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The genetics of relatively healthy obesity

Image of an overweight individual

In general, obesity is linked with a large range of health problems—for most people, at least. But, for a substantial minority of those who are overweight, obesity is accompanied by indications of decent health, with no signs of impending diabetes or cardiovascular disease. These cases have probably received unwarranted attention; who doesn’t want to convince themselves that they’re an exception to an unfortunate rule, after all? But the phenomenon is real, and it’s probably worth understanding.

To that end, a large international team of researchers has looked into whether some of these cases might be the product of genetic influences. And, simply by using existing data, the team found 61 instances where a location in our genomes is associated with both elevated obesity and signs of good health, cardiovascular or otherwise.

Good and bad

The team’s method of searching the genome is remarkably straightforward, and it relies on the fact that many research groups have already done so much work to look for factors associated with obesity, diabetes, and cardiovascular health. This work includes searching for areas of the genome associated with measures of obesity, like body mass index, body fat percentage, and waist-to-hip ratio. Insulin and glucose levels have also been studied genetically, as these give some indication of how the body is responding to weight and food intake. Cardiovascular health measures have included things like cholesterol and triglyceride levels, as well as blood pressure, and have also been explored.

Combining all the past studies in these areas, the researchers were able to leverage a sample of hundreds of thousands of individuals.

To find the sorts of genes the team was interested in, the researchers had a simple criterion: the same area of the genome has to be associated with both one of the measures of obesity and one of the measures of metabolic or cardiovascular health. After doing the pairwise comparisons, they checked whether any of the areas that came out of the analysis was associated with more than one measure (so, for example, health levels of both cholesterol and glucose).

Overall, 62 different sites within the genome came out of this analysis. The authors broke these down into three different groups, based on their behavior. And, by looking at health outcomes of participants in the UK Biobank, it was possible to see what happens in individuals who have a large number of the variants associated with obesity. For the full group of 62 sites, having lots of obesity-associated variants seemed to be related to the distribution of body fat, which is less harmful when deposited under the skin than when it builds up around the waist.

One group had elevated levels of body fat but broad indications of good cardiac and metabolic health. At least some members of this group appeared to influence where the fat ended up being deposited (less around the gut). People with a lot of these variants tended to have less fat-free mass and, somewhat oddly, were taller.

Another group—the largest, with 31 sites—seemed to be involved with fat regulation, since it was associated with a better ratio of good to bad cholesterol and lower triglycerides. Here, there was no indication that body fat distribution was more favorable in those who have a lot of these variants. Finally, the third group seemed to be associated with a general increase in fat and reduced indications of diabetes risk, without a focus on any particular aspect of them. Consistent with this, people with an abundance of these variants tended to have changes in glucose levels.

What’s there?

In many cases, these variants are inside of genes (or very close to them), so we can look into what the genes linked to these variants are actually doing. A look at the past research on these genes indicated that the genes were frequently associated with processes that affect adipose tissue, as you might expect, including altering the activity of other genes in adipose cells. There were also indications that the genes might be involved in metabolism, with associations with the adrenal cortex, liver, and pancreas.

A number of the variants appear to reside in DNA that helps control surrounding genes. This makes knowing what gene is affected by the genetic differences a challenge. But the researchers use a variety of criteria (which genes are active in fat cells, etc.) to get a sense of what the relevant genes are.

Overall, the researchers suggest these 62 genes affect a variety of relevant processes. Some of these are upstream of fat deposition, such as insulin signaling and glucose control. And others seem to regulate the process of breaking fats back down. Still others seem to control how adipose tissue develops, the switch between white and brown fat, and the location where fat forms. None of those is especially surprising, but it’s not necessarily predictable that they’d influence things in a way that seems to limit the damage that’s associated with fat accumulation.

While some people might view carrying these variants as a license for carrying a few extra pounds, the work doesn’t really get into how much impact each of these factors has on any of the things it has looked at, either in terms of obesity or health. If the variants are typical of other factors that influence complex traits, the individual impact of any of them is going to be extremely small.

The value of this sort of study really lies elsewhere. While we know obesity is linked with a variety of health risks, those links are complex and poorly understood at the moment. Research like this could cut back on the unknowns and help us figure out ways in which we might separate obesity, which doesn’t seem to be going away, from some of its consequences.

Nature Metabolism, 2021. DOI: 10.1038/s42255-021-00346-2  (About DOIs).

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