The Connection Between Fat Metabolism and Obesity (PPARG)

The PPARG gene encodes a protein called PPAR-gamma (peroxisome proliferator-activated receptor-gamma) [R].

PPARG affects metabolic health and response to diet, acting as a master regulator between [R, R]:

• Nutrient intake 
• Weight control
• Inflammation
• Fat burning
• Insulin sensitivity 

Different dietary compounds activate different PPARs, making them a central topic in nutrigenomics and personalized nutrition. The primary PPAR-gamma activators are omega-3 fatty acids (DHA and EPA) and omega-6 fatty acids (linoleic acid, alpha-linolenic acid) [R, R]. 

The PPARG gene encodes a protein with crucial roles in metabolism, weight control, and response to nutrients.

The Role in Obesity

On the one hand, PPARG seems to maintain the function of existing fat cells but decreases their size, preventing weight gain, obesity-related inflammation, and mitochondrial dysfunction [R, R, R].

On the other hand, studies suggest that PPARG can also jump-start the creation of new fat cells. This effect may protect against metabolic issues due to overeating but also contribute to persistent obesity [R, R].

PPARG also reduces inflammation and allows fats cells to take up glucose and free fatty acids, enhancing insulin sensitivity [R, R, R, R].

Depending on a variety of factors, PPARG can have both protective and detrimental effects on obesity and metabolic health.

Out of different SNPs in the PPARG gene, researchers have mostly focused on rs1801282 (Pro12Ala) and its link with metabolic health and weight control.

In a large meta-analysis of 75 studies and 49,000 subjects, the “G” allele correlated with a slightly higher body mass index (BMI). The link was more robust in European (Caucasian) populations. A 2015 meta-analysis of 56 trials came to a similar conclusion [R, R].

A group of Chinese authors reviewed 25 studies with over 14,700 participants from different ethnic groups. According to their results, the “G” allele is associated with 55% higher obesity rates [R].

On the other hand, some studies failed to confirm a significant relationship between rs1801282 and body weight, and some have even observed the opposite, protective effect of the “G” allele [R, R, R, R, R].

The explanation for these conflicting results probably lies in the baseline body weight of participants and a range of dietary factors that varied between the studies. In the following chapter, we will outline the key nutritional factors influencing the link between PPARG and weight control.

The “G” allele at rs1801282 is associated with obesity and higher BMI, but this genetic link depends on different dietary factors.

Dietary Fat

Total Fat and MUFA

One study looked at how rs1801282 affects weight loss and enrolled 1,465 people in a program for obesity based on the Mediterranean diet, physical activity, and education [R].

Participants with the “G” allele lost less weight when their fat intake was high (>43% of total calories), compared to CC carriers. However, they were significantly less obese when their monounsaturated fatty acid (MUFA) intake was high (≥56% of total fat). The G-allele carriers also had lower markers of insulin resistance (HOMA-IR) in response to high-MUFA intake.

People with rs1801282-G may lose more weight on a diet with a higher intake of MUFAs from sources like olive oil. However, they may want to avoid high-fat diets.

PUFA vs. Saturated Fat

In a trial of 592 people, the G-allele carriers had higher BMI and insulin levels than the “CC” carriers if their intake of polyunsaturated fatty acids (PUFAs) was lower. However, when they had a high intake of PUFAs over saturated fat, their BMI and insulin levels dropped more, compared with the “CC” carriers [R].

Olive Oil

Among 149 severely obese people (BMI≥ 35), those with the “G” allele lost significantly more fat when supplemented with extra virgin olive oil [R].

The “G” allele carriers may lose more weight on a diet rich in olive oil and PUFAs and low in saturated fat.  

Mediterranean Diet 

A 2019 study of 144 postmenopausal women with belly fat (abdominal obesity) tested the link between rs1801282 and two diets: the Mediterranean diet and the Central European diet. The Mediterranean diet is higher in healthy fats, while the Central European diet is higher in fiber. Both diets were energy-restricted [R].

Women carrying the “G” allele had more belly fat at the beginning of the study, but they lost more belly fat on the Mediterranean diet than the “CC” carriers.

One study of 774 middle-aged people at a high risk of heart disease compared Mediterranean-style diets with a conventional low-fat diet. The G-allele carriers in the low-fat group gained more belly fat after two years, while those following the Mediterranean diets lost belly fat  [R].

People with rs1801282-G may have more belly fat, but they seem to lose it more efficiently in response to the Mediterranean diet.

Other Factors

Among 978 elderly subjects, rs1801282-G correlated with 66% higher obesity rates. The lack of physical activity and increased intake of carbs amplified this genetic effect. The “G” allele carriers consuming >246 g of carbs/day had 2.67 times higher odds of obesity, compared with the “CC” genotype [R].

Three more studies of 1,172 total participants have found that people with rs1801282-G respond better to physical activity when it comes to metabolic improvements [R, R, R].

The lack of physical activity and increased intake of carbs may worsen the metabolic impact of rs1801282-G.

How It Works

The discussed SNP changes one amino acid in the PPAR-gamma structure, reducing its ability to activate target genes [R, R].

Among other roles, PPAR-gamma limits the size of fat cells and fat stores.  This effect may be hindered in people with the “G” allele, making them prone to weight gain [R, R, R].

On the other hand, PPARG can contribute to persistent obesity by forming new fat cells, which might explain the conflicting results for this SNP [R, R].

People with the “G” allele may prefer the Mediterranean diet because PUFAs are the primary PPARG activators. Since PPAR-gamma is crucial for fat metabolism, people with this variant don’t tolerate high amounts of saturated fat [R, R]. 

This variant reduces the ability of PPAR-gamma to control weight gain and process saturated fat.

Limitations

Although PPAR-gamma has been a hot research topic for decades, scientists are still to unravel its complex roles in metabolism and weight control.

Studies have only partly explained the conflicting link between rs1801282 and obesity. Dietary and lifestyle interventions have also produced mixed results: people with this SNP were resistant to weight loss in some of them [R, R].

Factors that may have contributed to opposing results include variations in study designs, sample sizes, age of participants, gene-diet interactions, and more.

SNP Summary and Table

Primary SNP:

PPARG rs1801282

• ‘G’ = associated with belly fat and higher rates of obesity
• ‘C’ = generally not associated with obesity

Frequency in Population: The G allele is relatively common in Europeans/Caucasians (up to 12%) and less common Japanese (4%), Chinese (1%), and African American (3%) descendants.