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Showing posts with label metformin. Show all posts
Showing posts with label metformin. Show all posts

Wednesday, 3 October 2018

Ketones and Autism Part 6 - Capric Acid (C10) for Mitochondrial Disease, in Particular Complex 1, plus more on Metformin



Capric Acid (C10) is so named because it smells like a goat (Goat in Latin = Caper)
Photographer: Armin Kübelbeck, CC-BY-SA, Wikimedia Commons

Rather than Goaty acid, C10 is called Capric acid, or indeed Decanoic acid (after its 10 carbon atoms). Today’s post is indirectly again about ketones, because if you eat a Ketogenic Diet (KD) you are likely to consume a fair amount of Capric acid (C10).
I have written a lot in this blog about mitochondria, even though I do not think my son has mitochondrial dysfunction. Clearly many people with autism do have a lack of one or more of the critical mitochondrial enzyme complexes that allow glucose to be converted to ATP (usable energy), by the clever process OXPHOS (Oxidative phosphorylation).

The “rate limiting” enzyme is usually Complex 1, meaning that is the one it is most important not to be short of.
Another favourite, but obscure, subject of this blog is PPAR gamma.

Peroxisome proliferator-activated receptors (PPARs) are a group of proteins that function as transcription factors regulating the expression of certain genes. Transcription factors are particularly important because they trigger numerous effects.
PPAR gamma plays a key role in fat storage and glucose metabolism, but has other functions. 

Activation of PPAR-gamma by Capric acid (C10) has been shown to increase the number of mitochondria, increase the mitochondrial enzyme citrate synthase, increase complex I activity in mitochondria, and increase activity of the antioxidant enzyme catalase. 
So, if you have autism and impaired mitochondrial function, C10 may well give a benefit because it can increase the peak power available to your brain.


The Ketogenic diet (KD) is an effective treatment with regards to treating pharmaco-resistant epilepsy. However, there are difficulties around compliance and tolerability. Consequently, there is a need for refined/simpler formulations that could replicate the efficacy of the KD. One of the proposed hypotheses is that the KD increases cellular mitochondrial content which results in elevation of the seizure threshold. Here, we have focussed on the medium-chain triglyceride form of the diet and the observation that plasma octanoic acid (C8) and decanoic acid (C10) levels are elevated in patients on the medium-chain triglyceride KD. Using a neuronal cell line (SH-SY5Y), we demonstrated that 250-μM C10, but not C8, caused, over a 6-day period, a marked increase in the mitochondrial enzyme, citrate synthase along with complex I activity and catalase activity. Increased mitochondrial number was also indicated by electron microscopy. C10 is a reported peroxisome proliferator activator receptor γ agonist, and the use of a peroxisome proliferator activator receptor γ antagonist was shown to prevent the C10-mediated increase in mitochondrial content and catalase. C10 may mimic the mitochondrial proliferation associated with the KD and raises the possibility that formulations based on this fatty acid could replace a more complex diet. We propose that decanoic acid (C10) results in increased mitochondrial number. Our data suggest that this may occur via the activation of the PPARγ receptor and its target genes involved in mitochondrial biogenesis. This finding could be of significant benefit to epilepsy patients who are currently on a strict ketogenic diet. Evidence that C10 on its own can modulate mitochondrial number raises the possibility that a simplified and less stringent C10-based diet could be developed.

Capric Acid (C10) as a PPARγ agonist

As shown in the above study the mechanism by which C10 benefits the mitochondria is via PPARγ agonism.

Here is another study confirming that C10 is indeed a PPARγ agonist.


Background: Mechanism of action of medium chain fatty acid remains unknown.

Results: Our results show that decanoic acid (C10) binds and activates PPARγ.

Conclusion: Decanoic acid acts as a modulator of PPARγ and reduces blood glucose levels with no weight gain.

Significance: This study could lead to design of better type 2 diabetes drugs.


Other PPARγ agonists
PPARγ agonists have been covered previously in this blog and we know that glitazones, a class of drugs for diabetes, do improve some types of autism. Glitazones are PPARγ agonists.

Metformin, a very widely used drug for type 2 diabetes, works differently to Glitazones, but I did suggest a while back it should help some types of autism. Last year it was indeed found to be beneficial in Fragile X.


 "Basically, it's something like a wonder drug," Sonenberg said.
The study suggests that metformin might also be used to treat other autism spectrum disorders, said Ilse Gantois, a research associate in Sonenberg's lab at McGill.
"We mostly looked at the autistic form of behaviour in the Fragile X mouse model," explained Gantois, who is co-lead author with McGill researchers Arkady Khoutorsky and Jelena Popic. "We want to start testing other mouse models to see if the drug could also have benefits for other types of autism."

Metformin is very cheap and has been used in humans for 60 years. It is another example of re-purposing a drug from Grandpa’s medicine cabinet to treat Grandson’s autism. 

Metformin has been trialled to combat obesity in idiopathic autism caused by antipsychotics. It did help with weight gain, but no comments were made about behavioural improvements, but then those studied were on antipsychotic drugs, which might mask such effects. 
Glitazone-type drugs appear more problematic than Metformin.

There are natural PPAR gamma agonists and they are often used to lower cholesterol, lower blood sugar and improve insulin sensitivity.
Sytrinol, a product containing flavanols tangeretin and nobiletin does indeed have a positive effect on some people’s autism, but for most people (but not all) the effect is lost after a few days.

Our doctor reader Maja, did suggest combining it with a PPARα agonist to see if the effect might be maintained.
This combination has indeed been researched for type 2 diabetes.               

The effect of dual PPAR alpha/gamma stimulation with combination of rosiglitazone and fenofibrate on metabolic parameters in type 2 diabetic patients.


There actually is another natural substance that is an agonist of both PPARγ and PPARα, Berberine, the alkaloid long used in Chinese medicine.
In the research it is suggested that BRB localizes in mitochondria, inhibits respiratory electron chain and activates AMPK”, which is not what you would want. But this may not be correct.

People who like supplements might want to follow up on Berberine.
Berberine is used by many people with diabetes and a few with autism, for all kinds of reasons, from mercury to GI problems.

Berberine is a potent agonist of peroxisome proliferator activated receptor alpha.


Although berberine has hypolipidemic effects with a high affinity to nuclear proteins, the underlying molecular mechanism for this effect remains unclear. Here, we determine whether berberine is an agonist of peroxisome proliferator-activated receptor alpha (PPARalpha), with a lipid-lowering effect. The cell-based reporter gene analysis showed that berberine selectively activates PPARalpha (EC50 =0.58 mM, Emax =102.4). The radioligand binding assay shows that berberine binds directly to the ligand-binding domain of PPARalpha (Ki=0.73 mM) with similar affinity to fenofibrate. The mRNA and protein levels of CPT-Ialpha gene from HepG2 cells and hyperlipidemic rat liver are remarkably up-regulated by berberine, and this effect can be blocked by MK886, a non-competitive antagonist of PPARalpha. A comparison assay in which berberine and fenofibrate were used to treat hyperlipidaemic rats for three months shows that these drugs produce similar lipid-lowering effects, except that berberine increases high-density lipoprotein cholesterol more effectively than fenofibrate. These findings provide the first evidence that berberine is a potent agonist of PPARalpha and seems to be superior to fenofibrate for treating hyperlipidemia.


                                                                                                                                     

Sources of Capric Acid (C10)
Goat milk is a good source of capric acid.
Capric acid is 8-10% of coconut oil and 4% of palm kernel oil

Capric acid is a large component (about 40%) of the less expensive MCT oil supplements.


1.2. Fatty acid composition in goat milk fat Average goat milk fat differs in contents of its fatty acids significantly from average cow milk fat, being much higher in butyric (C4:0), caproic (C6:0), caprylic (C8:0), capric (C10:0), lauric (C12:0), myristic (C14:0), palmitic (C16:0), linoleic (C18:2), but lower in stearic (C18:0), and oleic acid (C18:1) (Table 1). Three of the medium chain fatty acids (caproic, caprylic, and capric) have actually been named after goats, due to their predominance in goat milk. They contribute to 15% of the total fatty acid content in goat milk in comparison to 5% in cow milk (Haenlein, 1993). The presence of relatively high levels of medium chain fatty acids (C6:0 to C10:0) in goat milk fat could be responsible for its inferior flavour (Skjevdal, 1979). 

             
Conclusion
If someone responds well to coconut oil or cheaper MCT oil the reason may have more to do with PPAR gamma and improved mitochondrial function than anything to do with ketones and what they do.
Cheaper MCT oils are mainly a mixture of C8 and C10. To maximize the production of the ketone BHB you really want just C8, but if what you really need is a PPAR gamma agonist, to perk up your mitochondria, it is the C10 you need.
You may indeed benefit from both ketones and agonizing PPAR gamma, in which case you either follow the Ketogenic Diet, or supplement BHB, C8 and C10.
I think this explains why some people with autism reportedly respond well to teaspoon-sized doses of cheaper MCT oil or small amounts of coconut oil.
If you have Complex 1 mitochondrial dysfunction then a dose of Capric acid (C10) is likely to help.
Berberine may, or may not be, as effective as C10. I doubt we will ever know. I think C10 is the better option. 
I wonder when the Canadian researchers will publish their results showing whether Metformin is beneficial beyond Fragile X syndrome. They do not really know why it helps, but that is a repeating theme in medicine.  It is a cheap safe drug, so it would be a pity to waste time finding out if it could be repurposed for some autism.



Monday, 8 May 2017

Pan-agonists of PPARs and PGC-1α in Mitochondrial Disease, Autism and Sport


Today’s post should be of interest to those concerned about mitochondrial disease and mTOR.


mTOR is a very important signaling cascade that often dysfunctional in autism. Many aspects of autism and its comorbidities can be traced back to mTOR.
The going is easier with a PPAR pan-agonist 

mTOR integrates the input from upstream pathways, including insulin, growth, and amino acids.   mTOR also senses cellular nutrient, oxygen, and energy levels. The mTOR pathway is a central regulator of metabolism and physiology, with important roles in the function of tissues including liver, muscle, adipose tissue, and the brain.  It is dysregulated in human diseases, such as diabetes, obesity, certain cancers and indeed autism.

One important process affected by mTOR is the creation of new mitochondria in your cells.  Each cell has many mitochondria, but in some people there are not enough and/or they may not work properly.  
In the above post we saw that Oxidative phosphorylation (or OXPHOS in short) is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing energy.  This takes place inside mitochondria.

The five enzymes required have simplified names: complex I, complex II, complex III, complex IV, and complex V.

The most common problem in autism is a lack of complex 1, this leads to a lack in the production of energy (ATP) in cells.  In your muscles this will appear as a lack of exercise endurance and in your brain as a lack of cognitive function.

On that rather intimidating chart (below), all about mTOR, tucked away at the bottom right is PGC-1α.
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is the master regulator of mitochondrial biogenesis.

PGC-1α may be also involved in controlling blood pressure, regulating cellular cholesterol homoeostasis, and the development of obesity.

PGC-1α is thought to be a master integrator of external signals. It is known to be activated by a many factors, including:-


·         Exercise  (gradual endurance training)


·         PPARδ , PPARγ and it was thought PPARα


·         AMPK (Metformin, or AICAR)


·         Sirt-1 (resveratrol and other polyphenolic ‎compounds)

Interestingly, massage therapy appears to increase the amount of PGC-1α which leads to the production of new mitochondria. Many autism parents believe in various massage therapies. 

Metformin is a very old drug to treat diabetes, it does activate AMPK but unfortunately it also inhibits the Complex 1 mitochondrial enzyme. This might explain why one reader of this blog found it had a negative effect in her son.  In some types of cancer metformin can be used to “starve” the cancer cells of energy and stop them proliferating.

AICAR was thought to have been used by cyclists in the 2009 Tour de France, it is a heart drug from the 1980s. It activates AMPK and increases nitric oxide production from endothelial nitric oxide synthase.













Here is the lower right part enlarged:-





  

The above chart, while complex does not give the complete picture regarding PPAR.

It appears that the type of PPAR that is needed to activate PGC-1α  is actually PPARδ  (PPAR delta). For a long time researchers thought it was PPAR α (PPAR alpha).


PGC-1 alpha induces mitochondrial biogenesis in muscle and its activity has been related to insulin sensitization. Here, we report that fibrates induce PGC-1 alpha gene expression in muscle both in vivo and in vitro. However, only activation via PPAR delta but not PPAR alpha underlies this effect. PPAR delta induces PGC-1 alpha gene transcription through a PPAR-response element in the PGC-1 alpha promoter. Moreover, PGC-1 alpha coactivates the PPAR delta-responsiveness of its own gene. A further positive autoregulatory loop of control relies on the induction of PPAR6 expression by PGC-1 alpha. These data point to a distinct value of PPARdelta rather than PPAR alpha agonists in the improvement of oxidative metabolism in muscle.



Peroxisome proliferator-activated receptors (PPARs)

There was a post in this blog a long time ago about all the PPARs. There are three types (alpha, delta and gamma) just to confuse us, sometimes delta is called beta.

  • α (alpha) - expressed in liver, kidney, heart, muscle, adipose tissue, and others
  • β/δ (beta/delta) - expressed in many tissues but markedly in brain, adipose tissue, and skin
  • γ (gamma) - although transcribed by the same gene, this PPAR through is expressed in three forms:
    • γ1 - expressed in virtually all tissues, including heart, muscle, colon, kidney, pancreas, and spleen
    • γ2 - expressed mainly in adipose tissue
    • γ3 - expressed in macrophages, large intestine, white adipose tissue.

It does seem that activating alpha, gamma and delta has potential benefit.

The PPAR alpha agonist PEA is available as a supplement and as food for medical purposes In Italy and Spain.  It has been proposed for various inflammatory and pain syndromes. A large trial at a Skoda car factory in 1972 showed that PEA was protective against flu and the common cold.


Fibrate drugs are PPAR alpha agonist drugs used to lower cholesterol. A key point here is that these drugs also activate other types of PPAR as well.
PPAR gamma agonists are widely used to treat diabetes.  They improve insulin sensitivity and decrease some inflammatory responses. They lower cholesterol.
PPAR delta has various antidiabetic effects and agonism of PPAR delta changes the body's fuel preference from glucose to lipids. Recently it was shown that PPAR delta can be activated to promote biogenesis of mitochondria.
It does appear likely that there is some interaction between the PPARs.
Using the mild PPAR gamma agonist, Sytrinol, which gives a long term cholesterol lowering effect, gives a short term cognitive and behavioral improvement in autism.
Pioglitazone is used to lower glucose levels in type 2 diabetes and is a PPAR gamma agonist.  It has been shown to have a positive effect in autism and more trials are in progress. It also binds to a lesser extent to PPAR alpha.
Our reader Maja is investigating whether Sytrinol will maintain its initial good effect when combined with a mild PPAR alpha agonist, like PEA. 

Pan-agonists of PPAR

Bezafibrate appears to be the best known “pan-agonist” of PPAR alpha, gamma and delta.

The PPARpan-agonist bezafibrate ameliorates cardiomyopathy in a mouse model of Barth syndrome 

   
Bezafibrate as treatment option in patients with mitochondrial complex I (CI) deficiency

These results support bezafibrate as a promising treatment option for specific subgroups of patients with CI deficiency.

Less well known is the natural substance Berberine. 




The multifaceted drug Telmisartan, from a recent post, is also a pan-agonist of PPARs. It is usually quoted as being a PPAR delta agonist. 




AICAR

The drug AICAR is thought of as an AMPK activator rather than a PPAR agonist, but it does affect all three types of PPAR.

Treatment with AICAR induced gene expression of all three PPARs, but only the Ppara and Pparg regulation were dependent on AMPK.


Conclusion

It looks like some athletes, seeking an advantage, are already using the above strategies to improve their exercise endurance; having more mitochondria is of course a competitive advantage.  A list of all the substances banned in sport might be another good source of therapies not only for autism, but also dementia.
Since mitochondrial dysfunction is a feature of Parkinson’s, Huntington’s and Alzheimer’s there are some investigations ongoing. There is even a trial to perk up the mitochondria in people with Bipolar using Bezafibrate.
It is odd that Sytrinol has only a short term positive effect in most people with autism, although our reader RG’s daughter has a long term benefit. I suspect some people may need a pan-agonist, there may be some interaction/crosstalk/ feedback that we are not aware of.
It would be nice to have some data on the relative potency of Bezafibrate,  Telmisartan and Berberine across alpha, delta and gamma receptors, otherwise we are left with trial and error.
The advantage of Berberine is that it is an OTC supplement.
AICAR is also interesting.









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