PPAR Alpha: The Protein That Revs Up Metabolism and Ketosis

PPAR alpha is a very important protein for metabolizing fat and for weight loss.

If you want to interpret your genes, you can put them into SelfDecode.

Intro to PPAR-alpha


I’ve spoken about PPAR gamma.  This post is about its related kin PPAR alpha, which has somewhat different effects.

PPAR-alpha is a protein (transcription factor) that increases fat breakdown in the liver and elsewhere.  Good metabolism is important for energy production.

PPAR-alpha alters the expression of a large number of genes.

PPAR-alpha is activated under conditions of calorie restriction and is necessary for the process of ketogenesis, a key adaptive response to prolonged fasting.

PPAR-alpha is mainly found in the liver and brown fat, followed by the heart and kidney. Lower PPAR-alpha expression levels are found in the small and large intestine, muscle and adrenal gland.

The Benefits of PPAR Alpha


Core Function

Activation of PPAR-alpha promotes uptake, utilization, and breakdown of fatty acids by increasing genes involved in fatty acid transport, binding, activation, and oxidation.

Besides increasing fat utilization, it increases glucose production and bile synthesis/secretion (R).

PPAR-alpha is critical for normal responses to fasting.  Without PPARa, there is major metabolic disturbances including low levels of ketone bodies, hypoglycemia, and fatty liver.

PPAR alpha helps with the detoxification of drugs and toxins (R).


PPAR alpha inhibits animal models of autoimmune disease such as Multiple Sclerosis (R).

PPAR alpha is protective against heart disease by inhibiting macrophage inflammation and increasing cholesterol efflux (via LXR and ABCA1) (R).

Interesting Mechanisms

PPAR-a inhibits COX2 (R).

PPAR-a can help increase IGF-1, which will help you build muscle.  Mice without PPAR-alpha have 40% less IGF-1 (R).

PPAR alpha increases UCP-3 (R), which is important for fat loss.  This and other mechanisms make PPAR alpha important for fat loss.

PPAR alpha increases MTHFR gene production (R).

Technical: PPAR alpha increases PXR (R), FGF-21 (R), CPT1A (R), HNF4, Catalase and LXRABCA1 (R), UCP3 (R), MTP, FATP, MDR2 (R), SREBP1c (R).

Males vs Females: PPAR Alpha Increases Th2 Immunity and Suppresses Th1 Immunity


Males are more prone to Th17 dominance, while females are more prone to Th1 dominance (R).

This is because Androgens increase PPAR alpha, which cause inhibition of Th1 dominance.  At the same time, men have lower PPAR gamma, which leads to Th17 dominance (R).

To some extent, Th1 and Th17 ‘compete’ with each other.  IL-2 produced by Th1 cells activates STAT5, which competes with STAT3 (which produces Th17 dominance) (R).

PPAR Alpha Negatives

PPAR-a causes insulin resistance in the liver (R).

As mentioned, PPAR alpha can increase Th17 dominance (R).

How to Increase PPAR Alpha

Omega-6/Linoleic acid metabolites/Arachidonic acid, as well as other polyunsaturated fatty acids, are the main ways we naturally activate PPAR alpha (R).

This is probably why omega-6’s have some benefits in various studies.  It’s good to get a good balance of DHA/EPA, MUFAs and Omega 6’s, with some saturated fat (not excess like some paleo recommends).

Unlike PPAR gamma, PPAR alpha has been found to be activated by both saturated and unsaturated fatty acids, such as oleic acid, palmitic acid, linoleic acid, and arachidonic acid (R).

PPAR alpha is also stimulated by stress, cortisol, and insulin” href=”https://selfhacked.com/2016/07/29/insulin-101/”>insulin (R).

PPAR alpha inhibitors

PPAR Alpha Gene

SelfDecode is the best gene analyzer around and helps you interpret your genetics from 23andme and ancestry.

You must buy 23andme to see if you have these genes.

  1. RS135551 (PPARA)
  2. RS1800206 (PPARA)
  3. RS4253655 (PPARA)
  4. RS4253728 (PPARA)
  5. RS4823613 (PPARA)

Circadian Control of PPAR Alpha (Technical)

Bottom Line: Circadian rhythm disruptions will cause problems with PPAR alpha.

PPAR alpha has a circadian rhythm in several organs, including the heart, muscles, liver, and kidney (R).

PPAR alpha is controlled by CLOCK and BMAL1 genes. PPAR alpha increases BMAL1 and BMAL1 increases PPAR alpha (R).

PPAR alpha directly regulates the gene activity of Bmal1 and Rev-erb alpha.  Per2 interacts with nuclear receptors including PPAR alpha and Rev-Erb alpha and serves as a co-regulator of nuclear receptor-mediated transcription (R).

Drugs that increase PPAR alpha also increase the production of and reset circadian expression of Bmal1, Per2, and Rev-erb alpha in mouse livers.  These drugs can phase advance the rhythmic expression (cause it to start earlier) of Bmal1, Per2, and Rev-erb alpha in several mouse peripheral tissues (R).


  1. JW

    I should note that my past success with CLA was while not actually trying to modify my diet or lose weight. The weight loss was somewhat accidental, and I was probably eating the Standard-American-Diet.

  2. JW

    So I dug in a little further… Livewello lists about 18 different SNP’s associated with PPARA, with rs1800206 being the most studied. I have several other minority PPAR SNP’s, like:

    (just minority PPARA SNPs):
    rs4253662 AG, occurs in 2% of population
    rs4253728 AA, occurs in 10% of population
    rs4823613 GG (10% of population)
    rs4253754 AG (11% of population)
    rs5766741 CC++ (0%?? of population, not sure how to interpret that)

    Always had high LDL and struggle to get my HDL to normal (fish oil, niacin, etc). I’ve been moderately overweight most of my life, since my teenage years. Before 12-years-old I was “bean-pole skinny”.

    Anyways, I did extensive blood-work before and I will do blood-work after. One confounding variable is that I’m also doing a probiotic/prebiotic experiement, which I’ll have ubiome before and after.

    So, I’m curious about PPARA activators. I’ve long-term (>10years) taken these activators in your list (unaware that they related to PPARA, of course):

    DHA, resveratrol, epimedium (only 2 years)

    I’ve experimented briefly with other things in your list.

    My weight-loss has been very slow in the last 6 weeks of keto. I’m mostly doing the BP butter-coffee, which I find is an amazing tool to kill my appetite ALL DAY. Instead of eating being driven by cravings, it’s now more driven by a more legit hunger feeling in my belly, which comes at around 7pm. So I’m skipping lunch often, and only really getting one meal, and I figure I’m under 1000 calories. At such low calories I’d assume I’d lose weight much faster, but I’ve only lost about 5lb in 6 weeks.

    The PPARA knockout mice have problems with fasting response. I’m guessing that I do as well. Although fasting like this has amazingly not impacted my hunger (it’s not any willpower struggle for me), I’m thinking that my body must be responding by conserving strongly, like starvation response or something.

    There’s a body-building site that mentions the following as significant PPARA activators:

    Most interestingly, they list:

    1) CLA. About 10 years ago I took high dosage of this for a few months, about 6 big pills per day (don’t remember dosage). Across maybe 2 months I lost over 15lb, which stayed off a couple of years. But there’s a confounding variable. It was also a period of my life where I was swing dancing 4 nights a week, which is a healthy amount of exercise. However, the dancing was constant for a few years, while the CLA was only a few months, and I recall the timing being more correlated with the CLA. I had some weird metabolic feeling with the CLA, which is hard to explain, but distinct enough that I’d recognize it if I felt it again. It seemed to me that the CLA effect wore off after a few months.

    2) Sesamin. I’m going to start taking this. I’m guessing that the mixed response from people is 2 factors: genetic (like PPARA genes), and fasting-related. I’m guessing that these PPARA agonists are most effective when combined with fasting.

    3) TTA. I’m also just starting to take this.

    I’ll report back.

  3. JW

    Regarding rs1800206. Ok, I just can’t ignore your last statement: “If you have the G allele, I wouldn’t even attempt ketosis.”

    I’m apparently one of the unlucky 2% minority that has the G allele. Also, I’m about 6weeks in to a ketogenic diet.

    Can you elaborate why I should avoid Ketosis. I noticed also that the GG phenotype is nonexistant out there, suggesting that GG is lethal (it should exist by chance), while AG is not.

    I’m able to get into ketosis. Not sure if I’m less effective than others. One curious thing is that I’m never in ketosis in the morning, in spite of being very low carb. You’d expect that mornings would be easiest to be in Ketosis (overnight fast), but not for me.

    If G is associated with diabetes, insulin resistance, etc, then avoiding carbs should be beneficial, right?

    Another note, I’m able to comfortably eat a very low amount of calories, especially since fats kill my appetite for almost 8 hours. It seems I’m under 1200 calories yet only very slowly losing weight (<1lb per week). So maybe my ketogenic fat burning system is working poorly.

      • JW

        Ok, here’s 13 days of results:


        The slope of my weight loss has improved 4.2x. I haven’t modified my diet or anything else. A couple of times I’ve felt hotter than normal, which might be related. Yesterday I also added Berberine, which will later become a confounding factor, but personally I’m closing the book on CLA/TTA/Sesamin as a success for me.

          • JW

            Data is at 4 months now. I hit a plateau for 10 days, but I’ve lost 28 lb overall in about 4 months. At the previous rate, before understanding PPAR-A, this progress would’ve taken me just under 2 years instead.

            The full post on reddit/keto:

            Since CLA/TTA/Sesamin are basically working like PUFA’s (after further investigation), I’m going to experiment with high-dose fish oil with my morning butter-coffee (and less butter). Fish oil will be taken by tablespoon, not in the coffee, to prevent rancidity.

            Also, I’m experimenting with refeeds. The data behind Leptin and refeeds is pretty compelling. Leptin response is asymmetric, meaning you can restore leptin levels by refeed much stronger/faster than you deplete by caloric restriction. So weekly/biweekly refeeds should have a significant benefit on metabolism.

      • JW

        It seems that my reply didn’t go through. Anyways, the following URL shows my weight loss progress on keto diet before and after adding TTA, CLA, and Sesamin:


        I’ve increased the weight-loss-slope from about half pound per week to about 2 pounds per week. 13 days of data maybe not enough to be confident, but I think it looks like a successful bio-hack.

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