypothalamic nuclei by hormone replacement. These data suggest that the transcriptional regulation of MAO by ovarian steroids may play a role in serotonin or catecholamine neurotransmission and hence, mood, affect or cognition in humans. Ovarian steroid regulation of monoamine oxidase-A and -B mRNAs in the macaque dorsal raphe and hypothalamic nuclei.
Estrogen replacement therapy is widely used in postmenopausal women. The current study examines the effect of varying concentrations of estrogen on the levels of activity of monoamine oxidase A and -B in brain and in other tissues. [...] High dose estrogen (5 mg/pellet) significantly decreased MAO-B activity and resulted in lesser or insignificant changes in MAO-A activity, respectively in liver (-30%, +1%), kidney (-22%, -11%), and uterus (-57%, -35%) (p Tissue-specific effects of estrogen on monoamine oxidase A and B in the rat.
These are shockingly large percentage changes. It’s the decreased MAO-A activity in the hypothalamus and amygdala that’s particularly interesting, as they are primitive parts of the brain. Hypothalamus, amygdala, and limbic system keep cropping up in my research as sites where the processing of amines and glutamate is altered somehow in food chemical intolerance spectrum syndromes including autism and fibromyalgia. One researcher even thinks that the amygdala is damaged in fibromyalgia. The hypothalamus controls body temperature, hunger, thirst, fatigue, anger, and circadian cycles, and links the nervous system to the endocrine system via the pituary gland. The amygdala plays a role in the processing and memory of emotional reactions.
So the next question is, if oestrogen levels make women more vulnerable than men to amines, why are there something like six male aspergers for every female asperger?
Well we know that asperger’s/autism/schizophrenia/bipolar disorder/epilepsy and other overlapping disorders seem to be connected to changes in dopamine processing in the brain.
This discussion is followed by a more detailed description of estrogen’s actions upon the dopamine transporter, which is hypothesized to serve as one of the major mechanism involved with nigrostriatal dopaminergic neuroprotection. Overall, estrogen appears to inhibit dopamine transporter function by decreasing the affinity of the transporter. Such an effect could prevent neurotoxic agents from entering dopamine nerve terminals, thereby decreasing nigrostriatal neurodegeneration. Neuroprotective effects of estrogen upon the nigrostriatal dopaminergic system.
Women seem to be less vulnerable to some dopamine related disorders because dopamine is processed differently in the presence of oestrogen. They seem to be less likely to suffer the effects of high dopamine. In addition to this, men have a special region on the Y chromosome called the Sex-determining Region Y (SRY), and it is this one region on the Y chromosome that determines whether you develop as a male or a female.
SRY has been linked to the fact that men are more likely than women to develop dopamine-related diseases such as schizophrenia and Parkinson’s disease. SRY makes a protein that controls concentrations of dopamine, the neurotransmitter that carries signals from the brain that control movement and coordination. Sex-determining Region Y (SRY)
Marry your cousin to have long-lived kids? Inbreeding is not usually mooted as the key to longevity, but Giuseppe Passarino of the University of Calabria in Rende, Italy, thinks it might be. “Everyone knows that inbreeding is bad – it increases your chances of catching a range of diseases,” he says. “But on the other hand, our study suggests that if inbreds don’t get those diseases when they’re young, they might have a better chance of long life.”
Passarino and his colleagues used census data to identify a geographically isolated region of southern Italy with more than its fair share of male nonagerians. When the team looked at the local phone book, they found many people in the region shared the same surname, suggesting marriage between related individuals was common (Annals of Human Genetics, DOI: 10.1111/j.1469-1809.2007.00405.x).
“The level of inbreeding can be measured quite precisely by studying surname distribution,” says Passarino. Because a surname is passed through the paternal line, it behaves like a gene transmitted through the Y chromosome, he says.
Everyone has two copies of each gene. In a large gene pool there is a high chance that those copies will be distinct. But in a small, inbred community, the gene pool remains the same and it is more likely that an individual will be “homozygous” – with two identical copies of a gene.
“Longevity seems to be linked to homozygosity,” Passarino says. This may be because certain copies of some genes boost lifespan, and carrying two of them doubles the effect. A number of DNA analyses have located regions of the genome where centenarians show an unusually high level of homozygosity, he says.
“It is theoretically possible to observe more centenarians as a result of inbreeding,” says Leonid Gavrilov at the University of Chicago, but he wonders why only men were the beneficiaries.
Passarino says it may be because the genetic component of longevity plays a more important role in men, whereas in women, environmental factors come to the fore. Healthcare has improved in western Europe over the past 60 years, which has benefited women more than men. For example, in Denmark the number of male centenarians is 10 times as high because of better healthcare, but the number of females is 50 times higher, he says. The region that Passarino identified is economically poor and has limited healthcare. This could explain why fewer women than men live to old age there.
Bruce Carnes of the University of Oklahoma cautions against marrying a relative, however. “Homozygosity is typically a very bad thing,” he says. “Almost every discussion of inbreeding that I have ever read has emphasised its downside.” Inbred humans live to a ripe old age
FACT 1: Use of monoamine oxidase inhibitors (MAOIs) are associated with significant weight gain:
Antidepressants such as tricyclic antidepressants and monoamine oxidase (MAO) inhibitors are most often associated with significant weight gain. Pharmacodynamics of drug-induced weight gain.
FACT 2: Common low activity monoamine oxidase single nucleotide polymorphisms are associated with increased weight and increased risk of obesity:
We investigated the association between the monoamine oxidase A (MAO-A) gene and obesity. [...] The TDT analysis of the EcoRV polymorphism showed in obese subjects with a body mass index (BMI) >/=35 kg/m(2) a preferential transmission of the low activity-related allele (chi(2)(TDT) = 8.0, p = 0.005). Our findings may provide evidence of a candidate gene involved in obese subjects with a BMI >/=35 kg/m(2). Family-based association study between the monoamine oxidase A gene and obesity: implications for psychopharmacogenetic studies.
We found, however, that both MAOA and MAOB show an excess of the low-activity genotypes in obese individuals. Additionally, the MAOA genotype was significantly associated with both weight and BMI. Obesity is associated with genetic variants that alter dopamine availability.
FACT 3: Monoamine oxidase activity is disturbed in diabetes:
MAO activity in pancreatic tissue is significantly reduced in diabetes. This decrease in MAO activity is associated with an increase in pancreatic tissue levels of adrenaline (ADR) and noradrenaline (NA). Studies on the level of 5-hydroxyindoleacetic acid of pancreatic tissues suggest that serotonin level is also increased in diabetics. Many studies show that MAO inhibits insulin secretion. However, some of its substrates including, serotonin, adrenaline and noradrenaline have been shown to stimulate insulin secretion. In conclusion, the activity and subcellular localisation of MAO suggests that MAO may play an important role in pancreatic beta cell function and hence in the pathogenesis of diabetes mellitus. The effect of diabetes mellitus on the morphology and physiology of monoamine oxidase in the pancreas.
In other words, high MAO activity inhibits insulin secretion. A number of monoamines (serotonin, adrenaline, noradrenaline etc) themselves stimulate insulin secretion, therefore low monoamine oxidase activity automatically leads to higher insulin levels.
FACT 4: Glucose regulates monoamine oxidase activity:
Islet beta-cell monoamines are known to influence the insulin-releasing mechanisms. These amines are localized in the insulin-secretory granules and are inactivated by the enzyme monoamine oxidase (MAO), a hydrogen peroxide (H2O2)-generating enzyme. The activity of islet MAO may consequently be of importance for insulin secretion. In the present investigation, we studied the relation between islet MAO activity and plasma levels of insulin and glucose in obese (ob/ob) hyperglycemic mice and their lean littermates. In addition, the effect of glucose on the MAO activity of in vitro-cultured islets was studied. MAO activity was assayed with serotonin, dopamine (DA), and beta-phenylethylamine (PEA) as substrates. After an overnight fast in adult (age, 6 months) lean mice, islet MAO activity was increased by 35% to 70%. Plasma levels of glucose and insulin were markedly decreased as expected. However, fasting in adult obese mice either did not affect islet MAO activity (PEA and DA) or induced a slight decrease (serotonin) of approximately 25% (P < .05). Plasma glucose levels in adult obese mice were not significantly affected by the overnight fast. However, a correlation analysis based on individual adult obese mice (fed and fasted) showed a negative correlation between plasma glucose concentration and islet MAO activity with PEA (r = -.65, P < .02) and DA (r = -.66, P < .02), respectively. Further, a positive correlation (r = +.58, P < .05) was found between glucose level and islet MAO activity when using serotonin as substrate. There was no difference in islet MAO activity with PEA and DA as substrates in fed obese versus fed lean mice. Glucose modulation of islet monoamine oxidase activity in lean and obese hyperglycemic mice.
In other words, lowering blood glucose through fasting caused monoamine oxidase activity to increase dramatically. In obese mice, blood glucose remained high and monoamine oxidase activity did not increase.
My own blood glucose levels are consistently on the edge of high-normal, even on a low-carb diet, and if they got any higher I would actually be classified as a T2 diabetic.
This explains to me why low carbohydrate diets and intermittent fasting have helped myself and a number of people I know who are sensitive to food chemicals. Even regular low calorie diets seem to help some people. I’ve often noted that the consumption of amine containing foods has the ability to cause massive, sudden weight gain in myself. I’ve also noted that when I am on a ketogenic diet I have a higher tolerance of amines.
It also explains something else. I’ve met a lot of people who really, really believe that low carbohydrate diets are THE answer to everything, and these people have been overweight for years and nothing worked except low carbing. Often they describe symptoms that correlate with food chemical sensitivity. What these people do not know is that they are overweight because they have low monoamine oxidase activity.
I imagine that when you combine low monoamine oxidase activity with other polymorphisms that increase insulin or insulin-like growth factor output (like the vitamin D receptor polymorphism VDR Fok), you have a recipe for reactive hypoglycaemia, weight gain and diabetes. Another reason for me to suspect I have both of these polymorphisms.
So now it seems that ALL failsafe food chemicals raise insulin levels – glutamates, salicylates, and amines.
I’ll spell this out again for the sake of the low-carbers whose eyes glaze over: the reason obesity is an increasing problem these days is not just due to increased consumption of carbohydrate. It is also due to the grossly increased amounts of food flavour chemicals eaten in the modern Western diet.
Catechol-O-methyl transferase is involved in the breakdown of the catecholamine neurotransmitters (dopamine, epinephrine and norepinephrine). The enzyme introduces a methyl group to the catecholamine which is donated by S-adenosyl methionine (SAM). COMT is an extracellular enzyme, so it breaks down dopamine and norepinephrine in the synapse. Any compound having a catechol structure, like catecholestrogens and catechol-containing flavonoids are substrates of COMT.
A functional single nucleotide polymorphism (a common normal variant) of the gene for catechol-O-methyl transferase has been shown to affect cognitive tasks broadly related to executive function, such as set shifting, response inhibition, abstract thought and the acquisition of rules or task structure. This polymorphism in the COMT gene results in the substitution of the amino acid valine for methionine. It has been shown that this valine variant catabolizes dopamine at up to four times the rate of its methionine counterpart, resulting in a significant reduction of synaptic dopamine following neurotransmitter release, ultimately reducing dopaminergic stimulation of the post-synaptic neuron. Consequently, neurons with valine-variant COMT show higher levels of activation during certain cognitive tasks, as they require higher levels of neuron firing to achieve the same level of post-synaptic stimulation.
The link between impairments in these sorts of cognitive tasks and the COMT gene is thought to be mediated by an effect on dopamine signalling in the frontal lobes.
Comparable effects on similar cognitive tasks, the frontal lobes and the neurotransmitter dopamine have also all been linked to schizophrenia. Unsurprisingly, an inherited variant of COMT is thought to be one of the genetic factors which may predispose someone to developing schizophrenia later in life, naturally or due to adolescent-onset cannabis use.
COMT inhibitors are found in green tea. Drinking green tea is, therefore, thought to provide a useful short-term boost to antidepressant medication by increasing the half life of extracellular noradrenaline and dopamine. COMT Wiki
This is what Wikipedia says about executive function:
The executive system is a theorized cognitive system in psychology that controls and manages other cognitive processes. It is thought to be involved in processes such as planning, cognitive flexibility, abstract thinking, rule acquisition, initiating appropriate actions and inhibiting inappropriate actions, and selecting relevant sensory information. [...]
The executive system is thought to be heavily involved in handling novel situations outside the domain of some of our ‘automatic’ psychological processes that could be explained by the reproduction of learned schemas or set behaviors. Psychologists Don Norman and Tim Shallice have outlined five types of situation where routine activation of behavior would not be sufficient for optimal performance:
- Those that involve planning or decision making.
- Those that involve error correction or troubleshooting.
- Situations where responses are not well-learned or contain novel sequences of actions.
- Dangerous or technically difficult situations.
- Situations which require the overcoming of a strong habitual response or resisting temptation.
Executive System Wiki
The diagram of dopamine degradation on the COMT page is interesting. Both degradation pathways require COMT for one step and MAO and aldehyde dehyrdogenase for another step. Asperger’s syndrome is characterised by a lot of sources as a condition of executive function deficits and challenges. Looking at the above list, I have to agree.
The fact that dopamine receptor polymorphisms like DRD4 R7 have also been connected to ADD/ADHD, and ADD/ADHD has also been characterised as a deficit in executive function is pretty interesting. ADHD and these polymorphisms have also been linked to increased creativity and risk taking.
Ritalin significantly increases levels of dopamine in the brain. So does cocaine. I feel that this fact might explain why a certain stereotype of person is led to abuse cocaine. Arty creative people, thespians and actors, high-flying London execs and city stockbrokers, military types on the front-line of danger, and young, risk-taking hollywood starlets (here I’ll mention no names but several young ladies who are famous for partying, substance abuse and being generally unhinged spring to mind).
This looks like an interesting book!
In his new work, the author, a former psychotherapist who has written previously on attention deficit/hyperactivity disorder (Attention Deficit Disorder: A Different Perspective), recommends techniques for raising children diagnosed with this condition. Although many of the specific strategies will be very useful to parents raising ADHD children, too much of the text is devoted to complex genetic and evolutionary theory. According to Hartmann, ADHD is a trait (referred to here as the Edison gene, because the inventor Thomas Edison is believed to have had the trait) rather than a disorder, because it once provided useful skills for functioning in a hunter-gatherer society. The hunter abilities contrasted sharply with the farmer trait, which carried the skills required in farming societies. For example, hunter children have a short attention span, beneficial in a dangerous world where the environment had to be constantly monitored. The innovative but impatient hunter child is usually placed in special ed classes and is looked on as a disciplinary problem; but Hartman believes that ADHD children should be thought of separately. He provides specific guidelines for parents, partly based on the work of Alfred Adler, which encourage mutual respect between parent and child. Hartmann is not an advocate of drug therapy, and he argues for educational reform and alternative schools or home schooling as better learning situations for ADHD children. Hartmann believes that creative outside-the-box thinking, characteristic of those with ADHD, is a real asset to solving many of the world’s serious problems. Amazon USA
Thomas Edison was expelled from school for behaviour that today would label him as having Attention Deficit Hyperactivity Disorder (ADHD), but his mother understood how to salvage his self-esteem and prepare him for a lifetime of success. In THE EDISON GENE Thom Hartmann shows that the creativity, impulsiveness, and distractibility that are characteristic of ADHD are not signs of a disorder at all, but instead are components of a highly adaptive skill set utilized by our hunting and gathering ancestors. These characteristics have been critical to the survival and development of our modern civilization and will be vital as humanity faces new challenges in the future. Hartmann, creator of the “hunter versus farmer” theory of ADHD, examines the latest discoveries confirming the existence of an ADHD gene and the global catastrophe 40,000 years ago that triggered its development. Citing examples of significant innovators in our modern era, he argues that the children who possess the “Edison gene” have neurology that is wired to give them brilliant success as innovators, inventors, explorers, and entrepreneurs. He offers concrete strategies for helping Edison-gene children reach their full potential and shows that rather than being “problems” such children are a vital gift to our society and the world. Amazon UK
This is an interesting take on the ADHD gene. DRD4 is supposed to have appeared somewhere between 10,000 and 40,000 years ago. Here, this author is suggesting it is a trait that is good for hunting rather than farming, which is the opposite of what DRD4 theorists have suggested – that it caused an innovative leap towards farming.
Whatever the case, the distinction being made between Asperger’s syndrome and ADHD/ADD seems to be paper-thin here.
I’ve been wondering for some time whether my factor V leiden related DVT could be connected to my food chemical intolerance. I came across this very interesting page that connects hyperhomocysteinemia caused by methylhydrotetrafolate reductase (MTHFR) mutations and cystathione beta synthase (CBS) polymorphisms to blood clotting. I had no idea the MTHFR mutation was so common:
Studies looking at the prevalence of homozygosity (both (2) copies of the gene are mutated) for the thermolabile variant mutation in MTHFR have shown a prevalence near 15% in European, Middle Eastern and Japanese populations, compared with a range at or below 1.4% in African Americans. Patients who are heterozygous (1 copy of the mutated gene) are seen in 30-40% of the population.
Heterozygosity for the CBS mutation is thought to occur in .4% to 1.4% of the population. Homozygosity for the CBS mutation is quite rare.
The risk factors for DVTs tend to multiply one another. They don’t have a combined risk factor listed for hyperhomocysteinemia, oral contraceptives, and heterozygous factor V leiden, but I bet it is pretty darn high. My sister also recently got a DVT – she has the same heterozygous FVL gene, she was smoking (naughty girl), and she got it within *a month* of being given the third generation pill, which seems suspiciously fast. To connect the dots, smoking also raises homocysteine levels.
I don’t know whether they test for high homocysteine on the standard clot risk tests in the UK. But I think I should get myself tested. Wonder if I could be an individual who has struck it particularly lucky with an MAO mutation (30% of popn), a MTHFR mutation (30% of popn), an SUOX mutation (also a hefty chunk of the popn), a leukotriene production mutation (no idea of frequency), oh, and FVL too (5-20% of popn). Because that would explain a lot. And it probably wouldn’t even be that rare.