Can This Gene Help You Lose Weight on the Mediterranean Diet? (PPARG)

The PPARG gene is responsible for producing a protein called PPARγ or PPARG (short for peroxisome proliferator-activated receptor gamma) [R].

PPARG is a member of the PPAR family, which affects metabolic health and response to diet. PPARG has been described as a master regulator of the interplay between [R, R]:

• Nutrient intake (fatty acids)
• Inflammatory mediators (prostanoids)
• Fat burning (peptides released from adipocytes)
• Insulin sensitivity, and 
• Susceptibility to obesity 

The PPARG gene works as a sort of “metabolic switch.” It’s in constant cross-talk with dietary nutrients, inflammatory compounds, and our fat stores. 

How PPAR Variations Can Impact Your Ideal Diet

Let’s remember what all PPARs have in common to better understand PPARG. Aside from PPARG, other PPARs include PPARA (PPARα) and PPARB/D (PPARβ/δ) [R]. 

As transcription factors, PPARs are proteins that can turn certain genes “on” or “off” by binding to nearby DNA. They are mostly activated by fatty acids. When PPARs turn genes “on,” they help transcribe information from the DNA to messenger RNA, which holds the key to producing proteins.

Where PPARs differ is by the exact dietary compounds they are naturally activated by and what downstream effect this has in the body. For this reason, PPARs have become a central topic in the field of nutrigenomics and personalized nutrition [R].

PPARs generally bind to polyunsaturated fatty acids, whereas saturated fatty acids are poor activators [R]. 

The main PPARG activators are omega-3 fatty acids (DHA and EPA), omega-6 fatty acids (linoleic acid, alpha-linolenic acid), and natural trans fat (conjugated linoleic acid) [R]. 

Researchers believe that PPARG may contribute to individual variability in body weight and belly fat reduction in response to various diets: from Mediterranean-style diets to less-known interventions like the Central European diet–both of which we’ll cover in this article [R, R, R, R]. 

PPARG belongs to the PPAR family of proteins that can turn genes “on” and “off” in response to fatty acids and other factors. Research reveals that PPARG variations may affect the effectiveness of weight-loss diets.

Is PPARG the “Fat Gene”?

PPARG is best known for helping to create and maintain fat cells and fat stores (adipogenesis and lipogenesis, respectively). It’s tempting to think that this makes PPARG an “unwanted gene,” since it favors fat storage over fat burning. Some scientists initially entertained this idea, with the hope that blocking (or deleting) PPARG might help prevent obesity [R]

Indeed, early studies showed that mice lacking PPARG have little fat tissue. A few days after the PPARG gene was removed from the animals’ DNA, their mature white and brown fat cells died. However, new PPARG-positive fat cells appeared [R]

Therefore, scientists concluded that PPARG likely has the biggest effect on formed, mature fat cells. PPARG seems to maintain the function of existing fat cells but decreases their size (reducing so-called adipocyte hypertrophy). This helps prevent additional weight gain, obesity-related inflammation, and mitochondrial dysfunction [R, R] 

On the other hand, studies suggest that PPARG can also jump-start the creation of new fat cells, which is called adipocyte hyperplasia [R, R] 

To an extent, an increased number of fat cells serves a good purpose: it protects against metabolic issues when people overeat. In excess and over the long term, too many fat cells become a big problem–one that sets off serious metabolic complications in obesity that are hard to reverse [R, R].

With further experiments, scientists realized that PPARG may have other positive roles in the body. It allows fat cells to effectively take up glucose and free fatty acids, enhancing insulin sensitivity. PPARG also reduces inflammation. Its potential antioxidant properties are another area of research, but studies so far have been limited to animals [R, R, R, R, R].

PPARG has both protective and detrimental effects on obesity and metabolic health that seem to depend on genetics, dietary cues, and lifestyle factors.

The G allele of rs1801282 causes a moderate decrease in PPAR gene activity and is thought to reduce its fat-forming potential. Some studies have associated this genotype (GG or GC) with greater insulin sensitivity, a more favorable lipid profile, and a lower BMI  [R]. 

PPARG has other SNPs, but rs1801282 has been most widely researched. Scientists believe it may explain important gene-diet interactions and why people respond differently to varying levels of total and saturated fat intake and carbs, but results so far have been conflicting  [R]. 

What makes this polymorphism especially unusual is that the rarer genotypes (GG or CG) seem to have more benefits than the more common one (CC homozygous). 

Overall, G-allele carriers (GG or CG) appear to have an easier time losing weight on the Mediterranean diet. They also seem to have better insulin sensitivity. But, G-allele carriers are more likely to experience weight fluctuations throughout their lifetime. Just as they lose weight easier, they also gain it easier with the wrong diet and lifestyle. Data suggest that they are more likely to have extra weight and belly fat in the first place. 

On the other hand, CC carriers seem to be better at maintaining stable body weight. They seem to be more resistant to both weight gain and weight loss. This means it may take extra effort to stick to a weight management program because the results might be harder to achieve.

The G allele of PPARG rs1801282 has been linked with lower PPARG activity and easier weight loss on the Mediterranean diet. CC carriers tend to be less prone to weight fluctuations, but they are also more resistant to weight loss. 

Please have in mind that many other genetic and non-genetic factors also influence a person’s response to diet and different nutrients. Additionally, remember that dietary interventions should always be part of a holistic weight management program. 

Next, let’s take a look at the specific dietary modifications that each genotype might benefit from. 

Weight Loss from the Mediterranean Diet

One study looked at how rs1801282 affects weight loss and enrolled 1465 people in a program for obesity based on the Mediterranean diet, physical activity, nutritional education, and behavioral techniques [R]. 

Participants with the G allele (also known as the Pro12Ala genotype) lost less weight overall when their total fat intake was high (>43% of total intake), compared to CC carriers. 

However, G-allele carriers were significantly less obese than CC carriers when their monounsaturated fatty acid (MUFA) intake was high (≥56% of total fat). MUFAs are found in olive oil, nuts and seeds, and avocados. G-allele carriers also had lower markers of insulin resistance (HOMA-IR) in response to high MUFA intake. 

Based on this study, it would seem that people with the GG or GC genotype for PPARG rs1801282 should follow a moderate-fat Mediterranean diet to lose weight, and particularly they may benefit from upping MUFA intake while cutting calories from other sources. 

CC carriers can follow a higher-fat Mediterranean diet to lose weight, but they should increase omega-3 fatty acid intake over MUFAs. On the other hand, CC carriers looking to increase their weight might want to up their intake of healthy MUFA sources such as olive oil.

In one study, PPARG rs1801282 G-allele carriers gained less weight when they ate plenty of MUFAs (found in olive oil). CC carriers might get better results with increased omega-3 intake. 

Belly Fat Loss from the Mediterranean Diet 

vs. the Central European Diet in Women

A smaller 2019 study on 144 postmenopausal women with prominent belly fat (central obesity) tested out associations between rs1801282 and two diets: the Mediterranean diet (37% total energy as fat) or the Central European diet (55% total energy as carbohydrates). The Mediterranean diet is higher in healthy fats while the Central European diet is higher in fiber. Both diets were energy-restricted [R].

At the beginning of the study, women carrying the G allele had more belly fat than their CC counterparts. After the intervention, G-allele carriers on the Mediterranean diet lost more belly fat than CC carriers. 

Also, G-allele carriers on the Central European diet lost more weight and lean mass than CC carriers. However, G-allele carriers also experienced a reduction in the “good” HDL cholesterol on the Central European diet, which wasn’t the case with the Mediterranean diet. For this reason, the Central European diet was considered to be a less healthy choice overall. 

The Mediterranean diet in this study was moderate–but not high–in MUFAs (20% energy and 54% of total fat as MUFAs), derived mainly from olive oil and nuts. In fact, many “flat belly” diets place emphasis on MUFAs.

Based on this study, it appears that women with the GG or GC genotype for PPARG rs1801282 looking to lose belly fat in a healthy way should follow the Mediterranean diet over a diet higher in carbs (like the Central European diet). 

Women carrying the CC genotype seem to be less prone to gaining belly fat after menopause, but they may have a harder time losing it. They should follow any healthy, energy-restricted diet as part of a general weight loss program. 

According to limited research, women with PPARG risk variants lose more belly weight on the Mediterranean diet than on higher-carb diets (compared to the non-risk variants). 

People at a High Risk of Heart Disease

One study followed up 774 middle-aged people at a high risk of heart disease over a 2-year nutritional intervention with Mediterranean-style diets. They included three groups: two followed Mediterranean-style diets and the third was a control group on a conventional low-fat diet [R].

G-allele carriers in the control, low-fat group gained more belly fat after two years. On the other hand, G-allele carriers following the Mediterranean diets lost belly fat. This was particularly prominent in type 2 diabetics with this genotype who lost the most belly fat, which helped support their heart health. 

Therefore, people with the GG or GC genotype for PPARG rs1801282 looking to improve their heart health and lose belly fat should follow a Mediterranean-style diet. They should avoid low-fat diets, which seem to increase belly fat and heart disease risk in the long term. 

CC carriers should follow a heart-healthy diet in general, but they’re not as likely to gain belly fat from a low-fat diet. The American Heart Association (AHA) recommends a diverse diet high in omega-3 fatty acids and low saturated and trans fat, along with regular, moderate physical activity [R]. 

People with the PPARG risk allele had improved heart health and less belly fat on the Meditteranean diet; the non-risk genotype is less likely to gain belly fat even with lower intake of healthy fats. 

Weight Loss from High PUFA vs. Saturated Fat Intake

Lastly, in another study of 592 people, G-allele carriers had higher body mass index (BMI) and fasting insulin levels than CC carriers if their intake of polyunsaturated fat (PUFAs) was low over saturated fats. However, when G-allele carriers had a high intake of PUFAs over saturated fats, their BMI and insulin levels dropped more than that of CC carriers [R]. 

Good sources of PUFAs are fish, walnuts, and flaxseeds. The main categories of PUFAs are omega-3 and omega-6 fatty acids. Saturated fats are found in meat, dairy, and some tropical vegetable oils. 

Reducing saturated fats and increasing PUFAs is usually seen as beneficial for general health. However, since our diets are much higher in omega-6s, most people should favor omega-3 foods as a source of PUFAs. 

Based on one study, people with the PPARG risk allele lose weight easier when they increase PUFAs and reduce saturated fats. People with the more common genotype seem to be less sensitive to the ratio of dietary PUFAs to saturated fats. 

Limitations and Unanswered Questions

Conflicting results have been reported. In some studies, the G allele of rs1801282 made people more responsive to beneficial dietary and lifestyle interventions; other studies reported an association between the G allele and resistance to weight loss. 

Some of these differences may be explained by baseline body weight and macronutrient specifics, such as the intake of saturated, polyunsaturated, and monounsaturated fats. 

However, discrepancies may also be related to other differences in intervention protocols, age of the participants, ethnicity, sample sizes, gene-gene interactions or gene-diet interactions. Future studies should clarify these inconsistencies [R].

You can see your genotypes for the main PPARG SNP in the table below. However, keep in mind that these results are based purely on association studies, and much more research will be needed to know what role — if any — these variants play in actually directly impacting a person’s response to diet.

Many different genetic, lifestyle, and environmental factors that can affect weight loss and diet compatibility. In other words, just having a “bad” PPARG genotype does not necessarily predict anything specific about a person’s response to diet— rather, these results illustrate just one of the many different genetic factors potentially related to it.

With that in mind, the following table summarizes your results for the main PPARG SNP that have been potentially linked to weight loss from the Mediterranean diet:

SNP Summary and Table

Primary SNP: PPARG rs1801282

• ‘GG’ and ‘CG’= More likely to lose weight on a Mediterranean-style diet moderately high in unsaturated fat. Low-fat diets and diets high in total and saturated fat increase weight gain.
• ‘CC’ = More resistant to weight loss and weight gain; normal weight loss on a Mediterranean diet; less prone to gaining weight from diets high in total and saturated fat intake. 

Frequency in the Population

The rs1801282 rare allele (G) frequencies are relatively high in Caucasians (up to 12%) and low in Asians (4% of Japanese and 1% of Chinese) and African Americans (3%). A high frequency of the G allele has also been reported in Asian Indians (11%) and Mestizo Mexicans (22%) [R, R].