Obesity Villain: FTO

Two of our previous posts have dealt with the general concept of genetic architecture and introduced the terms SNP (single nucleotide polymorphism) and GWAS (genome-wide association studies.) Previously, scientists had suspected that the whole obesity topic would turn out to be more complicated than anybody could imagine. In the public mind, which appreciates simplicity, a search was on for “the obesity gene.”

There were clues along the way, combined with much perplexity. Tara Parker-Pope wrote,

[…] while there is widespread agreement that at least some risk for obesity is inherited, identifying a specific genetic cause has been a challenge.

But a research team at the University of Exeter figured out that the human subjects with a fat mass and obesity-associated protein known as FTO were between 30% and 60% more likely to be obese than others, and that was an unignorable red flag. The metabolic disorders linked with diabetes were also obvious, and children with that trait were observably fond of eating. Altogether, it was a very promising path.

The FTO gene lives on chromosome 16 of typical humans, and some varieties of it seem to correlate with their obesity. Work on this began in 2007. In 2009, things picked up when FTO variants lined up with increased BMI in two sizable genome-wide association studies. By 2011, researchers had thus far confirmed 32 distinct genetic variations having to do with BMI and/or obesity.

A 2014 paper published by ScienceDirect noted that FTO had come a long way since being identified by GWAS only six years before. A number of studies contributed to showing that the FTO gene does impact food intake, but does not affect energy expenditure, so that was a bit of a puzzle. One FTO allele was suspected of having some relation to metabolic syndrome.

It was seen that FTO expression exerts influence on various internal circuits and cell populations, and in fact affects the entire central nervous system, particularly where the homeostatic control of eating takes place, in the hypothalamic nuclei.

Addiction, Self-Medication, and More

Rodent studies revealed that FTO variants indeed associate with obesity, and have something to do with energy homeostasis, dopaminergic signaling, and protein translation. It was found that “‘risk-allele’ carriers exhibit increased intake of highly palatable food and exhibit aberrant food responsiveness and satiety,” and “the inverse associations of the obesity risk alleles with psychiatric disorders such as addictive behavior, ADHD and depression are surprising.”

However, the researchers were unable to make a connection between FTO expression and fasting, or to resolve some other questions that perplexed them. The Discussion section began,

Clearly, by nature of the method, GWA studies can neither deliver any insight into the biological function of the gene in question, nor if the associated single nucleotide polymorphisms are functionally related to the gene in question at all.

The most prominent finding always seems to be that the role of FTO, in relation to obesity, is “complex and multidimensional.” There is also acknowledgement of a widespread trope:

Imbalances in dopaminergic signaling are closely related to the psychiatric disorders ADHD, addiction and depression. Eating and especially the enjoyment of food, on the other hand, impinge on the very same pathway. Hence, the observed overeating of highly palatable food in ‘risk-allele’ carriers may present a self-medication, leading to an attenuation of the symptoms of ADHD, addiction and depression.

(To be continued…)

Your responses and feedback are welcome!

Source: “The Fat Trap,” NYTimes.com, 12/28/11
Source: “The fat mass and obesity-associated (FTO) gene: Obesity and beyond?,” ScienceDirect.com, October 2014
Photo credit: Martin Abegglen (twicepix) on Visualhunt/CC BY-SA

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About Dr. Robert A. Pretlow

Dr. Robert A. Pretlow is a pediatrician and childhood obesity specialist. He has been researching and spreading awareness on the childhood obesity epidemic in the US for more than a decade.
You can contact Dr. Pretlow at:


Dr. Pretlow’s invited presentation at the American Society of Animal Science 2020 Conference
What’s Causing Obesity in Companion Animals and What Can We Do About It

Dr. Pretlow’s invited presentation at the World Obesity Federation 2019 Conference:
Food/Eating Addiction and the Displacement Mechanism

Dr. Pretlow’s Multi-Center Clinical Trial Kick-off Speech 2018:
Obesity: Tackling the Root Cause

Dr. Pretlow’s 2017 Workshop on
Treatment of Obesity Using the Addiction Model

Dr. Pretlow’s invited presentation for
TEC and UNC 2016

Dr. Pretlow’s invited presentation at the 2015 Obesity Summit in London, UK.

Dr. Pretlow’s invited keynote at the 2014 European Childhood Obesity Group Congress in Salzburg, Austria.

Dr. Pretlow’s presentation at the 2013 European Congress on Obesity in Liverpool, UK.

Dr. Pretlow’s presentation at the 2011 International Conference on Childhood Obesity in Lisbon, Portugal.

Dr. Pretlow’s presentation at the 2010 Uniting Against Childhood Obesity Conference in Houston, TX.

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