I’m geeking out this week and diving deep into the genetics of weight and obesity.
One fairly well-studied variant, rs5443, confers a 2x to 3x risk of obesity and is found in the GNB3 gene.
So what is the GNB3 gene? The G protein β-polypeptide 3 gene (GNB3) is involved in translating signals from the cell surface into a cellular response. A Nobel Prize was awarded in 1994 for the discovery of G-proteins and their role in signaling. So if your last biology class was prior to 1994, here is a video explaining G proteins: https://www.youtube.com/watch?v=wC2_7Ror3qY The Wikipedia article on G proteins is also good to read.
rs5443 – minor allele is T, also known as GNB3 C825T (v.4 and v.5)
While the minor allele is T for most populations, it is actually the most common allele for those of African descent. For example, Caucasians have approximately 10% with T/T while Africans have approximately 80%.
In a nutshell, this variant has been linked to cardiovascular events, hypertension, and obesity.
Before we get into the weight-related aspect of this SNP, let’s look at a couple of other things that are linked to it.
How does this GNB3 polymorphism work?
First off, apparently this variant isn’t exactly what actually causes the changes in the signaling activity, but it is linked to a deletion further along. “This polymorphism does not affect the amino acid sequence. However, the T allele is in almost complete linkage disequilibrium with a series of other polymorphisms within the GNB3 gene, the so-called ‘T-haplotype’, which is associated with deletion of nucleotides 498–620 of exon 9, due to alternative splicing. It has been shown that this splice variant is functional and is postulated to be associated with enhanced signaling activity”[ref]
If you watched the video (above) on the G proteins, it explains how the alpha subunit is turned on and off, releasing GDP in the cell. The consensus seems to be that this variant induces a “splice variant” which is a structural change in the beta subunit. The change in the beta subunit is theorized to help the GDP exit and increase the activity of the G protein. The link to higher blood pressure comes from an increased sensitivity to the vasoactive pressor hormones. [ref]
A 1999 study, Worldwide Ethnic Distribution of the G Protein B3 Subunit 825T Allaele and Its Association with Obesity in Caucasian, Chinese and Black African Individuals, is worth reading for the background on how the variant may affect both BMI and blood pressure. It looks at it from the “thrifty” gene hypothesis.
Re-cap and tie it together:
The T allele leads to enhanced signaling for a G Protein beta, which causes the alpha subunit to be more active. This leads to overall more sensitivity to certain hormones.
Serotonin, dopamine, and norepinephrine are involved.
Sodium plays a role. Na+ / H+ exchanger activity is involved, as is an influence from high salt (>12.4 g/ day) diet.
Lipolysis is the breaking down of fat cells, so an antilipolytic effect would keep the fat stored in the fat cells.
Estrogen upregulates the number of antilipolytic α2-adrenergic receptors specifically in subcutaneous fat. [ref]
In a study on the effect of the C825T variant on lipolysis: “Fat cells of T/T carriers showed a significant 10-fold decrease in the half-maximum effective concentration of agonists selective for lipolytic beta(1)- and beta(2)-adrenoceptors as well as for the antilipolytic alpha(2)A-adrenoceptor. In T/T carriers, maximum beta-adrenoceptor agonist-stimulated lipolysis was decreased, but the maximum antilipolytic effect of alpha(2)-adrenoceptors was less marked. Norepinephrine-induced adipocyte lipolysis and circulating fasting levels of free fatty acids and glycerol were reduced by half in T/T carriers.” [ref] This study also found “Our lipolysis data therefore suggest that the T-to-C substitution alters the Gβ3 protein in a way that decreases signaling of β1–, β2-, and α2-adrenoceptors for adipocyte lipolysis at some earlier steps above protein kinase A. The polymorphism may have a more marked effect on Gαs– than Gαi-coupling, as responsiveness for norepinephrine was decreased in adipocytes of T/T carriers. Norepinephrine’s effects on lipolysis reflect the net sum of β- and α2– adrenoceptor signaling” [ref]
Possible weight loss strategies for GNB3 variants:
Norepinephrine levels could be boosted using foods with tyrosine and phenylalanine such as bananas, chicken, cheese, chocolate. Be Brain Fit has a good article outlining balancing norepinephrine naturally. Edited to add: Maca, a Peruvian medicinal plant, was shown to raise both dopamine and norepinephrine in a 2014 study involving mice. [ref] Also, anyone with COMT variants may want to be careful with anything that changes dopamine and norepinephrine levels.
Fasting may not be the way to go. A 2009 study looked at the effects of an 8-day modified medical fast (<350 kcal/day) stratified by GNB3 C825T polymorphism type. It found “Whereas weight loss was not dependent on genotype, both mood and hunger were significantly associated with genotype, with homozygous C/C genotype carriers having best mood (p = 0.004) and least hunger (p = 0.036) during fasting compared to T/T genotype carriers.” … “Pronounced mental discomfort during fasting in 825T allele carriers might partly explain their increased risk for obesity. The strong association between the subjective response to fasting with GNB3 genotypes indicates a role of the gene in the behavioral regulation of food intake, which should be further considered in nutritional intervention studies.” [ref]
Yohimbine is an alpha2 adrenoceptor antagonist. It makes sense to me that it might work for weight loss in those who have GNB3 825T. (Note that I could be completely wrong on this.)
A Japanese herbal weight loss supplement, bofutsushosan, has been studied in relation to this variant. The study did find that those with the T/T and C/T alleles lost a little more body fat with this supplement compared to C/C. But when you look at the numbers, overall the study subjects lost no more with the supplement than the placebo (average weight loss of around 2 lbs over 8 weeks). The discussion at the end of the study brings up the fact that the ephedra in the supplement was thought to be what worked best for those with the 825 T alleles. Ephedrine stimulates norepinephrine. [ref] Supversity has an article on bofutsushosan if you are interested in learning more. I believe that supplements with ephedra are banned in the US.
While sibutramine was shown to work better for those with the T allele in some studies, a study combining sibutramine with orlistat found that the “GNB3 825T allele was associated with blunted fat mass reduction in obese females.” [ref] Note that sibutramine is no longer on the market due to increased cardiovascular events (i.e. heart attacks!). Orlistat is sold as Alli in the US.