Weight Loss Genetics – UCP2

Weight Loss and Your Genes – UCP2 Polymorphisms

Several variants in the UCP2 gene have been tied to obesity in a number of studies.  So what is UCP2 and what does it do?  The UCP2 gene codes for an uncoupling protein that works in the mitochondria (energy powerhouse) of our cells. It is found in a variety of tissues throughout the body including white and brown fat cells, muscle, liver, kidney, heart, liver, lungs, and more. [ref]

One study explains that “UCP2 activity influences glucose homeostasis by fine-tuning intracellular events related to the cellular energy status, thereby controlling insulin secretion, food intake behavior and adiponectin secretion in pancreatic β-cells, brain and white adipose tissue, respectively.” [ref]  It does this through regulating the membranes of the mitochondria to move anions and protons.

A 2011 study explains the role of uncoupling proteins in the mitochondrial respiration chain:

“It was proposed that both UCP2 and UCP3 only mildly uncouple respiration, slightly dissipating membrane potential energy, and thus slightly decreasing ATP production (8,18) (Figure 1A). Nonetheless, unlike UCP1, UCP2 and UCP3 only uncouple MRC after suitable induction by cold, ROS (particularly superoxide), ubiquinone, high levels of glucose and/or non-esterified fatty acids, high impact exercise, sepsis, and hyperthyroidism. Their activities are inhibited by purine, such as ATP and GDP, and by interleukin-1β (24,25). As already mentioned, MRC uncoupling generated by UCP2 leads to protection from excess ROS production, while it also seems to be associated with inhibition of insulin secretion by beta cells and regulation of FFAs metabolism and transport (18,22,26).

“Mild uncoupling” of MRC due to UCP2 activity allows a more rapid flux of electrons through the mitochondrial inner membrane, reducing membrane potential and decreasing ROS production (6). Since even “mild uncoupling” has a large effect on reducing ROS production, the hypothesis that UCP2 protects against oxidative stress is strongly supported and is now generally accepted (6).”[ref]

Note that after reading quite a few studies, I don’t believe that there is a real consensus on how UCP2 works.

Studies have found: 

rs659366 (minor allele is T (23andMe orientation), also referred to as -866G/A)

  • “Thus, the minor A-allele [T for 23andMe] directs higher rates of transcription from the UCP2 promoter compared with the G-allele.” [ref]
  • The minor T allele (23andMe orientation) is associated with larger waist circumference, obesity, and higher BMI. [ref] [ref] [ref]
  • A Bali study found that those with T/T had a higher BMI — but only in those living in an urban area.  Those who were homozygous for the T allele who lived in a rural area had no increase in BMI.  [ref] So environment definitely plays a role in the risk for obesity with this polymorphism.
  • The minor allele is associated with a higher risk of diabetes in women [ref]
  • A small study of diabetic patients (around 100 participants) found that those with the minor allele on β-blocker treatment were 11 times more likely to be re-hospitalized for cardiac events compared to those not on β-blockers.   Those who did not carry the T allele had an 80% reduction in re-hospitalization for cardiac events. [ref]  The full study is available to read and should be considered if you are diabetic and on β-blockers.  No effect was found for non-diabetics.
  • Note that other studies have found little links to obesity. [ref]
  • Sibutramine (a weight loss drug that has now been pulled from the market) only worked in those with the T allele in this study.  [ref]

rs660339 (A in 23andMe orientation,  aka Ala55Val)

  • The A allele is associated with obesity, higher BMI, and waist circumference [ref] [ref]
  • A study found that the minor allele contributes to a longer lifespan. [ref]
  • Those with the minor allele had greater weight loss after gastric banding. [ref]

rs1800849 (minor allele is G (23andMe orientation) also known as T55C in UCP3)

  • Indians homozygous for the minor allele had higher fasting glucose, HbA1c, and triglycerides (study participants all had heart disease). [ref]
  • A 2016 study looked at the effect of this variant on a high protein/low carb diet vs. a hypocaloric diet of 1,000 calories/day.  The study found that for both diet types, individuals without the minor allele lost more weight.     [ref]

What to do if you have this variant and want to lose weight?

Other than sibutramine (weight loss drug pulled from the market for risk of cardiac events), I didn’t find any research studies showing weight loss methods associated specifically with the above-listed variants.

Aster_spathulifolius2
Aster spathulifolius

There are several things that should increase UCP2 in general:

  • An extract from asters – specifically Aster spathulifolius- was recently found to lower body weight gain in rats on a high-fat diet.  UCP2 expression was increased by the aster extract.  Again, this was a rat study, so it may not apply exactly to humans. [ref]  Here is another article on using aster extract for weight loss.
  • UCP2 is increased by cold and high-fat feeding [ref]  Ben Greenfield has a good article on cold thermogenesis.  (I won’t be trying this one out since I really dislike being cold and take a long time to warm back up!)  One form of high-fat feeding would be a ketogenic diet.
  • Bariatric surgery increases UCP2 [ref]
  • Going without oxygen increases UCP2 [ref]  (Not trying this one either!)
  • A high-fat diet, red wine and resveratrol increase UCP2 expression in muscle tissue (rat study).  Grape juice increased UCP2 expression in adipose (fat) tissue. [ref] This is one that I am willing to try out!

Overall, I’m not convinced that trying to increase UCP2 is a good idea in the long run.  It seems to be a balancing act between reactive oxygen species, inflammation, and energy balance.  Maybe the way to look at this variant is that it makes a person more ‘metabolically thrifty’.

Comments 1

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