Weight Loss Genetics – FTO variants

The FTO gene is nick-named the ‘fat gene’ because of its association with obesity.  It was identified less than ten years ago in genome-wide association studies that looked at tens of thousands of people at a time to find out which genes are involved in obesity.  But identifying the gene didn’t explain why it was so widely linked to higher BMI as well as ADHD, depression, and dementia.

Early studies concluded that those with increased BMI and these variants also tended to have an increased energy intake with an association with elevated fat consumption. [ref]  In 2013, a study found that those with variants in the FTO gene are expressing more FTO which was thought to alter ghrelin mRNA causing higher ghrelin levels.[ref]  Some studies found that FTO deficient mice suffer from growth retardation and have reduced lean mass and fat mass,[ref] while other studies found different results.[ref]

Most recently, a 2015 study published in the New England Journal of Medicine points to FTO polymorphisms disrupting ARID5B which leads to increase IRX3 and IRX5.  These two genes are involved in turning fat cells into white fat that stores lipids instead of brown fat which is involved in thermogenesis.  Most of the current research is pointing to the variants in the FTO gene region really being associated with increased IRX3 levels.

FTO Genetic Variants

The first variants listed below are a block that are linked together (if you have a variant in one, you probably have a variant in all of them).  All of these are well studied with many links to obesity and  increased BMI.  A couple of the studies related to diet are listed below, but a quick search of PubMed will give you a lot more studies on each of these polymorphisms.

rs9939609 (A is the minor allele, fairly common)

  • one study found a low-fat, low-calorie diet worked better for those carrying the A allele [ref]
  • in children, the minor allele affected childhood weight gain more for those with low vitamin D levels.  [ref] [ref]

rs1421085 (C is the minor allele  )

  • considered the ‘causal variant’ by one study.  Prevents the binding of repressor protein ARID5B, therefore leading to increased FTO activity.  ARID5B represses IRX3 and IRX5, which leads to more white fat tissue instead of heat-producing brown fat.  [ref]

rs8050136 (A is the minor allele)

  • C allele carriers had 3x greater fat loss response due to exercise compared to AA [ref]
  • A allele carriers had 2.5x greater risk of obesity with high carb intake compared to CC [ref]

rs1121980 (A is the minor allele)

  • in one study, minor allele linked to higher BMI only with a high saturated fat intake. [ref]


Other FTO variants:

rs1558902 (A is the minor allele, fairly common in Caucasians)

  • Carriers of the risk allele had a greater reduction in weight, body composition, and fat distribution in response to a high-protein diet, whereas an opposite genetic effect was observed on changes in fat distribution in response to a low-protein diet. [ref]

rs3751812 (T is the minor allele )

  • Associated with higher BMI, lower HDL, higher LDL [ref]


Possible weight loss strategies:

Diet: There seems to be a small link between higher protein / lower fat diets and FTO genes.

Vitamin D studies:    A higher BMI leads to a lower vitamin D status, but not vice-versa, according to one study.  [ref]  But the studies on childhood obesity and FTO seem to tell a different story.  Vitamin D levels in childhood may make a difference in weight gain. [ref]

Angelica Sinensis, also known as Dong Quai,  has been shown in mouse studies to ameliorate obesity in a mouse model of FTO variants.  This is a traditional Chinese herbal supplement available in stores and online.

Back to IRX3 and IRX5…

After the initial study that was published in the New England Journal of Medicine in 2014, an MIT article sums up the new research as follows:

“Follow-up experiments showed that IRX3 and IRX5 act as master controllers of a process known as thermogenesis, whereby adipocytes dissipate energy as heat, instead of storing it as fat. Thermogenesis can be triggered by exercise, diet, or exposure to cold, and occurs both in mitochondria-rich brown adipocytes that are developmentally related to muscle, and in beige adipocytes that are instead related to energy-storing white adipocytes.”[ref]

That article goes on to say “Similarly, repression of IRX3 in mouse adipocytes led to dramatic changes in whole-body energy balance, resulting in a reduction of body weight and all major fat stores, and complete resistance to a high-fat diet.”

So the key seems to be to decrease IRX3 and/or IRX5 levels.  There are studies being done on different synthetic/pharmaceutical inhibitors, but so far I’m not finding much about natural foods or supplements that inhibit or decrease these two genes.

One interesting thought and rabbit trail is that according to a doctoral thesis from June 2016:  “Irx3 is stimulated under hypoxic conditions in vitro and mimics the expression pattern of EPAS1 under pro-angiogenic conditions.” The study is in endothelial cells and may not translate to adipose tissue. But if it does translate, then looking at decreasing hypoxia (lack of oxygen) may decrease IRX3.  So where does this lead me?  Breathing correctly as a way to decrease hypoxia.   Yoga and yoga breathing methods have been associated with health for thousands of years.  Tai Chi also involves a breathing component.[ref]

Here is a website on Normal Breathing with information on how many times per minute a person should be breathing. Deep breathing and hyperventilating cause less oxygen in your cells (hypoxia).  There is a chart on their homepage showing how breathing has changed over the last 100 years — and it is shaped a lot like charts for obesity.  (I know – correlation is not causation.)  Another resource to check out is Dr. Ray Peat’s articles on CO2.  The Normal Breathing website says “When we breathe more than the medical norm, we lose CO2 and reduce body oxygenation due to vasoconstriction and the suppressed Bohr effect caused by hypocapnia (CO2 deficiency). Hence, overbreathing leads to reduced cell oxygenation, while slower and easier breathing (with lower respiratory rates) improves cell-oxygen content.”

There are also supplements that claim to ‘oxygenate’ the blood.  CellFood is one such supplement, though I’m not sure if it works for weight loss or not.  The Amazon reviews seem to be mixed, but then everyone is different and what works for one person may not work for another.

As a side note, it is interesting to note where the weight goes in ‘weight loss’.  Turns out the majority of it is expelled as carbon dioxide from the lungs.  [ref]

The other issue involved in IRX3 and IRX5 seems to be brown fat and thermogenesis.  Cold showers and ice baths may be an option for weight loss here.

And finally coming full circle, an inhibitor of IRX5 (in prostate cancer cells) is Vitamin D, specifically the active version,  1,25-Dihydroxyvitamin D3. [ref]

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