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Tuesday, 14 March 2017

Leptin Signaling and JAK Inhibitors in Early Onset Autism - perhaps RORα and Adiponectin?


A future baldness therapy (a JAK inhibitor) to treat some autism?

Today’s rambling post has been pending for some time. It got left on one side, but is interesting and can be applied.
As we know there are distinct sub-types of autism and fortunately so does Paul Ashwood at the UC Davis MIND Institute. He often splits his findings into regressive vs early onset autism. 


There is evidence of both immune dysregulation and autoimmune phenomena in children with autism spectrum disorders (ASD). We examined the hormone/cytokine leptin in 70 children diagnosed with autism (including 37 with regression) compared with 99 age-matched controls including 50 typically developing (TD) controls, 26 siblings without autism, and 23 children with developmental disabilities (DD). Children with autism had significantly higher plasma leptin levels compared with TD controls (p<.006). When further sub-classified into regression or early onset autism, children with early onset autism had significantly higher plasma leptin levels compared with children with regressive autism (p<.042), TD controls (p<.0015), and DD controls (p<.004). We demonstrated an increase in leptin levels in autism, a finding driven by the early onset group.

A second study also found elevated leptin levels. 


Results: We found decreased levels of resistin, increased levels of leptin and unaltered levels of adiponectin in plasma from ASD subjects in comparison with controls. There was also a negative correlation between the levels of adiponectin and the severity of symptoms as assessed by the SRS. Conclusion: There are significant changes in the plasma levels of adipokines from patients with ASDs. They suggest the occurrence of systemic changes in ASD and may be hallmarks of the disease.


So today's post is really investigating what high levels of leptin in early onset autism might mean.  Is this just another abnormality produced by autism, or is it something to be fixed?  It appears to be the latter.



In my simplification of classic autism one of my four broad categories is neuroinflammation. These four categories interrelate, so a problem with one may affect all four. There are all kinds of mechanisms involved in chronic inflammation and this is why there are so many types of treatment for arthritis, IBS, IBD etc.
Recall all those posts about the activated microglia, the brain’s main form of active immune defence, and how in autism the body’s “immunostat” is somehow stuck on maximum.
So there is a long list of immune-modulating therapies that might help autism.  There is already a long list for conditions like arthritis. 
What works wonders for a few, like the TSO parasite worms, fails to help the majority when a larger clinical trial is carried out. 
One mechanism involved in the immune response is leptin signaling, the subject of today’s post.
It should be most relevant to people with unusually high levels of leptin that includes obese people and people with early onset autism.
So we have a hormone (leptin) driving inflammation. We saw in an earlier post how an imbalance in testosterone/estrogen connects with an ion channel dysfunction (KCC2/NKCC1) via ROR. So the hormone dysfunction is making the channelopathy worse.  Not so surprisingly we will see how high leptin associates with high testosterone (and hence low aromatase/estrogen).  The α4 subunit of ROR appears to drive leptin production.
We then have the choice of blocking the negative effects of high levels of leptin or we can go back to RORα and again consider treating autism like aromatase deficiency.  Aromatase is the enzyme that converts testosterone to estrogen in males.


We saw in autism a lack of estrogen receptors and a lack of aromatase, this then resulted in a lack of the neuroprotective effects of estrogen, which protects females from developing autism.
So if we increase estradiol not only do we  affect neurolin2 to produce more KCC2 and so lower intracellular chloride, but via  RORα we should produce less leptin in adipose (body fat) tissue.

Option A
Use JAK inhibitors to block the negative inflammatory effect of excess leptin.  There are potent inhibitors approved for arthritis and it looks like milder ones will be approved for treating some kinds of hair loss.

Option B
Deal with the proposed Purkinje-RORa-Estradiol-Neuroligin-KCC2 axis, by increasing estradiol and hope that via RORα, and more precisely RORα4, leptin levels reduce.
We know that high testosterone is associated with high leptin.
Since we want to solve as many of the damaging abnormalities found in autism, using the smallest number of therapies, Option B seems attractive.


Option C
Use a drug that reduces leptin.
Some PPAR gamma agonists are known to reduce leptin, including the thiazolidinedione Rosiglitazone. Some others do not.
PPAR gamma agonists have been used in autism for other reasons.

A natural PPAR gamma agonist is tangeritin/sytrinol.
There is a relationship between PPAR and RORα that is not yet understood in the literature.
Some readers of this blog are already using Option C.

Option D
Use a drug that raises adiponectin. Adiponectin is another hormone made in your fat cells and it reduces leptin. In some studies, low levels of Adiponectin are found in autism and that is not good for your wider health.
There is naturally some overlap with the therapies in option C.
Ways known to increase Adiponectin include:-

·        PPAR-γ agonists like rosiglitazone

·        PPAR- α agonists, like fibrates

·        ACE inhibitors, like Trandolapril

·        some statins (not simvastatin)

·        Niacin

·        renin-angiotensin-aldosterone system blockers

·        some calcium channel blockers, like Verapamil

·        mineralocorticoid receptor blockers,

·        new β-blockers

·        vanadyl sulfate (VS)

·        natural compounds; resveratrol has a modest effect, also reported in research are curcumin, capsaicin, gingerol, and catechins
  
What is Leptin?
Leptin is the satiety hormone and ghrelin is the hunger hormone.  They act together to regulate appetite.  In obese people leptin resistance occurs and they become desensitized to leptin.
People with obesity tend to have high levels of leptin, but it does them no good.
Unfortunately leptin has other functions unrelated to regulating how much you eat.  This is another example of evolution reusing the same substance for entirely different purposes.

Leptin plays a key role in the immune system and the regulation of the inflammatory response.
Leptin is a member of the cytokine superfamily and resembles IL-6, Autism’s public enemy #1. 
Chronically elevated leptin levels are associated not only with obesity but inflammation-related diseases, including hypertension, metabolic syndrome, and cardiovascular disease.   It is speculated that leptin responds specifically to adipose (body fat) derived inflammation.  Adipose tissue (body fat) produces hormones such as leptin, estrogen, resistin, and the cytokine TNFα.
Leptin also affects the HPA axis, which regulates the interactions among three endocrine glands, the hypothalamus, the pituitary gland and the adrenal.
The HPA axis is involved in the neurobiology of mood disorders and functional illnesses, including anxiety disorder, bipolar disorder, insomnia, post-traumatic stress disorder, borderline personality disorder, ADHD, major depressive disorder, burnout, chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, and alcoholism  

Leptin and testosterone levels? 

This study demonstrates a close association between serum levels of testosterone and leptin in males which has not been described previously. Serum testosterone levels could be an important contributor to the known gender difference in serum leptin levels which can be found even after correction for body composition.

The Leptin-JAK-STAT pathway
We can now jump forward in sophistication to the Leptin-JAK-STAT pathway.  This is the signaling pathway that lies behind much of what is going on with leptin.  It explains the comorbidities that people with high leptin may experience.
The pathway only makes full sense if you know a bit about the relevance of things like PKC, AKT etc. These pathways underlie how your body is regulated.  They are mainly being studied to understand all the types of cancer, but are equally relevant to the molecular understanding of autism. 
Tamoxifen, recently shown to reverse autism in a SHANK3 mouse model, is a PKC inhibitor. Aberrant loss or gain of Akt activation underlies the pathophysiological properties of a variety of complex diseases, including type 2 diabetes and cancer. PKC (and PKA) are reduced in regressive autism.

In general terms the Leptin-JAK-STAT pathway leads to inflammation and so it is a target for therapies to treat inflammatory disease like arthritis on inflammatory bowel disease.
You can reduce leptin signaling by inhibiting JAK.





After leptin binds to the long isoform of the leptin receptor (OB-Rb), Jak2 is activated at the box1 motif, resulting in the autophosphorylation of tyrosine residues and phosphorylation of tyrosines that provide docking sites for signaling proteins containing src homology 2 (SH2) domains. The autophosphorylated Jak2 at the box 1 motif can phosphorylate insulin receptor substrate1/2 (IRS1/2) that leads to activation of phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Akt can regulate a wide range of targets including FOXO1 and NF-κB. Activation of NF-κB after leptin binding has been shown to induce Bcl-2 and Bcl-XL expressions. Leptin binding to OB-Rb can also activate the phospholipase C (PLC) for stimulation of c-jun N-terminal protein kinase (JNK) via protein kinase C (PKC).

Both Tyr1077 and Tyr1138 bind to STAT5, whereas only Tyr1138 recruits STAT1 and STAT3. STAT3 proteins form dimers and translocate to the nucleus to induce expression of genes such as c-fos, c-jun, egr-1, activator protein-1 (AP-1) and suppressors of cytokine signaling 3 (SOCS3). SOCS3 negatively regulates signal transduction by leptin by binding to phosphorylated tyrosines on the receptor, to inhibit the binding of STAT proteins and the SH2 domain-containing phosphatase 2 (SHP2). SHP2 activates the mitogen-activated protein kinase (MAPK) pathways including extracellular signal-regulated kinase (ERK1/2), p38 MAPK and p42/44 MAPK through an interaction with the adaptor protein growth factor receptor-bound protein 2 (GRB2), to induce cytokine and chemokine expression in immune cells. SOCS2 binds to Tyr1077 and might interfere with STAT5 binding. After stimulation with leptin, Src associated in mitosis protein 68 (Sam68) can form a complex with activated STAT3, leading to its dissociation from RNA. Sam68 can also be directly activated by Jak2 to phosphorylate IRS1/2 for Akt activation.



Leptin is a hormone whose central role is to regulate endocrine functions and to control energy expenditure. After the discovery that leptin can also have pro-inflammatory effects, several studies have tried to address - at the molecular level - the pathways involved in leptin-induced modulation of the immune functions in normal and pathologic conditions. The signaling events influenced by leptin after its binding to the leptin receptor have been under scrutiny in the past few years, and considerable experimental work has elucidated the consequences of leptin effects on immune cells. This review examines the biochemistry, function and regulation of leptin signaling in view of possible intervention on this molecule for a better management and therapy of immune-mediated diseases.


Janus kinase inhibitors/ JAK inhibitors
Janus kinase inhibitors, also known as JAK inhibitors inhibit the activity of one or more of the Janus kinase family of enzymes (JAK1, JAK2, JAK3, TYK2), thereby interfering with the JAK-STAT signaling pathway
The currently approved drugs are:-
  • Ruxolitinib against JAK1/JAK2 for psoriasis, myelofibrosis, and rheumatoid arthritis.
  • Tofacitinib against JAK3 for psoriasis and rheumatoid arthritis.
  •  Oclacitinib against JAK1 for the control of pruritus associated with allergic dermatitis and the control of atopic dermatitis in dogs

Both aspirin and Metformin have some related effects, but do not appear to be JAK inhibitors. 



JAK inhibitors for baldness?

Much of modern medicine is stumbled upon.  This has happened at least twice in the search for treatments for hair loss.  Merck developed Proscar based on the observation of a tribe that never had enlarged prostates, and then they found their new drug caused hair growth as a side effect, so they marketed a low dose version as Prospecia. Researchers at Columbia were treating a man with psoriasis using the JAK inhibitor Tofacitinib. He regrew a full head of hair within seven months.  He had a type of hair loss called Alopecia Areata.
Since haircare is a huge business, new JAK inhibitors are being developed for hair loss, both oral and topical.
Perhaps less potent JAK inhibitors than used for arthritis may be enough for people with autism and high leptin?


Natural JAK Inhibitors
We can also look in nature for potential JAK inhibitors.
By chance, before deciding to complete this post that been unfinished, I did look at some other unfinished once.  One that was all about the medicinal benefits of Nigella sativa, often called black cumin.
At least one reader of this blog is already a fan of Nigella sativa.
It turns out that one constituent of Nigella sativa is Thymoquinone. We know that Thymoquinone affects STAT3 in the complicated diagram above.  It is known to have anti-inflammatory and anticancer properties, but does it affect higher up the pathway at JAK?
For example, another natural product Cucurbitacin B, used in Chinese herbal medicine, is a dual inhibitor of the activation of both JAK2 and STAT3.
Brevilin A, a novel natural product, inhibits Janus Kinase Activity and blocks STAT3 Signaling. 






Back to Option B - RORα 


Here we show that gene expression of the nuclear receptor RORalpha is induced during adipogenesis, with RORalpha4 being the most abundantly expressed isoform in human and murine adipose tissue. Over-expression of RORalpha4 in 3T3-L1 cells impairs adipogenesis as shown by the decreased expression of adipogenic markers and lipid accumulation, accompanied by decreased free fatty acid and glucose uptake. By contrast, mouse embryonic fibroblasts from staggerer mice, which carry a mutation in the RORalpha gene, differentiate more efficiently into mature adipocytes compared to wild-type cells, a phenotype which is reversed by ectopic RORalpha4 restoration.

Previous studies have identified a role for RORa in cerebellum development, immune function and circadian rhythmicity. Recent reports have also outlined a function for RORa in cholesterol and lipid metabolism. In the present study we show that the RORa1 and RORa4 genes are expressed in adipose tissue and that RORa increases upon differentiation of preadipocytes into adipocytes, identifying RORa4 as the principal isoform in adipose tissue. Moreover, RORa4 over-expression in 3T3-L1 cells inhibits adipocyte differentiation, impairs fatty acid and glucose uptake and reduces expression of genes known to be involved in both adipocyte differentiation (including PPARc, CEBPa and aP2) and function (such as FAS, PEPCK, and the fatty acid and glucose transporters FATP, CD36 and Glut-4).

Although our experiments did not address the molecular mechanism(s) involved in the RORa-mediated inhibition of adipogenesis, several hypotheses can be put forward. Inhibition of adipocyte differentiation may occur principally through inhibition of positive regulators such as PPARc or CEBPa, or through the induction of inhibitory factors like GATA, KLF2, CHOP or Wnt signaling [3]. Alternatively, RORa may regulate other factors known

to inhibit adipocyte differentiation, for instance, through induction of p21CYP1/Waf1 leading to growth arrest. Along this line, Rev-erba acts as a p21 repressor in hepatic cells [27], and RORc induces p21 in liver. Thus, RORa might act, at least in part, by up-regulating p21 transcription in adipose cells. Another possible explanation may lie in the recent observation that Rev-erba represses PPARc2 gene expression during adipocyte differentiation [6]. The fact that RORa induces Rev-erba gene transcription ([28] and this report, not shown) may constitute an additional potential mechanism for adipogenesis inhibition by RORa.

Although future studies are necessary to further delineate RORa-regulated pathways in adipose cells, our findings clearly identify RORa4 as novel negative modulator of adipocyte differentiation and function.



Option C – reduce Leptin

Thiazolidinediones/glitazones
Thiazolidinediones also known as glitazones, are a class of medications used in the treatment of diabetes mellitus type 2.

Thiazolidinediones act by activating PPARs (peroxisome proliferator-activated receptors with greatest specificity for PPARγ.
Chemically, the members of this class are derivatives of the parent compound thiazolidinedione, and include:


PPARgamma agonist have been trialed with some success in autism.


These results indicate that antidiabetic thiazolidinediones down-regulate leptin gene expression with potencies that correlate with their abilities to bind and activate PPARgamma.


The thiazolidinedione BRL 49653 and the thiazolidinedione derivative CGP 52608 are lead compounds of two pharmacologically different classes of compounds. BRL 49653 is a high affinity ligand of peroxisome proliferator-activated receptor gamma (PPARgamma) and a prototype of novel antidiabetic agents, whereas CGP 52608 activates retinoic acid receptor-related orphan receptor alpha (RORA) and exhibits potent antiarthritic activity. Both receptors belong to the superfamily of nuclear receptors and are structurally related transcription factors. We tested BRL 49653 and CGP 52608 for receptor specificity on PPARgamma, RORA, and retinoic acid receptor alpha, a closely related receptor to RORA, and compared their pharmacological properties in in vitro and in vivo models in which these compounds have shown typical effects. BRL 49653 specifically induced PPARgamma-mediated gene activation, whereas CGP 52608 specifically activated RORA in transiently transfected cells. Both compounds were active in nanomolar concentrations. Leptin production in differentiated adipocytes was inhibited by nanomolar concentrations of BRL 49653 but not by CGP 52608. BRL 49653 antagonized weight loss, elevated blood glucose levels, and elevated plasma triglyceride levels in an in vivo model of glucocorticoid-induced insulin resistance in rats, whereas CGP 52608 exhibited steroid-like effects on triglyceride levels and body weight in this model. In contrast, potent antiarthritic activity in rat adjuvant arthritis was shown for CGP 52608, whereas BRL 49653 was nearly inactive. Our results support the concept that transcriptional control mechanisms via the nuclear receptors PPARgamma and RORA are responsible at least in part for the different pharmacological properties of BRL 49653 and CGP 52608. Both compounds are prototypes of interesting novel therapeutic agents for the treatment of non-insulin-dependent diabetes mellitus and rheumatoid arthritis.

BRL-49653 became the drug Rosiglitazone
CGP 52608 was not commercialized.



In our study, activation of PPAR𝛾 also negatively regulates leptin signaling. PPAR𝛾 and its agonist ciglitazone downregulate leptin, and its receptor mRNA expression, inhibit leptin-induced STAT3 phosphorylation and activation and increase STAT3 inhibitor SOCS3 expression. These findings indicate that PPAR𝛾 and leptin signaling pathways are mutually regulated in growth plate chondrocytes. The imbalance between the levels of PPAR𝛾 and leptin may facilitate the dysfunction of the growth plate observed in obese children.


Option D – Increase Adiponectin

Adiponectin restrains leptin-induced signalling

Another hormone you may not of heard of is Adiponectin; is it secreted from the same adipose tissue that produces leptin.
Whereas the high levels of leptin found in classic autism appear to be bad for you, it is the low levels of Adiponectin found in autism, and indeed ADHD, that may be bad for. Low levels of Adiponectin are associated with many conditions ranging from NAFLD to type 2 diabetes.
Another way to reduce leptin signaling is to increase the level of Adiponectin.
Much is known about ways to increase adiponectin and many readers of this blog are actually already doing it. Ways to increase it include:-

·        PPAR-γ agonists like rosiglitazone

·        PPAR- α agonists, like fibrates

·        ACE inhibitors, like Trandolapril

·        some statins (not simvastatin)

·        Niacin

·        renin-angiotensin-aldosterone system blockers

·        some calcium channel blockers, like Verapamil

·        mineralocorticoid receptor blockers,

·        new β-blockers

·        vanadyl sulfate (VS)

·        natural compounds; resveratrol has a modest effect, also reported in research are curcumin, capsaicin, gingerol, and catechins
Combining an ACE inhibitor with the calcium channel blocker verapamil has an even bigger effect on Adiponectin levels.


Reduced levels of adiponectin are found in some Autism studies  


The neurobiological basis for autism remains poorly understood. We hypothesized that adipokines, such as adiponectin, may play a role in the pathophysiology of autism. In this study, we examined whether serum levels of adiponectin are altered in subjects with autism. We measured serum levels of adiponectin in male subjects with autism (n = 31) and age-matched healthy male subjects (n = 31). The serum levels of adiponectin in the subjects with autism were significantly lower than that of normal control subjects. The serum adiponectin levels in the subjects with autism were negatively correlated with their domain A scores in the Autism Diagnostic Interview—Revised, which reflects their impairments in social interaction. This study suggests that decreased levels of serum adiponectin might be implicated in the pathophysiology of autism.  

Autism is a neurodevelopmental disorder with pathogenesis not completely understood. Although a genetic origin has been recognized, it has been hypothesized a role for environmental factors, immune dysfunctions, and alterations of neurotransmitter systems. In young autistic patients we investigated plasma leptin and adiponectin levels over a year period. Thirty-five patients, mean age at the basal time 14.1 ± 5.4 years, were enrolled. Controls were 35 healthy subjects, sex and age matched. Blood samples were withdrawn in the morning at the baseline and 1 year after. In patients leptin concentrations significantly increased, while adiponectin did not significantly change. Leptin values in patients were significantly higher than those found in controls at each time; adiponectin values did not differ at each time between patients and controls. Since patients were not obese, we could hypothesize that leptin might participate to clinical manifestations other than weight balance. The role of adiponectin in autism is still debatable.


Modulation of adiponectin as therapy
In many conditions it is already considered wise to modulate adiponectin as a therapy.  Examples are diabetes and cardiovascular disease.  The subject is quite well studied.

Adiponectin is produced predominantly by adipocytes and plays an important role in metabolic and cardiovascular homeostasis through its insulin-sensitizing actions and anti-inflammatory and anti-atherogenic properties. Recently, it has been observed that lower levels of adiponectin can substantially increase the risk of developing type 2 diabetes, metabolic syndrome, atherosclerosis, and cardiovascular disease in patients who are obese. Circulating adiponectin levels are inversely related to the inflammatory process, oxidative stress, and metabolic dysregulation. Intensive lifestyle modifications and pharmacologic agents, including peroxisome proliferator-activated receptor-γ or α agonists, some statins, renin-angiotensin-aldosterone system blockers, some calcium channel blockers, mineralocorticoid receptor blockers, new β-blockers, and several natural compounds can increase adiponectin levels and suppress or prevent disease initiation or progression, respectively, in cardiovascular and metabolic disorders. Therefore, it is important for investigators to have a thorough understanding of the interventions that can modulate adiponectin. Such knowledge may lead to new therapeutic approaches for diseases such as type 2 diabetes, metabolic syndrome, cardiovascular disease, and obesity. This review focuses on recent updates regarding therapeutic interventions that might modulate adiponectin.

  
The Secretome of human adipose tissue

The genome, the epigenome and the microbiome, we now have the secretome. Human body fat is an endrocrine organ producing more than 600 different proteins; the first one, leptin, was identified only in 1994.

Adipokines: A treasure trove for the discovery of biomarkers for metabolic disorders

So clearly scientists have a very long way to go to understand how the human body works.




Conclusion
It is odd how in this blog we keep coming back to drugs that are helpful for diabetes and high cholesterol. Obesity also recurs as a theme.
Interesting present day options seem to be:-
·        JAK inhibitors (Ruxolitinib, Tofacitinib)

·        Estradiol, my hunch with some evidence

·        PPAR gamma agonists Rosiglitazone (Avandia) or lots of Tangeretin/Sytrinol

·        ACE inhibitors, some statins, verapamil, fibrates and niacin 

I think some people will benefit from the following, but perhaps not due reduced leptin signaling

·        Low dose aspirin

·        Metformin, in human use for more than 50 years to treat type 2 diabetes the molecular mechanism of metformin is incompletely understood

·        Nigella sativa / Thymoquinone






9 comments:

  1. Excellent post Peter.

    Nevertheless, my gut (no pun intended) tells me in all of this is that this is yet another chicken and the egg problem so I am not so sure if DIRECTLY countering leptin is what is needed here.

    In the arcuate nuclei of the hypothalamus which gets special access to the bloodstream that the rest of the brain is largely shielded from, generally speaking the two major classes of metabolism neurons are the orexigenic Neuropeptide Y (NPY) and Agouti Related Protein (AgRP) producing neurons and the anorexigenic Pro-opiomelanocortin (POMC) and Cocaine and Amphetamine regulated transcript (CART) neurons. There are I think like 11 total between the two classes, but those 4 are the big ones. The superficial way of describing how they respond to leptin and ghrelin is that the orexigenic neurons respond to insulin, glucose, fats, and of course leptin and then they send signals to the rest of the brain that you should not eat anymore. This could be a sensation of fullness or even nausea if you eat too much. One interesting thing about POMC is that it is further synthesized in other parts of the hypothalamus into opioids such as beta-endorphin. Excess opioid signaling in autism seems to be a major issue and of course opioids have strong effects on other neurotransmitter systems in the brain such as dopamine.

    Even though you didn't mention "leptin resistance" in this blog post, I am 99% sure you know what it is. Leptin resistance occurs when you paradoxically have high levels of leptin in the blood, yet the brain never gets the message that no more food is required whioh then causes the animal (which could be a human of course) to go into a state of hyperphagia (overeating). In a few studies on autism and the hypothalamus, the size of the hypothalamus overall seems to be decreased, and especially the anterior areas such as the arcuate nucleus. So high leptin levels could be partially the result of this feedback loop in the hypothalamus being dysfunctional due to morphological abnormalities. Simply decreasing the levels of leptin won't fix the problem as the receptors might be desensitized or the neurons might be unhealthy for any number of reasons including oxidative stress (which was directly mentioned in one paper I read on the subject).

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  2. Now excess levels of POMC (precursor to opioids) increases SIB:

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2577125/

    and POMC is supposed to be released in response to leptin as POMC is responsible for driving anoreigenic behavior, however, obviously in many people with autism obesity seems to paradoxically be over-expressed in the population. Ghrelin which is released in the gastrointestinal tract due to a lack of food, trigger orexigenic behavior by NPY/AgRP neurons being activated in the hypothalamus. In studies on mice and rats, injecting NPY into the hypothalamus will cause hyperphagia leading to obesity. Interestingly enough, NPY expression also seems to be one of the major drivers of the positive health benefits of caloric restriction and fasting (that is a topic for another day).

    So there seems to be some really strange stuff going on here even though to say the HPA axis is not super-duper complicated and I am just superficially explaining this because there are tons of feedback loops between different brain areas all influencing each other with respsect to appetite, temperature regulation, sex drive, etc.

    So lets just say there is a problem with excess ghrelin being produced because of some gut dysfunction. Well that would cause more NPY/AgRP signaling leading to the brain wanting to eat more. Eating more food would of course produce more glucose, fats, insulin, and leptin in the blood in response which could drive more leptin being produced in response and more leptin in the blood and more leptin signaling in the brain which would cause more POMC output possibly leading to higher levels of opioids that can directly drive some of the worst symptoms of autism.

    When working properly, these systems are supposed to inhibit each other and if inhibitory signaling is compromised (such as with GABA) then that could be a cause of the hiccups as well, but if ghrelin has its foot stuck on the gas pedal all the time, you can get excess leptin being produced which means simply reducing leptin won't get at the root of the problem, rather you might have to address excess ghrelin signaling as well. And like I said I am all speaking about this stuff superficially because it is not like you can just address X peptide/hormone and expect to get Y result because there are many more factors involved, but before you do an anti-leptin intervention you might want to look at what is potentially driving the high levels of leptin.

    Nonetheless, if you cannot determine what is driving the excess leptin (such as too much ghrelin) doing nothing is not an option with our kids and perhaps your suggestion of going directly after leptin signaling might be a prudent choice. After all, nobody really knows for sure what is going on here for sure (leptin itself was only discovered in 1994), otherwise we would not be here discussing such things here and there would be reliable and useful medical therapies for autism that didn't do more harm than good.

    One last thing I thought of was that of the positive benefits of fasting and the fact that if leptin is not being produced (because of fasting), then POMC signaling will be reduced, which of course will reduce opioid signaling as well and possibly leading to improved symptoms. So perhaps maybe attacking ghrelin and leptin at the same time might be the best approach since there is only so much you can do safely with drugs and other interventions to minimize one or the other.

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    1. To followup on ghrelin, when administered directly in high quantities into various brain areas, ghrelin had effects on overeating in the dorsal raphe nucleus, memory retention in the hippocampus (hyperplasticity), and anxiety in the DRN, amygdala, and hippocampus.

      https://www.ncbi.nlm.nih.gov/pubmed/14697239

      Any of that sound like familiar symptoms of a certain neurodisorder?

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  3. Hi Peter, Would blood tests like leptin, cholesterol levels, etc help you determine if you could be helped. Are there clinical considerations. I am struggling as you have laid out a lot of different approaches in this post alone -- how would you decide to trial?

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    1. I think leptin levels are just one of many considerations that could go into developing a personalized treatment plan. There may be hundreds of abnormal lab results, but you would not want hundreds of therapies. Many apparent dysfunctions can be traced back up stream to common points. Inflammation is a feature of many people’s autism, but there has been no universally effective therapy.

      In my son’s current Polypill, two of the therapies have a secondary effect of lowering leptin, but that was not why I chose them. It is increasingly clear that really good therapies will yield multiple beneficial biological benefits.

      People are different and that is why therapy needs to be tailored either into subgroups or individually. Leptin may be a biomarker for one such subgroup.

      I think it reflects a broadly disturbed hormonal system and what I call an over-activated immune system.

      If you have very high leptin, very high testosterone, low aromatase and are past puberty I think treating with estradiol should be effective and have broad benefits. This has been done in schizophrenia and also genetic low aromatase. If you are very young this would be unwise.

      People should have some anti-inflammatory elements in their autism therapy. My main one is atorvastatin, but verapamil has the secondary effect of lowering leptin, as well as increasing autophagy etc.

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    2. And then there is the other extreme - the very skinny kids on the spectrum who seem more like adhd. The thrill seekers looking for dopamine boosts who eat very well (healthy nutirent dense foods) yet would never gain a pound even if fed a diet of cakes and cookies. This is my son. And he has never had the "autistic large head" that is mentioned often here in the comments. Interestingly enough, we tested leptin for my son many years ago, along with other tests for biotoxin illness. His leptin was normal.

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  4. Just came across some novel, yet strange research on schizophrenia that might give us some more clues with respect to autism:

    Press Release (contains links to two papers):

    https://www.sciencedaily.com/releases/2017/03/170314081539.htm

    Now maybe my understanding is wrong on modern theories of schizophrenia, but I thought the leading theory these days was due to a lack of NMDA signaling in schizophrenia leading to impaired pyramidal cell firing. In these papers they suggest low levels of GABA in CSF and abnormal microglial activity have something to do with the condition. The GABA finding was especially puzzling based upon what I know (or at least think I know).

    So is this all due to a lack of glutamatergic signaling for driving inhibitory interneurons which leads to a lack of GABA release or is there a recycling problem going on. I would think high levels of GABA in schizophrenia might exacerbate problems, though I know higher GABA levels are related to higher levels of brainwave activity (gamma waves) and gamma waves seem to be impaired in schizophrenia for whatever reason. Nonetheless, with respect to autism and its links to schizophrenia I found this very interesting to think about.

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  5. Peter, speaking of hair loss brings me back to high dose biotin.

    I found this article about MS and high dose biotin as a promising treatment.

    Biotin, a vitamin that helps cells to produce energy, boosts nerve function in high doses, opening the door to a possible treatment for progressive forms of multiple sclerosis.

    I know that its initial effect fades over time, but in the article they used as much as 300mg to have results. My 10mg dose it's tiny comparing to MS dose.


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    Replies
    1. Petra, this seems to vary very much from person to person with all these B vitamins. Some people get a short term benefit, but then things turn negative. Lots of possible explanations exist.

      One option is just to find if you can use it two weeks on and one week off, for example. Like some people do with the L.reuteri probiotic.

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