This is a take of mine to provide an introduction post on the genetics of obesity. Obesity is one of the noncommunicable diseases that is one of the significant public health concerns globally, not only in developed countries but developing as well.
My idea is to continuously update this blog post and keep it as a live document on the most recent research focusing specifically on the genetics of obesity. I will try to write it in plain language so it’s accessible to a broader audience.
As usual, I will provide a table of contents so you can quickly jump into the sections you find most interesting for you:
⚖️ What is Obesity?
Let’s first start with defining what obesity is. A simple technical definition would be that obesity is a medical condition characterized by an excessive accumulation of body fat. Over the past four decades, the prevalence of obesity has skyrocketed, tripling in number and imposing significant health risks.
According to the World Health Organization (WHO), the global prevalence of obesity nearly tripled between 1975 and 2016. In 2016, more than 1.9 billion adults aged 18 years and older were overweight, and of these, over 650 million were obese [reference].
Obesity has a significant economic impact, as it can lead to increased healthcare costs and lost productivity. The costs associated with treating obesity-related conditions, as well as the indirect costs, such as loss of income due to disability or premature death, can be substantial.
🧬 🍲 🏃♀️What Causes Obesity? Genetics & Environment
A combination of genetic, physiological, behavioral, and environmental factors is considered the leading cause of obesity. While all these multiple factors contribute to obesity, two primary causes are our surrounding environment and our very own genetic makeup.
For example, our diet is determined by both genetics and environment. To simplify, the environmental component of diet relates to socioeconomic factors. In contrast, the genetic component of diet would be related to taste preferences and eating behaviors, among others. Similar decomposition of physical activity or inactivity can be done, which would lead to genetic and environmental factors defining your physical activity/inactivity. This goes on for all other listed factors that contribute to the onset of obesity, like psychological factors and other medical conditions where the contribution of genetics and environment differs.
Our environment plays a crucial role in our health, especially regarding obesity. There is a concept called "obesogenic environment," which refers to surroundings that promote weight gain, often characterized by the easy availability of high-calorie foods and sedentary lifestyles.
Still, while environmental factors set the stage, our genes actually determine how we interact with the environment. Just as two individuals can eat the same diet but have different weight outcomes, and our genetic blueprint plays a role in how our bodies process and store energy.
👪🏽So, Is Obesity Heritable? What is the heritability of obesity?
So, Yes, many studies have shown that obesity has a strong genetic component. These include twin, family, and adoption studies, which estimated that the heritability of obesity ranges between 40% and 70%. This means that a significant portion of an individual's risk of becoming obese can be attributed to their genes.
However, it's essential to remember that genes alone don't dictate our weight; they interact with our environment in a complex interplay.
📊 What Type of Genetics Control Obesity?
The genetic component of obesity can be broadly categorized into two types: monogenic obesity and polygenic obesity.
Monogenic Obesity is caused by a mutation in A SINGLE OR FEW GENES and is typically RARE; it has EARLY ONSET and shows SEVERE SIGNS. For example, mutations in the "ob" gene in mice lead to severe obesity. In humans, specific chromosomal deletions or single-gene defects can lead to monogenic obesity. For example, well-described ones are those in LEPR (Leptin Receptor), POMC (Proopiomelanocortin), and PCSK1 (Proprotein Convertase Subtilisin/Kexin Type 1) genes, among others.
Polygenic Obesity is a MORE COMMON form resulting from the interaction between hundreds and thousands of genetic variants in a LARGE NUMBER OF GENES and the obesogenic environment. Each genetic variant has a SMALL EFFECT, but collectively, they can significantly influence body weight. For example, while one gene might slightly increase your craving for sweets, another might slow your metabolism. Together, they can set the stage for weight gain, especially in an environment where high-calorie sweets are readily available.
☯️ The Difference Between Monogenic and Polygenic Obesity
I assume you already know the main differences between monogenic and polygenic obesity by just reading those two definitions.
While both monogenic and polygenic obesity have genetic underpinnings, their causes differ in complexity:
Monogenic Obesity is the result of a mutation in one specific gene. It's like a single faulty piece in a complex machine that leads to a breakdown. This type of obesity is often severe, early-onset, and doesn't require significant environmental triggers to manifest.
Polygenic Obesity arises from the cumulative effect of small variations in multiple genes. It's akin to having several slightly worn-out parts in a machine, each contributing a little to its suboptimal performance.
Figure 1. aims to visualize the key features of monogenic and polygenic obesity.
✍️ Examples of Genes Causing Monogenic Obesity
I already mentioned some of the genes which, when mutated, can lead to monogenic obesity. As I already mentioned two times, monogenic obesity results from mutations in a single gene and is characterized by severe, early-onset obesity. Here is the list of well-described genes known to be involved in the onset of monogenic obesity:
LEP (Leptin): Mutations in this gene lead to leptin deficiency. Leptin is a hormone produced by adipose tissue (fat) that regulates food intake and energy expenditure.
LEPR (Leptin Receptor): Mutations in the LEPR gene result in a lack of response to leptin, leading to uncontrolled appetite and severe obesity. I also wrote a blog post about the LEPR gene that you can check out here.
POMC (Proopiomelanocortin): Mutations in this gene can affect the production of several hormones, including those that regulate appetite. I also wrote a blog post about the POMC gene you can check out here.
PCSK1 (Proprotein Convertase Subtilisin/Kexin Type 1): This gene is responsible for the processing of several precursors into their active hormones, including those involved in appetite regulation. Here you can check a series of posts we wrote about PCSK1 gene.
MC4R (Melanocortin 4 Receptor): Mutations in this gene are one of the most common genetic causes of obesity. MC4R plays a crucial role in regulating food intake and energy balance.
SIM1 (Single-minded 1): Mutations can lead to both obesity and a specific pattern of neurodevelopmental abnormalities.
BDNF (Brain-Derived Neurotrophic Factor) and its receptor NTRK2 (Neurotrophic Receptor Tyrosine Kinase 2): Both are involved in the development and function of the brain regions that regulate energy balance.
SH2B1 (SH2B Adaptor Protein 1): This gene is involved in leptin and insulin signaling, and mutations can lead to severe early-onset obesity.
KSR2 (Kinase Suppressor of Ras 2): Mutations in KSR2 can result in obesity, insulin resistance, and impaired cellular energy metabolism.
TUB (Tubby Bipartite Transcription Factor): Mutations can lead to obesity in both humans and mice.
It's important to note that while mutations in these genes cause obesity, they are relatively rare. Most cases of obesity are multifactorial, resulting from genetic, environmental, and behavioral factors. Additionally, with the advances in genomics, more genes associated with monogenic forms of obesity will likely be identified. If you're interested in the most up-to-date information, consulting current scientific literature or specialized genetic databases would be advisable.
🔗What is the Link Between Monogenic and Polygenic Obesity?
Monogenic and polygenic obesity might seem distinct, but studies have shown they might share some underlying biology. The central nervous system, particularly neuronal pathways controlling food intake, seems to be a common factor in both cases.
There is some early evidence that even suggests that the expression of mutations causing monogenic obesity may be influenced, at least to some extent, by an individual's polygenic susceptibility to obesity. This overlap hints at the intricate genetic factors influencing our body weight.