Visceral Fat, Blood Pressure, Diabetes, Cardiovascular Risk, Metabolomics … and Me

Let’s talk about cardiometabolic health.

Overweight and Metabolically Unwell

I used to be quite overweight and had been for many years until not so long ago. I thought about it very recently when I went to replace my soon-to-be-out-of-date passport with a new one and I compared the photo of old me with current me. My old face was much rounder. About four years ago my wife persuaded me to see my Doctor to get my blood tested for the usual suspects – cholesterol, blood sugar (glucose), total triglycerides and so on. She was concerned about me as I have a family history of type 2 diabetes (T2D). Well, all was not well. For example, my triglycerides were abnormally, extremely high, my cholesterol was a little high but my glucose was normal. This along with other findings and my family history did imply that while I was not yet diabetic I did need to do something about my metabolic health. So I did.

Running free

I took up running and cycling and watched what I ate, for example, reducing total carbohydrates in my diet, eating more fruits and vegetables and drinking less alcohol. Well, all that worked and I lost a large amount of weight and discovered a joy in exercise which has turned into a bit of a hobby, and for now, all is well. I travel a lot for my work and am lucky enough to enjoy the experience of travel. Instead of just going to a gym and running on a treadmill, which I detest, I put my running shoes on, go outside early in the morning usually and while running try and take in the sights as much as possible. One thing I need to work on more though is that I am packing some visceral fat. Why is that important?

Visceral Fat

Visceral fat, in the sense of visceral obesity, has been linked with dyslipidemia, insulin resistance and increased cardiovascular risk. Apart from that, and perhaps showing that I have something of a shallow nature, I don’t like the way it looks in the mirror. But back to the population health issue rather than the very slightly less important ‘does my tummy look big’ issue. I mentioned already my family history of diabetes. Well unfortunately for me there is also some history of cardiovascular risk and of course the two may well be related as the one can lead to the other.

I want to tell you about some interesting research on visceral fat, blood pressure, diabetes and cardiovascular risk and how they relate to each other and understanding that with metabolomics.

Visceral Fat and Energy Metabolism

We know that abdominal obesity is associated with increased risk of type 2 diabetes and cardiovascular disease but literally how is visceral fat (VF) mass related to diabetes and cardiovascular risk? In this study by Menni and coworkers1 published in Obesity last year they identified a set of metabolites, using a global metabolomics approach, in 2,401 women from the TwinsUK cohort that associated partly with VF mass and T2D. All of these metabolites were involved in energy metabolism, in particular, glycolysis and the TCA cycle (glucose was of course in there plus lactose and branched chain amino acids, BCAA). They then hypothesized that reducing VF mass in diabetes patients might result in improvements to mitochondrial TCA cycle efficiency, which overall process (there is a little more to it) is known to be disrupted in diabetes patients. What was particularly interesting was that a different set of metabolites associated with VF mass and blood pressure (hypertension) but that some of those metabolites were still involved in energy metabolism, although via lactose and a free fatty acid. Additionally, steroid hormone and inflammation markers also linked blood pressure with VF mass. There was very little overlap between metabolites that associated VF mass with either blood pressure or T2D (and insulin resistance). Interestingly a metabolite, hexadecanedioate, a dicarboxylic fatty acid, previously linked with elevated blood pressure2 was again linked with blood pressure in this study but was not associated to VF mass and blood pressure. This would imply that whatever the action of hexadecandioate is (more later) it is not mediated via VF mass.

Branched Chain Amino Acid Intake and Cardiometabolic Health

Jennings et al3 set out to clarify the confused relationship between circulating levels of BCAA and dietary intake of BCAA with cardiovascular health and what impact genetics has on that relationship. They conducted a study of 1997 female twins on the relationship of dietary BCAA, measured with a food-frequency questionnaire, and a range of markers of cardiovascular health. In addition, they performed global metabolomics on blood plasma samples. This work revealed the associations between BCAA in the diet, cardiometabolic health and what impact, if any, genetics played. The results were fairly dramatic. Higher dietary intakes of BCAA, equivalent to a glass of milk, were associated with better cardiometabolic health as measured by reduced insulin resistance, inflammation, blood pressure and adiposity-related metabolites. Further, this was independent of genetics. Intake of BCAA was not associated with plasma BCAA concentrations, which is relevant as higher circulating levels of BCAA have been associated with increased risk of T2D. This result is of obvious potential clinical significance since previous studies have shown that reduced insulin resistance and inflammation are associated with lower rates of obesity, T2D and cardiovascular disease.

Hexadecanedioate and blood pressure

It was recently demonstrated that hexadecanedioate, a long chain dicarboxylic acid, was uniquely associated with both blood pressure and mortality2 while other metabolites, measured with a global metabolomics approach, were associated with blood pressure alone. This was observed in either the serum or plasma of a large female cohort from TwinsUK and then observed in a further two independent cohorts. Further work in animal models went on to demonstrate that oral hexadecanedioate increased both the level of circulating hexadecanedioate and blood pressure. This and further experiments showed that there is a causal connection between hexadecanedioate and blood pressure regulation. In addition, Yu et al.4 identified loss of function (LoF) mutations that altered the levels of several metabolites, assessed with metabolomics, with some of those metabolites being biomarkers of risk or diagnosis and indeed seemed to be causal, using a technique to assess causality known as Mendelian Randomization. One significant gene with LoF mutations was SLCO1B1 which elevates the levels of hexadecanedioate. Further, SLCO1B1 LoF mutations significantly increase the risk of heart failure again supporting the conclusion that hexadecanedioate is in the causal pathway of disease.

What’s going on with hexadecanedioate?

The last piece of research to consider today sought to identify the molecular pathways linking blood pressure to hexadecanedioate levels using genomics and transcriptomics5. To cut a long story short three genes popped up as of interest. These were SCLO1B1 (as above), the CYP4 cluster and a gene for a subunit of alcohol dehydrogenase, ADH1B. An allele of SCLO1B1 that has previously been linked to increased risk of statin associated myopathy was associated with higher hexadecanedioate levels. However, and importantly, this allele did not show association with blood pressure or hypertension. Now here comes the really interesting part, hexadecanedioate appears to influence the role of alcohol on blood pressure. Alcohol intake has a much stronger effect on individuals with high hexadecanedioate levels. Thus, if this finding is borne out by further work, strategies for reducing blood pressure in alcohol-induced hypertension may be different depending on the subject’s hexadecanedioate levels. 

Hexadecanedioate is a product of omega-oxidation. The first step adds a hydroxyl group which is carried out by members of the CYP4 family as well as other enzymes. The next step to producing hexadecanedioate is the oxidation of the hydroxyl group to an aldehyde which is catalyzed by alcohol dehydrogenase. The third and final step is the oxidation of the aldehyde to a carboxylic acid. This produces finally a dicarboxylic fatty acid. Now tell me that alcohol dehydrogenase and CYP4 being linked to hexadecanedioate does not make sense! It really, really does.

Metabolomics

We can see from this brief (I say it is brief anyway) survey of a small number of relevant studies that there are multiple influences on cardiometabolic health at the level of metabolism, at least partly elucidated with a global metabolomics approach. Some metabolites link to the gut, so to speak, while others play a part in hypertension, particularly mediated through alcohol, while yet others may play a role in lowering the risk of diabetes. No doubt there is much left to discover but I am persuaded that metabolomics is a powerful tool to uncover these associations between metabolism and chronic illness such as diabetes and cardiovascular disease.

The interplay of metabolism in diabetes and cardiovascular disease is complex but the role of metabolism in these diseases and others is becoming clearer and metabolomics is assisting with that vital undertaking.

Vital indeed.

P.s. Before you run off to find out more about metabolomics I would like to point out that I work for a company, which among other things, provides a metabolomics service, called Metabolon. Clearly therefore I have an interest. I hope you enjoyed this article and that it was not too heavy a read.

P.p.s. That is not my tummy.

References

1.Menni C. et al., Metabolomic profiling to dissect the role of visceral fat in cardiometabolic health Obesity (2016) 24, 1380-1388

2. Menni C. et al, Metabolomics identification of a novel pathway of blood pressure regulation involving hexadecanedioate (2015) Hypertension 66, 422-429

3.Jennings A. et al., Associations between branched chain amino acid intake and biomarkers of adiposity and cardiometabolic health independent of genetic factors: A twin study (2016) International Journal of Cardiology 223, 992-998

4. Yu B. et al., Loss-of-function variants influence the human serum metabolome (2016) Sci Sdv 2: e1600800

5.Menni C. et al., Molecular pathways associated with blood pressure and hexadecanedioate levels (2017) PLoS One 12(4): e0154479