Wednesday, 5 March 2014

PPAR alpha, beta and gamma in Autism, Heart Disease and Diabetes


In recent posts we have looked at PPARα (Peroxisome proliferator-activated receptor alpha) and PEA (Palmitoylethanolamide), which activates it.  Both appeared to me to have some very interesting properties.  PPARα has siblings - PPARβ, and PPARγ.  It may not come as a surprise that one of these is currently at the centre on clinical trials for autism.  But is it the right one?
Thiazolidinediones (TZDs) are agonists of PPAR gamma (PPARγ), a nuclear hormone receptor which modulates insulin sensitivity, and have been shown to induce apoptosis in activated T-lymphocytes and exert anti-inflammatory effects in glial cells. The TZD pioglitazone (Actos) is an FDA-approved PPARγ agonist used to treat type 2 diabetes, with a good safety profile. Pioglitazone is currently in Phase 2 trials for autism.

The full version of the earlier study was:-

In view of its established safety profile, the current results provide the rationale or further testing of pioglitazone in autism and other forms of ASD. 
It is interesting that  PPARγ agonists are currently used in type 2 (non-insulin dependent) diabetes because in my earlier post is was shown that activating PPARα could treat a nasty side effect of both type 1 and type 2 diabetes, Peripheral Neuropathy;  this is damage to the peripheral nervous system.  An example is sharp pain in the sole of your feet, even when lying down.
Fibrates are a class of drug identified in the 1930s and are used in accessory therapy in many forms of hypercholesterolemia, usually in combination with statins. Clinical trials do support their use as monotherapy agents. Fibrates reduce the number of non-fatal heart attacks, but do not improve all-cause mortality and are therefore indicated only in those not tolerant to statins.
Although less effective in lowering LDL and triglyceride levels by increasing HDL levels and decreasing triglyceride levels, they seem to improve insulin resistance when the dyslipidemia is associated with other features of the metabolic syndrome (hypertension and diabetes type 2). They are therefore used in many hyperlipidemias. Fibrates are not suitable for patients with low HDL levels.

In the 1990s, the mechanism of action was discovered;  fibrates activate PPARα.
Fibrates are the main PPARα activating drugs in use, but there do seem to be various problematic side effects.  In an earlier post we did discover a naturally occurring PPARα activator that seems to have no side effects or contraindications, PEA (Palmitoylethanolamide).

Heart Disease
Heart disease is the leading cause of death in developed countries and so is very well researched.  What is remarkable is how closely related autism is to heart disease.

Almost all of the ingredients in my autism Polypill are actually drugs normally given to people with heart disease and of course people with autism are known to be prone to heart disease.
Atherosclerosis is a chronic inflammatory disease as well as a disorder of lipid metabolism.  So is autism.
Let’s look what we can learn from research into PPARs in heart disease.

"Atherosclerosis is a chronic inflammatory disease as well as a disorder of lipid metabolism. The accumulation of cholesterol-rich lipoproteins in the artery wall results in the recruitment of circulating monocytes, their adhesion to the endothelium, and their differentiation into tissue macrophages. Lipid-loaded macrophages play an important role in the production of chemokines, cytokines, and reactive oxygen species in the early stages of lesion formation. Therefore mechanisms that limit macrophage cholesterol accumulation and/or prevent the production of inflammatory mediators all have the potential to inhibit lesion development.

The PPAR family is comprised of 3 different proteins: PPARα, PPARβ, and PPARγ. Natural ligands for these receptors include fatty acids and oxidized fatty acids. The relevance of PPAR pathways to metabolic disease is underscored by the use of the fibrates (PPARα agonists) and thiazolidinediones (PPARγ agonists) to treat hyperlipidemia and type 2 diabetes, respectively."


"PPAR signaling pathways influence macrophage gene expression and foam-cell formation. Ligand activation of PPARα and PPARγ, but not PPARβ/δ, inhibits the development of atherosclerosis in LDLR_/_ mice. Both systemic and local mechanisms might contribute to these beneficial effects. Previous studies have suggested that PPARα and PPARγ increase LXRα expression in macrophages and promote expression of ABCA1, which mediates cholesterol efflux to apoAI. Results from the study in this issue by Li et al.  suggest that PPARγ may also inhibit cholesterol accumulation in macrophages through direct regulation of ABCG1, which has been implicated in cholesterol efflux to HDL. Activation of each of the PPARs with selective agonists also inhibits the expression of inflammatory markers in the artery wall. These findings reinforce potential use of PPAR agonists as antiatherosclerotic therapies."

"The study by Li et al.  provides new insights into pathways regulating macrophage lipid accumulation and rounds out the family picture of PPARs in atherosclerosis. Both The study by Li et al. provides new insights into pathways regulating macrophage lipid accumulation and rounds out the family picture of PPARs in atherosclerosis. Both PPARα and PPARγ ligands were shown to protect against atherosclerosis in LDLR–/– mice and inhibit macrophage foam-cell formation. ligands were shown to protect against atherosclerosis in LDLR–/– mice and inhibit macrophage foam-cell formation. In contrast, the authors did not observe any effect from PPARβ activation. Given the discrepancies between PPARβ agonist effects in mice and primates, however, the possibility that PPARβ ligands may have beneficial effects on cardiovascular disease in humans is not excluded by the present study."

So it would appear that activating PPARα and PPARγ has benefit in heart disease, but likely not PPARβ.
It seems that the traditional PPARα activator drugs, the fibrates, are problematic.  PPARγ activators are widely used in diabetes therapy and there are safe choices.

In autism, a PPARγ activator has already been shown itself to be effective in initial phase 1 trials.  

Heart disease is well researched by clever, very well-funded, people so I am sure they will have figured out to trial PEA instead of Fibrates as a PPARα activator and of course to look at the benefits of Pioglitazone as a PPARγ activator.
Autism is not so well researched.  The PPARγ activator trial is proceeding slowly forward in Toronto.  The PPARα activator trial will commence shortly, but not with Fibrates.



  1. Peter what are your thoughts on possiblity of mitochondrial dysfunction and the problems in autism such as elevated leptin (almost all autism cases) aswell as decreased adiponectin (almost all cases aswell).
    Omega3 fatty acids are also known to increase adiponectin aswell.

    I have just been reading up a bit on the subject of fatty acids amides, it seems there are a alot of different types of them with a few of them looking promising as PPAR-alpha agonists such as Palmitoylethanolamide and Oleoylethanolamide (both naturally occurring in chocolate)

    Oleoylethanolamide decreases leptin and increases adiponectin

    OEA (Oleoylethanolamide) has been shown to increase oxytocin levels in the BRAIN in a manner dependent on PPARα activation[26] and oxytocin itself stimulates the production of OEA in adipocytes (following intracerebroventricular infusion and without stimulating serum OEA or cannabinoid metabolites[23]) and appears to also require the presence of PPARα

    Due to a positive feedback mechanism between OEA and oxytocin, both agents are implicated in increasing levels of the other. Increases in central oxytocin appear to be able to be transported towards adipocytes and increases local OEA production

    Oleoylethanolamide stimulates lipolysis by activating the nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR-alpha).

    Peroxisome proliferator-activated receptor alpha plays a crucial role in behavioral repetition and cognitive flexibility in mice

    'Ppar-α −/− mice display enhanced behavioral perseveration and repetition.'

    'Ppar-α loss of function promotes an NMDA hypofunction-like condition'

    'Risperidone improves repetitive behavior in Ppar-α null mice'

    'Pharmacological activation of Ppar-α reduces NMDAR antagonist–induced locomotion and reduces repetitive behavior in BTBR T+ tf/J mice.'

    Administration of URB597, Oleoylethanolamide or Palmitoylethanolamide Increases Waking and Dopamine in Rats

    mitochondrial dysfunction->impaired ppar-alpha functioning->malfunctioning of fat metabolism->bad fat metabolis=less signals to the brain

    Also might sound a bit far fetched but to me it seems that the brain has alot of 'sensors' controlling the release of hormones,neurotransmitters and peptides and that the driving force behind the release of these are regulated by things such as osmoregulation (vasopressin, oxytocin), injury/sickness/fever (pge2, heatshock proteins), detection of food intake, including sensors in the gut (ghrelin/leptin balance, insulin and adiponectin).

    In normal people it would go something like this:
    normal/high adiponectin release by fat cells->detection by the brain that precious stored calories around the waste are being burned-> hormetic response by the brain releasing a pro-social neurosoup that would make one more social->better team work/fitting into a group->improving survival by increasing the chances by getting access to food and water

    1. Aspie1983, I did try Palmitoylethanolamide (PEA), but it had no effect. Sytrinol which contains tangeretin, a PPAR gamma agonist, has a good effect that last for just a few days. Thiazolidinedione class drugs, used to treat type 2 diabetes, are also PPAR gamma agonists and they have shown a positive effect in autism research.

      For some people, autism appears like a metabolic syndrome with numerous different imbalances, but it is hard to see if there is a single starting point. I doubt there is, but fixing certain dysfunctions does seem to be therapeutic.


Post a comment