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Introduction

ppar-activity

PPAR is a protein that binds to DNA to increase gene expression i.e. to produce other important proteins.  There are three types: alpha, beta/delta, and gamma.  This post is mainly about the gamma variety, but the other two often have similar effects.

PPAR-alpha is probably the healthiest kind, followed by delta and gamma.

The natural compounds listed here are so-called “partial agonists of PPARgamma.”  The drugs that activate PPARgamma (thiazolidinediones) are considered “full agonists” and have somewhat of a different effect.

The partial agonists are weaker, but also have fewer side effects.

To activate PPARs, you need to also activate retinoic acid receptors (RXR). RXR is activated by the vitamin A found in animals (retinol), not plants.  Although beta-carotene, which is found in plants, converts to it.

See the picture below how PPAR partners with RXR to bind to unique DNA regions called PPAR-gamma response element (PPRE) (R).

gt93484.f1

PPAR gamma can be activated in various cells, but most significant in fat cells/adipose tissue, followed by the colon, then kidney, then liver cells.

The Good

PPAR Compressed

PPAR gamma (PPARy) most significantly increases insulin sensitivity and insulin secretion, which decreases blood glucose (R, R2).

PPARs are generally anti-inflammatory and block inflammation (MAPK, NF-kappaB, and others). PPARs induce an immune profile more similar to Th2 dominance.  See all the effects in the image below (flat bar indicates that it blocks an effect):

It’s not surprising then that PPAR gamma activation is one mechanism by which mice can live longer (and maybe people) (R).

PPARy increases FGF-21. FGF-21 has been shown to benefit insulin sensitivity, blood glucose, cholesterol profile and decrease body weight in obese mice and diabetic monkeys, without increased cancer or other side effects (R).

FGF-21 leads to increased energy expenditure, fat utilization, and excretion (R).

PPARs also cause the browning of white fat (good), which should help combat obesity.

Even though PPAR gamma increases FGF-21, which in turn increases energy expenditure, obese people have higher levels of FGF-21 (R). This is simply because in the modern environment we just eat way too much for the amount of exercise we do.

PPAR gamma decreases inflammation in your heart and reduces cholesterol (R).

PPAR gamma has also been shown to reduce blood pressure in rats bred to have high blood pressure. (R).

Through these mechanisms, it’s believed that it decreases heart disease (R).

Diseases such as Multiple sclerosis and Alzheimer are associated with lower PPARgamma (R).

PPAR gamma decreases inflammation and can help IBD (Crohn’s, colitis(R).  PPAR gamma plays a relatively large role in colon cells.

PPAR gamma increases ApoE (R), which 25% of the population have lower levels of and is implicated in Alzheimer’s.  ApoE is an anti-inflammatory, anti-oxidant and junk removal protein.  It also lowers cholesterol.

PPAR gamma increases PON1 (R), which is an antioxidant and protects your heart.  It’s important for handling pesticides.

Technical: PPAR gamma increases lipoprotein lipase, CD36, LXR alpha, and ABCG1 (R).

The Bad

obesity_348926726

PPAR gamma can cause weight gain in some ways, even though it decreases it in other ways.  Overall, it seems to promote more weight gain, whereas PPAR alpha  seems to promote more weight loss.

PPAR gamma can cause an increase in weight by increasing food intake, the production of fat cells and also makes fat cells bigger by increasing the uptake of fat and glucose in these cells (R).

When mice are bred without PPAR gamma, they don’t get fat on a high-fat diet (R).

However, PPARs also cause weight loss by increasing energy expenditure and the browning of white fat.

My guess is that whether you gain or lose weight will depend on your caloric intake and other factors.

CLA is a popular weight loss supplement. One component, t10c12, inhibits PPAR gamma. Another component, c9t11, activates PPAR gamma (R).

Berberine is also a popular weight loss supplement that inhibits PPAR gamma (R).

In cancer cells, PPAR gamma has been shown to be involved in tumor growth (R). Activation, in general, could theoretically increase your risk for cancer.

However, that’s not always the case. Honokiol is a supplement that increases PPARy in fat cells but decreases it in some cancer cells. Also, it reduces weight gain in diabetes and doesn’t increase fat cells (RR2, R3). So substances can modify PPARy differently.

PPARs are not good for bone density.  They increase bone destroying cells (osteoclasts) and decrease bone-producing cells (osteoblasts).

It’s been proposed that Vitamin D may cause weight loss because by binding to the Vitamin D Receptor it ‘crowds out’ PPAR gamma from binding to DNA.  This causes it to become less active and less effective, which causes weight loss (R).

PPARs increase sodium and fluid retention.

On the skin, PPAR gamma increases sebum, which leads to acne. (R).

My PPAR Gamma Theory

shutterstock_324768497

My theory is that PPARgamma is somewhat protective in the modern environment of abundant food.  This is because you have more leeway by being able to eat more and having that go into fat storage instead of stressing your body in other ways and causing inflammation. It also gives you more leeway by burning more calories via increasing energy expenditure.

From my clients and informally questioning people over the years, I’ve noticed that people who are capable of gaining weight relatively easily are generally healthier if they restrict their calories. The problem is, these same people don’t feel the negative effects/inflammation of eating too much in the short term.

Obese people only start to feel worse when they become obese because it’s an independent cause of inflammation. By then they are addicted to eating and it’s hard to cut back because they’ve created a new homeostasis.

Good eating habits need to be formed from a young age, not when you’re already obese. This is why I think the Japanese and Koreans are thin even though they eat plenty of junk food: they have good eating habits from a young age.

The thin people who never had to deal with being overweight generally experience the most inflammation. I think low PPARy is in part responsible for that.

Scientists have found that those with type 2 diabetes who were of normal weight around the time of their diagnoses were twice as likely to die during the study period, compared with those who were overweight or obese (R). This is because of increased inflammation.

When I see people who are thin in the modern environment who don’t try hard to eat less, that signals a problem to me. In this environment of abundant and amazing food, eating less should be a struggle.  A big part of that, I believe, is low PPAR activation.

So if you are capable of putting on weight and you don’t suffer from chronic inflammation, then congratulations – your genes are more suited for the modern environment (at least in one way).  But you’re also at risk for putting on weight if you don’t watch yourself.

The only people who have it worse than the thin people who don’t try to lose weight are the obese people who are very Th2 dominant (e.g. severe allergies and asthma). These people are lectin sensitive, which causes leptin resistance and they are obese no matter what they do as long as they consume lectins (think Dave Asprey).

These people might have relatively higher PPARs (compared to the thin) and are always Th2 dominant (in my experience). This makes sense because PPARs shifts your system to Th2 dominance.

Indeed, PPARy’s necessary partner in crime (RXR) also shifts the immune system to a Th2 profile. RXR is controlled by Vitamin A/Retinol. Excess vitamin A will, therefore, worsen Th2 dominance but help you if you’re Th1 dominant (R).

It’s interesting that the subtype of PPAR gamma (2) that is found in fat cells is also found in intestinal cells (R), highlighting the link between being thin and having intestinal problems.

The PPAR gamma and AMPK Tradeoff

AMPK is a very healthy pathway that activates SIRT1, increases longevity, lowers blood glucose and causes weight loss. The two most effective weight loss drugs are metformin and berberine, which work most prominently by activating AMPK.

The problem is that AMPK inhibits PPAR gamma (R) and, indeed, metformin and berberine inhibit PPAR gamma.

Adiponectin and ghrelin activate AMPK, while insulin inhibits AMPK (R). We see higher adiponectin, lower insulin and probably higher ghrelin in people with lectin sensitivity and thin people in general. Obese individuals have lower fasting ghrelin levels than their lean counterparts (R, R).

These hormonal changes all cause increased AMPK.

Ghrelin actually increases appetite through cannabinoid receptors (R), which suggests that if the cannabinoid system isn’t working well, Ghrelin won’t cause your appetite to increase. People with anorexia have higher ghrelin (R), which causes anxiety but seemingly doesn’t cause them to want to eat. This might be because of cannabinoid problems.

Cannabinoids are a bit tricky because they activate AMPK in the hypothalamus (which stimulates hunger), but it inhibits AMPK in liver and fat cells (R).

People who are thin and have a lower functioning cannabinoid system will have lower AMPK in the hypothalamus, but higher levels in the liver and fat tissue. The result is a reduced appetite, weight loss and lower fat/triglycerides. This is probably part of the reason why my thin clients have low triglycerides.

These hormonal and cannabinoid differences cause increased AMPK.  While this is healthy in many ways, it will cause lower PPAR gamma and weight loss.

ampk_brain

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980534/

Are You PPAR Gamma Dominant?

Ok, I’ve made this concept up, but I think it’s just another way to differentiate how something will affect me versus how it will affect you.  I’m more interested in how we’re different than how we’re similar.

Obviously, how much PPAR activation you have is on a spectrum, where most people straddle in the middle.

Indicators of low PPARs:

  • You are thin and never tried to be thin,
  • Have issues with Th1 dominance (PPARy blocks IFNy),
  • Have high inflammation. Cytokines like TNF and IL-1 decrease PPARy and PPARy also decreases inflammation (R).
  • Have low fasting insulin (mine was below 2) (PPARs increase insulin),
  • You have an HBA1C that’s not low even though you eat REALLY healthy (no sugar).  PPARs lower blood glucose. Mine was a 5.5 three years ago and I was meticulous in eating little carbs, no sugar and I exercised a lot. My calorie intake was low. Most people who don’t watch what they eat have this level at that age.
  • Low Adiponectin (PPAR gamma increases adiponectin) (R, R).
  • High TGF (R) (PPARy lowers TGF).
  • High IGF-1 (R)

Indicators of normal PPARs:

  • You are capable of gaining weight,
  • You’re hungry often,
  • Don’t have chronic inflammation,
  • You have high fasting insulin,
  • You’re Th2 dominant.  PPARy shifts you to a Th2 profile.

Is a Low Carb Diet Right For You?

It’s possible that people who have low PPARs do worse with a low carb diet because they have low insulin levels and staying away from carbs exacerbates this issue.

I always knew I was insulin resistant in my fat cells, but not my muscle cells.  That’s why I didn’t put on weight easily and gained muscle with little exercise.  Low PPAR gamma might be partly responsible for that.

A low carb diet for people like me is good because it’s also a low lectin diet.  But I do better by staying away from lectins and eating carbs or a kind of elemental diet.

It could be if you have high PPARs, a high-fat diet will be better for you, at least health wise. Although there are other factors at play and you need to experiment for yourself.

On the other hand, it also could be that if you’re a high PPAR producer, you will be more likely to get fat from dietary fat.

PPARG is known to be activated by dietary fatty acids (especially omega-3 & omega-6), which are the natural PPARG activators (R).

PPARG plays a critical role in fat cell enlargement under a high-fat diet (R).

Calorie restriction decreases PPARG gene expression, whereas a high-fat diet increased PPARG gene expression in the fat cells of mice (R).

Similarly, in humans, a low-calorie diet was shown to decrease PPARG expression in fat cells (R).

There’s some support that people with genes that (likely) result in a more drastic reduction of PPARG in response to calorie restriction (1200 calories/day) are more likely to lose weight from this (R).

Common PPAR Gamma Activators

In general, PPAR gamma apparently prefers polyunsaturated fatty acids such as linoleic acid, arachidonic acid, and EPA (R).

Even though PPAR gamma activators can cause obesity, there are other mechanisms by which these supplements work that they either break even or cause weight loss.

Lifestyle to Increase PPAR Gamma

Nutrition to Increase PPAR Gamma:

  • Omega 6: Linoleic acid (R), Arachidonic acid and arachidonic acid metabolites (R)
  • Omega 3: α-linolenic acid (R) (Flax, chia)
  • EPA+DHA: Fish oil  (R) (R)
  • Dietary Fats (R), Fatty acids and prostanoids (R). Lard increases expression in mice (R).
  • Plant Oils, Safflower Oil, Palmitates/Palmitic Acid (R) (R)
  • Coconut oil/19% Myristic Acid (R)
  • Plant oils increase expression in humans (R)
  • Safflower oil increases expression in animals (R)
  • CLA found in dairy (R)
  • Gamma-Linolenic Acid increases activity in humans (R) (R)
  • MCT‘s – Caprylic (C8), Capric (C10) and Lauric (C12) (R, R)
  • Dietary Carbohydrates increases expression in humans (R)
  • Fructose and Sugar increases the expression and reaction in animals (R)
  • Iron – increases expression in humans (R)
  • Zinc increases expression in humans (deficiency causes impaired binding to DNA) (RR)
  • Selenium increases expression in mice (R)
  • Manganese -increases expression (R)
  • Lithium – increases expression in humans (R)
  • Phosphorous increases localization in humans (R)
  • Vitamin A and Tretinoin increases expression in rats and humans (R).  Beta Carotene increases it in cancer cells (R)
  • Vitamin E – Tocotrienols (R), Alpha-Tocopherol (R), Gamma Tocopherol (R)
  • Phosphatidylcholine increases expression in mice (R)
  • Glycine found in collagen (R)
  • Niacinamide (R) and Niacin (R)
  • Iodine increases PPAR gamma expression (R)

Hormones That Increase PPAR gamma:

Natural Ways to Increase PPAR Gamma

My favorite:

Immune Stimulants That Increase PPAR gamma:

Pathways/Endogenous Moleculaes

Drugs to Increase PPAR Gamma:

Bad Things That Increase It:

PPAR Gamma Inhibitors

Circadian Rhythms and PPAR Gamma (Technical)

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

PPAR gamma exhibits variations in daily expression in mouse fat, liver, and blood vessels (R).

Deletion of PPAR gamma in mouse suppresses or diminishes daily circadian rhythms (R).

PPAR gamma contributes to maintaining the daily fluctuations of both blood pressure and heart rate.  Daily variations in blood pressure and heart rate are blunted mice without PPAR gamma (R).

This shows the important role of PPAR gamma in the coordinated control of circadian clocks, metabolism, and heart function (R).

Rev-Erb alpha is increased after PPAR gamma activation (by binding to the response element Rev-DR2) (R).

Nocturnin, a circadian-regulated gene, promotes fat by stimulating PPAR gamma (R).

The PPAR Gamma Paradox

Overall, PPAR gamma is a healthy protein (transcription factor) that lowers inflammation and increases insulin sensitivity.

The paradox with PPAR gamma genes is that the SNPs that cause lower levels of PPAR gamma sometimes have benefits, such as lower BMI.  This is because PPAR gamma causes weight gain.

In the modern environment with high omega-6 consumption and overeating, we activate PPAR gamma quite a bit and we store more fat, without feeling the immediate consequences.  When we have more fat, this causes inflammation and other issues.

So SNPs genotypes that are higher producers of PPAR gamma sometimes have more problems than lower producers.

The ideal is to be a high PPAR gamma producer but eat less and not be overweight.

Some PPAR Gamma 23andMe Genes

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

Here are PPAR gamma SNPs that the program has from 23andme (the letters are my genotype):

  1. RS10865710 (PPARG) GG
  2. RS1175540 (PPARG) CC
  3. RS1175543 (PPARG) AA
  4. RS12636454 (PPARG) CC
  5. RS17036314 (PPARG) CC
  6. RS1797912 (PPARG) AA
  7. RS1801282 (PPARG) CC
  8. RS1805192 (PPARG) CC
  9. RS1899951 (PPARG) CC
  10. RS2197423 (PPARG) GG
  11. RS3856806 (PPARG) CC

To see if you have these genetic mutations, buy 23andme and upload your raw data on SelfDecode.

rs1801282 (Pro12Ala)

G=lower PPAR gamma activity, more benefits to exercise, reduced weight gain, lower heart disease, lower risk for diabetes, worse with a high-fat diet, protective against colorectal cancer, protective against psoriatic arthritis.

The g=higher risk for rheumatoid arthritis and sarcoidosis.

The G allele reduces the ability of PPAR gamma to activate its target genes (decreases transcriptional activity) (R).

For some reason, however, it seems like the G allele has more benefits than the more common C allele (R).

For this SNP, The effect on the individual is weak, but because over 75% of people have the high-risk C allele, the population-attributable risk is enormous (R).

Moderate reduction in PPAR-gamma as a result of the polymorphism decreases the release of insulin-desensitizing free fatty acids, tumor necrosis factor-alpha, and resistin and increases the release of the insulin-sensitizing hormone adiponectin, which results in improvement of insulin sensitivity of glucose uptake and suppression of glucose production (R).

Once diabetes has developed, the protective effect of the G allele may be lost, since increased vascular complications and more pronounced beta-cell dysfunction have been reported from the G allele (R).

Having one G allele makes you more responsive to the beneficial health effects of exercise (R).

The G allele has been associated with reduced weight gain, improved insulin sensitivity and a lower risk for type 2 diabetes in several studies. But these associations are not as strong in obese subjects. Some researchers have actually found that among obese subjects, the G allele is associated with increased – not decreased — weight gain (R).

In mice, the G allele did worse with a diet high in fat (58% of calories). The researchers suggest that diet affects the PPARG protein’s interactions with hormones and other molecules involved in metabolism. When an animal (mouse or human) eats a normal diet, the C version of the PPARG protein is more efficient at storing fat than the G version. But in animals that take in more energy than they expend, the G version of the protein ends up being more pro-fat/weight gain (note, a study was done using trans fat) (R).

G is protective against colorectal cancer but increases gastric cancer. (R).

Hypertensive and obese G carriers had lower fasting glucose and lower triglycerides than hypertensive and obese CC carriers (R).

G was also associated with lower heart disease, with a 90% risk reduction for ischemic heart disease and a 76% reduction of vascular death. Having two G’s were the most protective (R).

G is protective against psoriatic arthritis (R).

One G allele (p=0.0101, OR=1.84) and GG (p=0.0020, OR=2.45) were more commonly found in patients with sarcoidosis (R). Sarcoidosis is caused, in part, by lower PPAR gamma (R).

GG was more common in people with rheumatoid arthritis (R).

C (+/FWD) allele=’Pro’

rs3856806 (C1431T)

T= lower heart disease, TNF, MMP-9….higher Adiponectin….

The T allele carriers (CT + TT) had significantly reduced Coronary Artery Disease risk compared with the CC homozygotes (odds ratio 0.547, P = .012) (R).

The T allele carriers also had lower MMP-9 and TNF-alpha levels compared with T allele carriers (R).

CT or TT is associated with lower Bone Mineral Density (R).

CT or TT is associated with higher adiponectin (P = 0.026) (R).

T is protective against psoriatic arthritis (R).

The T allele was more frequent in overweight people (BMI >25) (P < 0.05) (R).

rs1175540

Each ‘A’ of this SNP predicts weight loss in response to calorie restriction (1200 calories/day) (R).

Presumably, this means there’s a more drastic reduction of PPARG in response to calorie restriction (R).

rs1797912

Each C of this SNP predicts weight loss in response to calorie restriction (1200 calories/day) (R).

Presumably, this means there’s a more drastic reduction of PPARG in response to calorie restriction (R).

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7 COMMENTS

  • Ricky

    This may explain why before I went Keto my body fat stayed around 7% and then after it shot up to 13% as soon as I put any carbs back into my diet. Been trying to undo this ever since. “If it ain’t broke, don’t fix-it” Right? I was just trying to optimize my health but I figured out my body seems to work better with some carbs.

  • Thompson

    Fascinating stuff Joe. Really great work.

  • JW

    I wonder if your description of rs1801282 is inverted. If you look at Table2 of the following study:
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2270805/

    You’ll see rs1801282 saying that GG has 0.38sigma z-score (look at 10y-olds column) higher BMI than average. If you translate that z-score, I think it means that the GG are roughly in the top 30 percentile of BMI, which means GG contributes to obesity.

    I’m CC also.

    Note that the same table mentions rs1800206, the PPAR-alpha gene, as being the other gene correlated with high BMI. I have CG, so one copy G here.

    1. Joseph M. Cohen

      GG=higher BMI, perhaps higher PPARy. What’s inverted?

      1. JW

        Ok, I guess you didn’t call-out any relationship with BMI in your article, sorry. But you did say “G was also associated with lower heart disease”, which is odd if it’s associated with obesity.

        1. Joseph M. Cohen

          Read the PPAR gamma post and it won’t seem odd.

          PPAR gamma causes fat cell production (and being overweight), but lowers heart disease risk (by increasing PON1 and lowering inflammation). Reread the article.

  • Solomon

    I’m in the Asprey category – severe, chronic inflammation, seperate from and in addition to lifelong obesity. I’m sure that eventually the majority of people will be like me or similar. I have found ways of dealing with it however other than butter coffee… FIBER. Multiple superior advantages this way. Plus, I prefer that the fat I eat come from my thighs and ass.

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