Can you increase your metabolic rate – even when resting – by eating a high-fat diet? Likewise, will exercise kick you into fat-burning mode?
PPARδ is a key player in how and when your muscles burn fat for fuel. Genetic variants in the PPARD gene impact how well your muscles utilize fatty acids. These variants also impact how much of a fat-burning benefit you get from exercise.[ref]
PPARδ: Fat burning and exercise response
PPARδ (PPAR-delta) is part of the PPAR family of receptors. These receptors are found in the nucleus of the cell, surrounding certain areas of the DNA. PPARδ is activated by fatty acids, and then it causes other genes to be transcribed into their proteins.
Essentially, PPARδ is a sensor for cellular metabolism, switching on the genes needed for burning fat instead of glucose.
PPARδ is found in many different tissue types, but it is most important in the liver, skeletal muscles, and heart muscles.
In the skeletal muscles, PPARδ is important in using fatty acids for fuel and how muscles respond to exercise.[ref]
In the liver, PPARδ increases the use of fat for fuel, and it is thus protective against fatty liver disease.[ref]
Increased levels of PPARδ are linked to less fat in the heart muscles and better uptake of glucose and fatty acids in the skeletal muscles. Increased levels of PPAR-delta can also lead to decreased cholesterol absorption in the intestines.[ref]
There are a number of different long-chain fatty acids that can bind to and activate PPARδ, produced in the body, or from foods. Common fatty acids from foods include polyunsaturated fats such as arachidonic acid and linoleic acid.[ref]
PPARδ in weight loss and exercise training:
There are different goals for exercising and training – and PPAR-delta influences how easily you can reach those goals.
Some people work out to lose weight; others train to increase muscle mass. For some, exercise gives greater cardiovascular health benefits; for others, it can raise (or lower) cholesterol levels.
PPARδ acts as an energy manager for endurance exercise – switching the muscles to burning fat and preserving some glucose. Animal studies show that stimulating PPAR-delta using drugs that bind to it can extend running time significantly. Research shows that it does this by using fatty acids for fuel and sparing glucose to be used as needed.[ref]
The PPARD gene codes for PPARδ. Genetic variants in the PPARD gene influence how exercise impacts weight loss, strength gains, cholesterol levels, and cardiovascular health benefits – often in opposite ways.
It is not as simple as “this is a good genetic variant” for PPARD. There are trade-offs, and your view of the variants may depend on your goals.
PPAR-delta and Muscle Fiber Type:
There are two main categories for muscle fiber type: type 1 (slow) and type 2 (fast-twitch). Type I muscle fibers are used more in endurance athletes (long-distance runners), and type 2, or fast-twitch muscle fibers, are important for a burst of speed such as in sprinting or powerlifting.
In animal studies, activating PPARδ causes a switch to forming more type 1, slow-twitch muscle fibers.[ref]
PPAR-delta is anti-inflammatory:
In general, increasing PPARδ can tamp down an overactive inflammatory response.
In a cell culture of heart tissue, increasing PPARδ caused a decrease in the production of the inflammatory cytokine TNF-alpha. In cells created without the PPAR-delta gene, the addition of a bacterial inflammatory molecule causes exaggerated TNF-alpha production (not good).[ref]
Your muscles accumulate tissue damage when you work out – or just through everyday life. Activating PPAR-delta, in turn, activates FOXA2, which tamps down the inflammatory response to tissue damage. Studies are now looking at drugs that activate PPAR-delta as a way of combating muscular pain disorders.[ref]
Can you influence PPAR-delta with fat intake?
Research from the 90s shows that a high-fat diet may increase overall metabolism in the muscles through increasing mitochondrial fatty acid oxidation.
Quick science refresher: Your mitochondria (the powerhouse of the cell :-) turn fat or sugar into energy in the form of ATP. Cells have hundreds to thousands of mitochondria, processing fuel and turning it into energy. More mitochondria, therefore, increases using up fat or sugar and causes an increase in energy.
Studies in rats show that increasing long-chain fatty acids increases mitochondrial fatty acid oxidation in the skeletal muscles. This is thought to be due to the increase in PPAR-delta.[ref]
Medium-chain fatty acids may not be the way to go, though. Animal studies also show that coconut oil, high in medium-chain fatty acids, inhibits PPARδ.[ref]
PPARD in cancer:
Studies show that PPARδ is upregulated in cancer cells, increasing the formation of new blood vessels for the tumors. Blocking PPARD represses metastasis.[ref][ref]
The PPARδ agonist known as GW-501 has been shown in cell studies and animal studies to promote tumorigenesis. Activating the PPAR-delta receptor in breast cancer cells also increases the spread of cancer. On the other hand, some studies show that PPAR-delta is downregulated in prostate cancer. Additionally, the topical application of a PPAR-delta agonist has been shown to delay chemical-induced skin cancer.[ref]
PPARδ in the brain:
In addition to its role in fatty acid metabolism in muscles, PPARδ is found abundantly in the brain, where it is neuroprotective.[ref]
People with Huntington’s disease, a progressive, genetic neurodegenerative disease, have low levels of PPARδ in the neurons. Animal studies show that specifically targeting neurons with certain PPARδ activators can reverse some of the neurodegenerative effects of Huntington’s.[ref][ref]
In animal models of depression, low brain levels of PPARδ are linked with chronic mild stress and learned helplessness. Increasing the brain PPARδ prevented depression-like behaviors.[ref]
PPARD Genotype Report:
Not a member? Join here. Membership lets you see your data right in each article and also gives you access to the members only information in the Lifehacks sections.
Check your genetic data for rs2267668 (23andMe v4, v5; AncestryDNA):
- A/A: common genotype; increased triglycerides from exercise training[ref]
- A/G: not as great of a response to aerobic exercise; lower skeletal muscle mitochondrial function
- G/G: not as great of a response to aerobic exercise[ref][ref]; lower skeletal muscle mitochondrial function[ref]; decrease in cholesterol levels from exercise[ref]
Members: Your genotype for rs2267668 is —.
Check your genetic data for rs1053049 (23andMe v4; AncestryDNA):
- T/T: common genotype; better response to lifestyle intervention for weight loss
- C/T: not as great of response to lifestyle intervention (exercise) for weight loss
- C/C: not as great of response to lifestyle intervention (exercise) for weight loss[ref]
Members: Your genotype for rs1053049 is —.
Check your genetic data for rs2016520 15C/T (23andMe v4, v5; AncestryDNA):
- C/C: higher transcriptional activity of PPARD; decrease in cholesterol from training[ref][ref]; lower average fasting glucose and fasting insulin levels[ref]; decreased coronary heart disease risk (Chinese pop.), especially for non-smokers[ref][ref]; linked to decreased BMI in men, but increased BMI in women[ref]; better dynamic balance on the beam (Chinese children)[ref]
- C/T: lower fasting plasma glucose, fasting insulin[ref]; decreased cardiovascular disease risk
- T/T: most common genotype; greater increase in HDL levels due to training (Caucasians)[ref]; increased triglyceride in response to exercise training[ref]
Members: Your genotype for rs2016520 is —.
Lifehacks for increasing PPARδ:
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Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.