UCP1 Polymorphisms: obesity, diabetic retinopathy

Uncoupling Protein 1 (UCP1 gene) is found in the mitochondria of brown adipose (fat) tissue.   It is activated by fatty acids and inhibited by purine nucleotides.  UCP1 is found in brown fat and in the retina.  There are several polymorphisms of the UCP1 gene that decrease its activity.   The pathway by which UCP1 is activated is described by the Wikipedia article, Thermogenin:

UCP1 is activated in the brown fat cell by fatty acids and inhibited by nucleotides. Fatty acids cause the following signaling cascade: Sympathetic nervous system terminals release Norepinephrine onto a Beta-3 adrenergic receptor on the plasma membrane. This activates adenylyl cyclase, which catalyses the conversion of ATP to cyclic AMP (cAMP). cAMP activates protein kinase A, causing its active C subunits to be freed from its regulatory R subunits. Active protein kinase A, in turn, phosphorylates triacylglycerol lipase, thereby activating it. The lipase converts triacylglycerols into free fatty acids, which activate UCP1, overriding the inhibition caused by purine nucleotides (GDP and ADP). At the termination of thermogenesis, the mitochondria oxidize away the residual fatty acids, UCP1 inactivates and the cell resumes its normal energy-conserving mode.

Brown adipose tissue primarily generates body heat, while white fat is used by the body to store energy.  Babies are born with up to 5% of their body mass as brown fat.  This helps to keep the newborn warm since they cannot shiver.  Adults have relatively little brown fat, and it is mostly in the neck and upper chest.  There has been a lot of studies and interest in turning on brown fat in order to induce weight loss and protect against heart disease.  There is an excellent article on brown fat on the Knowledge of Health website that includes information on inhibiting and inducing brown fat activation.

Inhibitors of UCP1 include beta blockers.  Looking at the pathway description above, beta blockers block the Beta-3 adrenergic receptors.  Iron deficiency also inhibits brown fat activation. [ref]

Brown adipose tissue activity is increased through induction of UCP1 by cold temperature and thyroid hormones. Bile acids were also shown to increase thyroid activity through induction of UCP1[ref]   Other inducers of brown fat include fish oil and iron (in those that are iron deficient). [ref]

UCP1 -3826A/G (rs1800592) polymorphism has been linked to obesity and diabetic retinopathy risk.  The risk allele is usually referred to as G in studies, and it is C in 23andMe data.   A 2013 study found that this polymorphism accelerated an age-related decrease in brown fat activity. [ref]  Another study showed that the polymorphism was only significant in women.[ref]  A 2011 study of young women showed that the G allele had less weight loss on a low-calorie diet than those without the polymorphism. [ref]

Other studies found that the G/G genotype (CC for 23andMe) has OR=3.5 for diabetic retinopathy in those with Type I diabetes.  [ref] [ref]  Note that not all studies link UCP1 to increased BMI.[ref]

Check your 23andMe results for rs1800592:

  • TT: normal risk for obesity
  • CC: weak UCP1 activity, higher risk of abdominal fat, obesity; diabetic retinopathy[ref]

 

Check your 23andMe results for rs3811787:

  • TT: normal risk for obesity
  • GG:  higher risk of abdominal fat[ref]

Excellent overview of the issues associated with UCP1 polymorphisms: The role of the uncoupling protein 1 (UCP1) on the development of obesity and type 2 diabetes mellitus

Diet and Supplements

One way to stimulate brown fat is through cold.

Rutin, a polyphenol found in fruits and vegetables, has also been recently found to stimulate brown fat in an animal study.  If you want to supplement with rutin, it is available in a powder form as well as in capsules.

 

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