Obesity and Genetics: What is the Connection?

Is Obesity Genetic?

Identifying the underlying causes of obesity can help equip us to more effectively treat this complex disease. Such insights may also benefit people living with obesity, since understanding the causes can ease some of the stigma and self-blame that sometimes accompany it. “It’s all in your genes” could provide a tidy explanation. It may also open opportunities for personalized medicine. However, genetics is only the start.

A growing body of evidence suggests that obesity is, in fact, genetic. Somewhere between 200 and 500 specific genes have been linked to the disease. Genes can influence things like how a person’s body stores fat, metabolizes nutrients, and signals feelings of fullness. Twin studies have supported the hypothesis that obesity is genetic. Several measures of obesity show a high rate of heritability, including BMI, waist-to-hip ratio, and skinfold thickness.

Whatever the role of genetics, there are typically additional factors at work. A combination of genetic and environmental factors influences body weight.

Genetic Causes of Obesity: Polygenic, Monogenic, and Syndromic Causes

Genetic causes of obesity tend to be polygenic, but can also be monogenic. The latter, owing to mutations in a single gene or groups of genes, are often sydomic and thus relatively rare. Examples include Prader–Willi or fragile X syndrome. Non-syndromic obesity could be monogenic, polygenic, or chromosomal in origin.

Polygenic Obesity: How Multiple Genes Contribute to Weight Gain

Polygenic obesity, as the name suggests, owes to multiple genetic factors. Sixty percent of genetic cases fit this category. According to Hinney and Hebebrand, “obesity results via the interaction of several of such polygenic variants and their combined interaction with environmental factors.”

No one of these gene variants guarantees obesity. Any one of them alone is generally considered low-risk. Many are also found in individuals without obesity. If a gene is found more commonly in individuals with obesity than in those without obesity, it is said to be associated with obesity. Some are found more frequently than others.

The Role of FTO in Obesity

One such gene is the fat mass and obesity-associated gene (FTO), which is found in up to 43% of the population. In the presence of readily accessible food, those with the fat mass and obesity-associated gene may have challenges limiting their caloric intake. The presence of this gene and other genes can cause:

• Increased hunger levels
• Increased caloric intake
• Reduced satiety
• Reduced control over eating
• Increased tendency to be sedentary
• Increased tendency to store body fat

The FTO allele allele associated with obesity is common in people with European ancestry, according to multiple studies and has been identified by genome-wide association studies (GWAS). It acts on a variety of biological and metabolic processes.

Researchers have taken a keen interest in FTO as a potential drug target for treating obesity. Several small molecule drugs and micronutrients have been found to control the expression or activity of FTO, thereby playing a role in regulating metabolism.

Monogenic Obesity: Severe Obesity Caused by a Single Gene

Monogenic obesity is less common, yet potentially easier to identify since it tends to affect people from a young age. Rare, high-risk genetic variations in roughly two dozen genes are known to cause monogenic obesity. The gene mutations linked to monogenic obesity are grouped into three broad categories:

1. Those that play a physiologic role in the hypothalamic Leptin-Melanocortin system of energy balance, including leptin, leptin receptor, melanocortin-4 receptor (MC4R), proopiomelanocortin (POMC), and prohormone convertase 1/3 (PC1/3).
2. Those necessary for the development of the hypothalamus, including SIM1, BDNF and NTRK2. Mutations of these genes lead to severe obesity.
3. Those whose functional relationship to obesity remains unclear, but in which obesity presents as part of a complex syndrome.

Rare single-gene defects cause severe obesity beginning in early childhood and are associated with extremely high levels of hunger. Individuals who developed severe obesity before age two should consider talking to an obesity medicine specialist about being screened for:

• Leptin deficiency
• POMC deficiency
• MC4R deficiency

Syndromic Obesity: The Links Between Genetic Syndromes and Obesity

Syndromic obesity is part of a rare inherited condition, present at birth and often associated with comorbidities. In addition to excess weight patients living with these conditions may also exhibit cognitive delay, dysmorphic features, organ-specific abnormalities, hyperphagia, and other signs of hypothalamic dysfunction.

Some of the more well-known syndromes that include obesity include:

• Prader-Willi syndrome
• Bardei-Bietl syndrome
• Cohen syndrome

An approach to treating or managing one of these syndromes would typically look very different from other types of obesity. Research is underway into molecules acting on the leptin-melanocortin pathway, a potential target in some forms of syndromic obesity.

Emerging Studies: Epigenetics and Obesity

Epigenetics, the study of gene expression that changes during a person’s lifetime due to environmental factors, presents a relatively recent but fertile area of research. Despite the large number of identified genes related to obesity, “these variants do not fully explain the heritability of obesity, other forms of variation, such as epigenetics marks, must be considered,” say Herrera, et. al. in the paper, “Genetics and epigenetics of obesity.” The authors continue, “environmental exposures during critical developmental periods can affect the profile of epigenetic marks and result in obesity.”

These critical developmental periods include pregnancy, with factors like maternal over- or under-nutrition, stress, and exposure to toxins. Early childhood is also a prime time in which poor nutrition is linked with epigenetic effects linked with obesity. Use of antibiotics during this phase is linked with metabolic dysfunction-associated steatotic liver disease (MASLD).

As a person moves through adulthood, environmental factors continue to affect gene expression. Factors linked to adult epigenetic modifications include high intake of sugary beverages, fried foods, and high saturated fats as well as poor sleep and a sedentary lifestyle.

Are Your Genes Your Destiny?

While genetic predispositions to obesity are very real and relevant, they are not the only thing that determines whether a person will develop obesity.

Environmental Factors

Exercise, diet, stress levels can all affect a person’s weight (irrespective of their epigenetic impacts). Even people with a genetic predisposition for obesity can reduce their risk through good nutrition and an active lifestyle. A 2008 study published in the journal Diabetes showed that physical activity offsets the effects of a common variant of FTO. Also consider that genetics would not explain the rapid global rise in obesity.

If someone has genes that predispose them to obesity, they are not predestined to develop obesity. While these genes can increase appetite and reduce metabolism, following a consistent treatment plan that incorporates effective nutritional, physical activity, and behavioral approaches can help prevent and treat obesity.

A patient struggling with weight may benefit from seeing an obesity medicine specialist to help develop a comprehensive medical obesity treatment plan.