Can Saturated Fat Make You Obese? (APOA2)

The APOA2 gene codes for apolipoprotein A-II, which builds HDL cholesterol and regulates lipid (fat) metabolism. Unlike apoE and apoB, the exact metabolic roles of apoA-II are still largely unknown [R].

Emerging research suggests the inhibitory effects of apoA-II on VLDL and triglyceride metabolism, as well as insulin sensitivity [R, R].

The Link Between APOA2 and Obesity

Scientists have observed the association between one APOA2 variation, rs5082, and obesity across different ethnic groups. People with the “GG” genotype have significantly higher BMIs (body-mass index) and obesity rates [R, R].

This variant failed to show the connection with body weight in specific populations, which led researchers to examine the potential environmental factors at play. Saturated fat intake has surfaced as a crucial dietary factor for APOA2-related obesity, and it will be the focus of this post [R].

Note: you might see some publications referring to rs5082 as “-265T>C” pr “T265C”. Unlike SelfDecode, they report on the opposite (negative) DNA strand, so “A>G” becomes “T>C.”

How It Works

Just like its metabolic roles, the exact ways in which APOA2 affects body weight are still under investigation. 

According to two major trials, the “GG” genotype at rs5082 lowers apo A-II levels and correlates with increased calorie intake. Detailed analyses have confirmed the role of apo A-II in appetite control [R, R, R].

Two Faces of APOA2: Effects on Blood Lipids and Heart Health

By reducing APOA2 expression, rs5082 can stimulate VLDL and triglyceride (TG) metabolism. Indeed, in a study of 88 participants, those with the “GG” genotype had lower TG and cholesterol levels in response to a high-fat meal [R, R, R, R].

Among 700 diabetes patients, the “GG” carriers also had significantly lower TG and total cholesterol but not HDL. In a trial of 982 Australian subjects, people with this variant had nearly two times lower rates of heart disease [R, R]. 

In a way, rs5082 may  “compensate” for its link with obesity by improving blood lipids and potentially shielding the heart.

Saturated Fat

The links between saturated fat, obesity, and heart health have been controversial. Genetic factors, such as rs5082, may partly explain why higher amounts of saturated fat (SF) are detrimental only to certain people.

One study gathered data from three populations (3,462 total participants) and found a robust association between rs5082, obesity, and SF intake. The “GG” carriers had 84% higher obesity rates compared with other genotypes, but only when their SF intake was high. In cases of low SF intake, APOA2 didn’t correlate with obesity [R].

After the initial observations, the authors followed one of these populations for 20 years and confirmed the same results, making them even more credible.

Another trial of 4,600 Asian and Mediterranean subjects came to the same conclusion. Additionally, the “GG” allele was associated with insulin resistance in Chinese and Indian people who consumed more SF [R].

Both studies defined increased SF intake as >22g daily, which roughly equals 10% of total energy intake for a person consuming 2000 calories a day.

According to robust clinical evidence, increased intake of saturated fat may worsen the impact of APOA2 rs5082 on obesity and metabolic health.

Potential Mechanisms

This APOA2 variant may increase the levels of ghrelin or the “hunger hormone.” A study of 1,225 obese subjects found that people with the “GG” genotype who consume more SF have higher ghrelin levels. In other words, SF fails to satiate their hunger [R].

According to a 2018 paper published in the American Journal of Clinical Nutrition, excess saturated fat may also trigger obesity-related metabolic pathways in people with this variant [R].

High-Fat Dairy

Dairy products are a significant source of saturated fat in western diets, especially in the US.

One study analyzed dairy intake in two populations (n=2,071) with a proven link between rs5082 and saturated fat. In both groups, the “GG” carriers who consumed more high-fat dairy had significantly higher BMIs [R].

The authors defined increased intake as >1.5 servings of high-fat dairy (>1% fat) [R].

Does this mean you should swap high-fat for low-fat dairy? Not really — stick with us for healthier, gene-based solutions.

Other Types of Fat

Among 180 diabetic patients, unsaturated fatty acids positively affected those with the “GG” genotype. Increased intake of omega-3 and MUFA was associated with lower inflammatory markers (IL-18 and CRP) and stronger antioxidant defense (SOD) [R, R].

SNP Summary and Table

Primary SNP:

APOA2 rs5082

• ‘A’ = not associated with obesity; typical response to saturated fat
• ‘G’ = associated with obesity and a poor response to saturated fat

Population Frequency: Around 15% of European descendants carry the “GG” genotype. This genotype is even less common in African and South Asian (5%) and East Asian (1.5%) populations.