The Link Between Genes and Weight in Humans

Genetic and environmental factors have a profound influence on how the body absorbs and utilizes energy. A growing body of evidence points to the link between genes and human weight, shedding light on the scientific basis of genetically-influenced obesity. In this article, we will explore the relationship between these two factors to find appropriate healthcare solutions for ourselves.

1. How do genes affect weight? An overview of genetic obesity

The number of calories your body uses and stores depends on your genetic makeup, physical activity level, and resting energy expenditure. You will gain weight if you take in more calories than you burn, and conversely, you will maintain your weight if you burn all the calories you consume in a day.

To date, scientists have discovered over 400 different genes linked to the causes of overweight/obesity. Genetic factors influence weight through various mechanisms, such as affecting appetite, feelings of fullness, metabolism, fat distribution in the body, and how you cope with stress. Numerous studies on twins have supported the hypothesis of genetic obesity. In addition, some studies evaluating BMI, waist-to-hip ratio, and skinfold thickness in obese people show that genetic causes account for a high percentage.

However, weight can still be affected by many factors other than genes, especially the living environment and daily habits. The influence of genes on weight varies from person to person. Research shows that in some people, genes account for only 25% of the factors causing overweight. Meanwhile, research on another group of subjects shows that the genetic influence can be as high as 70-80%.

The weight of the following individuals is at high risk of being strongly influenced by genetic factors:

• BMI at an overweight level from a young age.
• Having a father or mother or other relative who is overweight. The probability is up to 80% if both parents are obese.
• Unable to lose weight even when increasing physical activity and adhering to a low-calorie diet for many months.

2. Which genes influence BMI and body fat distribution?

There are about 20 genes that pose a high risk of causing obesity inheritance if mutations occur. Accordingly, these genes are divided into 3 main groups as follows:

2.1. The Leptin-Melanocortin Energy Balance Gene Group in the Hypothalamus

This group of genes encodes proteins that regulate the amount of food intake into the body, including peripheral molecules such as leptin, leptin receptor, ghrelin, peptide YY, and alpha-cell stimulating hormones such as pro-hormone convertase ⅓ (PC1/3), melanocortin-4 receptor (MC4R), and pro-opiomelanocortin (POMC).

Defects in the above genes lead to obesity due to excessive appetite. These patients can lose weight through restricting energy intake and taking appetite suppressants. Mutations with leptin, POMC, and MC4R deficiencies can lead to congenital obesity, accompanied by a feeling of severe hunger almost all the time. Therefore, people with severe obesity before the age of 2 should consider screening for the above gene mutations to find the cause and have an appropriate treatment plan.

In addition to the above gene group, scientists have also discovered a number of other mutations related to inherited obesity. SIM1 is a transcription factor essential for the development of the hypothalamus. Studies in SIM1 heterozygous mice show a decrease in the number of hypothalamic cells, leading to early-onset appetite syndrome and obesity. In humans, severe obesity is associated with gene translocations that cause SIM1 gene mutations.

The decreased expression of the neurotrophic factor BDMF affects eating behavior, according to data from many reports. BDNF and tyrosine kinase receptors affect the MC4R signaling pathway. Severe obesity has been recorded in children with inversion mutations in a chromosomal region containing the BDNF gene.

2.2. The group of genes that regulate fat cell distribution and differentiation 

Mutations in genes for adipocyte differentiation (peroxisome proliferator-activated receptor γ (PPAR-γ), diacylglycerol acyltransferase-1 (DGAT-1)) and pre-lipolytic genes (perilipin, β-adrenergic receptor) are associated with obesity in people without an appetite syndrome.

PPAR-γ increases the expression of some important adipocyte differentiation genes, regulates triglyceride synthesis and storage, and decreases leptin expression. PPAR-γ gene polymorphism mutations are also associated with obesity and the body’s insulin sensitivity.

Among them, the Pro12Ala gene mutation of PPAR-γ accounts for a relatively high rate, causing a decrease in PPAR-γ gene transcription, thereby reducing the process of adipogenesis. Therefore, people with this polymorphism mutation have a 2 times lower risk of obesity than normal people. In contrast, the Pro155Gln gene mutation of PPAR-γ promotes adipocyte differentiation, increasing the risk of obesity in patients.

Triglyceride synthesis in mammals is catalyzed by DGAT1 and DGAT2. According to research in mice, DGAT1 deficiency increases insulin and leptin sensitivity, leading to increased thermogenesis, decreased adipocytes, and more calories burned than normal mice. The results show that DGAT1-deficient mice are leaner and more resistant to diet-induced obesity.

The lipid breakdown of triglycerides is regulated by catecholamines and sympathetic stimuli through β-adrenergic receptors. Many different polymorphism mutations of β-2 and β-3-adrenergic receptors have been reported to be associated with genetic obesity.

Perilipin A is a protein that coats lipid droplets in adipocytes, which functions to control lipid breakdown. When the body is deficient in energy, β-adrenergic receptors are activated, promoting perilipin A to be phosphorylated by cAMP/PKA, allowing lipids to come into contact with lipase (fat-breaking enzyme). Mice lacking perilipin have the ability to prevent obesity because lipids are in direct contact with the catabolic enzyme, increasing the rate of lipid breakdown and metabolism.

2.4. The group of genes controlling mitochondrial biogenesis and adaptive thermogenesis

This group of genes is a therapeutic target in obese individuals who are unable to lose weight. Accordingly, adaptive thermogenesis is the process of expending energy in the form of heat in response to cold weather or excessive calorie intake. This process mainly takes place in brown adipose tissue and skeletal muscle.

The increase in mitochondrial number and the activity of the electron transport system is related to the adaptive thermogenesis process. In particular, PPAR-γ gene transcription plays an important role in controlling cellular energy pathways and mitochondrial biogenesis. Activation of cAMP/PKA promotes calorie burning by increasing thermogenesis and insulin sensitivity. Therefore, PKA mutations have been shown to be involved in energy regulation and obesity.

In addition, the transcription factor FOXC2 has been shown to increase cAMP/PKA pathway expression through stimulation of β-3-adrenergic receptors. Studies in mice overexpressing FOXC2 have shown a lean phenotype and increased insulin response. FOXC2 also increases the expression of several genes involved in mitochondrial biogenesis.

3. How do genetic and environmental factors affect weight loss? Why do some people maintain weight easily while others gain weight easily despite having the same lifestyle?

While there is ample evidence for genes linked to obesity, genetics is not the sole determinant of whether a person becomes obese. Environmental factors during development also greatly influence gene expression, such as sugary drinks, fried foods, foods high in saturated fat, lack of sleep, stress, and a sedentary lifestyle.

In addition, maternal overnutrition or undernutrition, stress, and exposure to toxins during pregnancy can also affect gene synthesis and lead to obesity. The use of antibiotics during pregnancy also leads to fatty liver due to metabolic dysfunction (MASLD).

Exercise, diet, and stress levels can all affect weight (even without any genetic mutations involved). Patients at high risk for genetic obesity can reduce their risk of obesity by adjusting their diet and building a healthy lifestyle, including regular physical activity. A 2008 study in the journal Diabetes showed that physical activity can inhibit the expression of the FTO allele (fat mass and obesity-associated gene). On the other hand, it is important to note that genetic factors cannot explain the rapid increase in the rate of obesity globally.

If you are at high risk for obesity due to genetics, that doesn’t mean you will definitely become obese. Although your genome may increase your appetite and decrease your metabolism, adhering to a weight loss plan combined with effective nutrition, physical activity, and behavioral control methods can help prevent and treat obesity. Obese patients who have been “struggling” with their weight should see a doctor to develop a weight loss plan that is as safe and effective as possible.

The information above highlights the connection between genes and weight in humans. It’s important to remember that genes are not the sole determinant of your weight. Individuals with a genetic predisposition to obesity can absolutely manage their weight through diet, exercise, and a healthy lifestyle.  If you are struggling to manage your weight, consult a doctor for advice and to develop a specific treatment plan.

References: health.harvard.edu, ncbi.nlm.nih.gov, healthline.com, healthlinkbc.ca, obesitymedicine.org