The Gene Glitch and the Metabolic Master Switch

Kellis drawing

Sketch by Alex Cagan (@ATJCagan) of one of the New England Journal of Medicine study authors, Manolis Kellis, referencing first author, Melina Claussnitzer.




What Is the FTO Gene and How Is It Related To Obesity?

We know Body-Mass Index (BMI) has a strong genetic component, and we know being obese is a risk factor for leading global causes of death such as Type 2 Diabetes, cardiovascular disease, and cancer. But until this week, we didn’t know how our genes might play a role in the mechanisms of obesity.

The strongest genetic signal for BMI is in the FTO gene, but the causal nucleotide sequence and its function have been murky since its discovery in 2007.

Obesity affects more than 500 million people worldwide, which is why a new study published in New England Journal of Medicine (NEJM) this week is so important. Melina Claussnitzer, Simon Dankel, Manolis Kellis, and colleagues at Harvard, MIT, Beth Israel Deaconess Medical Center, and the Broad Institute show how a faulty variant of FTO causes human adipocytes (fat cells) to store energy from food rather than burn it.

The Gene Glitch

Diet and exercise affect energy balance—unused energy is stored, primarily as lipids in white adipocytes—but how might genetics also contribute to metabolism? That is the question; the $2-trillion-dollar question if you consider obesity’s health-related costs and global economic impact.

Brown adipose tissue is a key site of heat production (thermogenesis), while its lighter-hued relative, also known as beige cells, are known to develop in white fat in response to various activators. There’s a hypothesis that obese persons have fewer beige adipocytes and therefore are primed to gain weight on high-fat diets. Having the FTO “gene glitch” doesn’t mean you are predestined to become obese, but you could be predisposed to it.

genes make me look fatThe Metabolic Master Switch

The FTO gene turns out to have an indirect influence on obesity, acting as a kind of “master switch” that affects two other genes that control thermogenics, or burning off energy by making heat. Thermogenesis can be triggered by mechanisms within the cells themselves or by the sympathetic nervous system in response to exercise, diet, or exposure to cold.

With the completion of the Human Genome Project in 2003 and the International HapMap Project in 2005, researchers can locate genetic contributions to common diseases. Analysis of whole-genome samples for genetic variations that contribute to the onset of a disease are called genomewide association studies. For this week’s NEJM study,  Claussnitzer, Dankel, Kellis, and colleagues collected subcutaneous fat samples provided by 100 healthy Europeans aged 20 to 50 years with normal BMI (20 to 24).

Fat cellsUsing a range of genomic techniques, the researchers found a mechanism whereby the basic function of human adipocytes shifted from storing fuel to using it.

This work has at least four implications.

  1. The results support previous studies indicating that browning of white adipose tissue can affect physiology.
  2. There’s now a new strategy for how to use data from genomewide association studies and translate that information to help identify new pathways in health-related conditions beyond obesity.
  3. It may be feasible for an anti-obesity drug to nudge cells to use energy instead of storing it. This is a long way off, but the researchers are seeking a patent.
  4. Stay tuned for more debate about genetic engineering, ethics, and the intersection of science, technology (e.g., CRISPR-Cas9) and human disease, such as the article in this week’s Economist magazine.

It might sound like science fiction or the next Harry Potter book, but the Gene Glitch and the Master Switch—or, more importantly, the potential link between genetics and obesity—is a most compelling scientific finding.  

About Amanda Pearson

Editing & writing @HarvardWCFIA on global politics, people, history, and health. Alumna @GWpublichealth @LSEGovernment
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