Genetic testing is a more recent advancement that can have profound impacts on health and weight management. Genetic testing helps to identify specific mutations in our genes that predispose us to certain health risks. Knowing this information, we can take a more personalized approach to treatment. In this article, we will discuss key genes related to weight loss and metabolic rate, lipid metabolism and cardiovascular risk, glucose and insulin sensitivity, hormone metabolism, and appetite and behavioral factors.
Several genetic polymorphisms can increase one’s risk for developing obesity. Let’s review some of the most common ones.
FTO (Fat Mass and Obesity-associated gene)
The fat mass and obesity associated (FTO) gene is one of the most significant genes associated with obesity. Certain risk alleles of FTO polymorphisms are linked to obesity and a higher body mass index (BMI). More specifically, scientists have investigated the rs1421085 and rs17817449 polymorphisms and the rs1421085–rs17817449 haplotype. Genome-wide associations studies indicate that these specific polymorphisms can lead to worse eating habits (increased hunger and emotional disinhibition), increased intake of refined starches and high fat foods, and increased depressive symptoms (1).
MC4R (Melanocortin 4 Receptor)
Mutations in the melanocortin 4 receptor (MC4R) are linked to inherited obesity. As many as two to five percent of severely obese children have an MC4R deficiency, and about one percent of severely obese adults (one in 500 of the population) have an MC4R deficiency. This is because individuals with an MC4R genetic mutation are predisposed to weight gain in early childhood. They tend to have increased fat mass, increased hunger, and impaired satiety (2).
PPARG (Peroxisome Proliferator-Activated Receptor Gamma)
Peroxisome proliferator-activated receptor gamma (PPARG) is involved in gene expression related to lipid metabolism, metabolic syndrome, obesity-induced inflammation, and atherosclerosis. PPARG variant has been associated with increased BMI and insulin resistance (3).
UCP1, UCP2, UCP3 (Uncoupling Proteins)
Uncoupling proteins (UCPs) such as UCP1, UCP2, and UCP3 are important to metabolic efficiency and energy balance. As such, single nucleotide polymorphisms (SNPs) have been associated with risks in cardiometabolic diseases such as obesity, lipid metabolism, type 2 diabetes, and cardiovascular disease (4,5).
Understanding these genes and an individuals’ genetic makeup can be integral to developing tailored weight loss strategies. For example, if a patient has an FTO gene polymorphism, they likely experience increased hunger and poor eating habits. As such, they may benefit from structured meal plans that include high protein and fiber-rich foods to increase satiety and prevent emotional eating.
Just as certain genes can increase someone’s risk of developing obesity, other genes can impact blood sugar regulation and insulin sensitivity.
TCF7L2 (Transcription Factor 7-Like 2)
Transcription Factor 7-Like 2 (TCF7L2) is strongly associated with an increased risk in type 2 diabetes. In particular, SNPs rs7903146 and rs12255372 are associated with the greatest odds ratio of 1.4 in terms of diabetes risk. Variants in TCF7L2 are linked to impaired blood sugar regulation and disordered insulin secretion (6).
IRS1 (Insulin Receptor Substrate 1)
The insulin receptor substrate-1 (IRS1) is important in pathways related to insulin signaling. As such, IRS1 genetic mutations can predispose somebody to insulin resistance and type 2 diabetes (7).
ADIPOQ (Adiponectin)
Mature adipocytes (fat cells) produce adiponectin, a protein that increase insulin sensitivity and that possesses anti-atherogenic effects. The Finnish Diabetes Prevention Study indicated that genetic variations in ADIPOQ can lead to differences in body size and adiponectin concentrations while also influencing one’s risk of type II diabetes (8).
Genetic insights regarding the aforementioned genes can help guide treatment regimens and lifestyle modifications to prevent diabetes. For example, individuals with variants in TCF7L2, which can be associated with impaired glucose regulation and diabetes, may benefit from a low-glycemic diet to prevent rapid blood sugar spikes.
Other genetic variations can impact the body’s metabolism of lipids and subsequent cardiovascular risk.
APOA5 (Apolipoprotein A5)
Apolipoprotein A5 (APOA5) is a gene that encodes apolipoprotein. Apolipoprotein is a protein that’s essential to regulating plasma triglyceride levels. Triglyceride concentrations are an important risk factor for coronary artery disease. As such, mutations in the APOA5 gene are linked to hypertriglyceridemia and hyperlipoproteinemia (9).
APOC3 (Apolipoprotein C3)
Apolipoprotein C3 (APOC3) codes for very low-density lipoproteins (VLDL), high density lipoproteins (HDL), and chylomicrons and impacts their metabolism. Mutations to APOC3 can lead to decreased triglyceride levels and lower risk of cardiovascular disease (10).
PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9)
Proprotein convertase substillisin/kexin type 9 (PCSK9) codes for a protein that regulates cholesterol levels, specifically low-density lipoprotein (LDL) receptors. PCSK9 gene mutations are associated with familial hypercholesterolemia and familial hypobetalipoproteinemia (11).
LPL (Lipoprotein Lipase)
Lipoprotein lipase (LPL) codes for an enzyme known as lipoprotein lipase. This enzyme is located in the capillaries of adipose tissue and is responsible for fat breakdown into triglycerides. As many as 220 LPL genetic mutations are known to cause familial lipoprotein lipase deficiency. This condition causes abnormal triglyceride breakdown, thus increasing fat (12).
Genetic testing can tell us on how our bodies metabolize lipids and where abnormalities occur, thus informing potential targeted treatments. For example, individuals with PCSK9 mutations would likely benefit from PCSK9 inhibitors that specifically target this pathway to lower cholesterol.
SRD5A2 (5-Alpha-Reductase Type 2)
The 5-alpha-reductase type 2 gene, or SRD5A2 gene, is responsible for encoding an enzyme known as steroid 5-alpha reductase 2. This enzyme is important to processing androgens, which are male sex hormones. More specifically, it modulates the conversion of testosterone into dihydrotestosterone (DHT).
Mutations in SRD5A2 are associated with 5-alpha reductase deficiency, which means the body cannot convert testosterone into DHT. Additionally, certain polymorphisms of SRD5A2 are associated with prostate cancer (13).
CYP19A1 (Aromatase)
The CYP19A1 gene codes for the aromatase enzyme. This enzyme is responsible for androgen conversion into the female sex hormone estrogen. CYP19A1 mutations can cause aromatase deficiency, which leads to low estrogen and high androgen levels. This can impair sexual development in females and cause abnormal bone growth and insulin resistance. Mutations can also cause aromatase excess syndrome, which results in gynecomastia (enlarged breasts) and short stature in men (14).
SHBG (Sex Hormone-Binding Globulin)
The sex hormone-binding globulin (SHBG) gene encodes a protein that is responsible for transporting androgens and estrogens throughout the blood. Genetic polymorphisms in SHBG can cause polycystic ovarian syndrome (PCOS) and type 2 diabetes (15).
ESR1 & ESR2 (Estrogen Receptors 1 and 2)
The ESR1 and ESR2 genes encode for proteins that are important to follicular development and ovulation. Mutations in these estrogen receptor genes can contribute to the development of PCOS, and as such these SNPs could be biomarkers to predict PCOS risk (16).
NR3C1 (Glucocorticoid Receptor)
The NR3C1 gene codes for the glucocorticoid receptor, which is where both cortisol and other glucocorticoids bind. As a result, mutations to this gene are linked to glucocorticoid resistance (17).
A baseline understanding of how genetics impact hormone metabolism can help us to manage hormonal conditions such as PCOS and menopause. For example, mutations to ESR1 and ESR2 impact the function of estrogen receptors, which can be predictive of someone’s PCOS risk. If someone has mutations in these genes, we can leverage these genetic insights to optimize lifestyle modifications and hormone replacement therapy to support hormone health.
LEPR (Leptin Receptor)
Fat cells secrete a hormone known as leptin, which is important to energy regulation and appetite control. Leptin binds its receptor known as LEPR. As such, mutations in LEPR have been linked to early onset obesity (18).
DRD2 (Dopamine Receptor D2)
The dopamine receptor D2 (DRD2) gene is a key component of the dopaminergic system. The DRD2 gene is associated with conditions impacting reward pathways such as alcoholism, polysubstance abuse, smoking, obesity, and attention deficit hyperactivity disorder (ADHD) (19).
BDNF (Brain-Derived Neurotrophic Factor)
The brain-derived neurotrophic factor (BDNF) gene encodes for a protein known as BDNF, found within the brain and spinal cord. This protein is important to the growth, development, and survival of neurons. As a result, BDNF protein regulates synaptic plasticity, an essential component to memory and learning (20). Additionally, BDNF is important to regulating body weight and energy homeostasis (21)
These genetic factors can shape somebody’s eating behaviors, cravings, and ability to manage their weight. Understanding these genes can thus inform strategies for weight management. For example, someone with a mutation in DRD2may struggle with addictive behaviors associated with eating, including experiencing cravings and overeating. Knowing this, we can implement psychological strategies like cognitive behavioral therapy (CBT) to address the reward system associated with food and implement dopamine-regulating activities like exercise.
In summary, there are a number of genes that can impact various aspects of our health, including our appetite, weight, hormones, and reward systems. Advanced precision testing allows us to identify genetic mutations, giving us a better understanding of our risk factors for disease. Knowing this information allows us to take a personal approach to medicine, enabling targeted treatments and lifestyle interventions that can support the unique needs of the individual that are encoded within their DNA.
If you’re struggling with your health, consider exploring genetic testing as a tool for tailoring your health and wellness strategies.
