The Genetics of Comparatively Wholesome Weight problems

In general, obesity is linked to a wide variety of health problems – at least for most people. However, for a significant minority of overweight people, obesity is associated with signs of decent health, with no signs of impending diabetes or cardiovascular disease. These cases have likely received unwarranted attention; Who doesn’t want to convince themselves that they are an exception to an unfortunate rule? But the phenomenon is real and it is probably worth understanding.

To this end, a large international team of researchers investigated whether some of these cases could be the product of genetic influences. And simply using the existing data, the team found 61 cases where a location in our genome is linked to both increased obesity and signs of good health, cardiovascular disease, or otherwise.

Good and bad

The team’s method of searching the genome is remarkably simple, based on the fact that many research groups have already done so much work looking for factors related to obesity, diabetes, and cardiovascular health. This work involves finding areas of the genome associated with measurements of obesity, such as body mass index, body fat percentage, and waist to hip ratio. Insulin and glucose levels have also been tested genetically, as these provide an indication of how the body reacts to weight and food intake. Cardiovascular health measures included, among other things, cholesterol and triglyceride levels, and blood pressure, and were also examined.

By combining all of the previous studies in these areas, the researchers were able to use a sample of hundreds of thousands of people.

To find the types of genes the team was interested in, the researchers had a simple criterion: the same area of ​​the genome must be associated with both one of the measures of obesity and a measure of metabolic or cardiovascular health. After the pairwise comparisons, they checked whether any of the areas that emerged from the analysis were associated with more than one measurement (such as health values ​​for cholesterol and glucose).


A total of 62 different locations within the genome emerged from this analysis. The authors have divided these into three different groups depending on their behavior. The health results of the participants in the UK biobank were used to determine what happens to people with a large number of variants related to obesity. For the entire group of 62 sites, it appeared to be related to the distribution of body fat, which is less harmful when deposited under the skin than when it accumulates around the waist.

One group had elevated body fat levels but broad evidence of good heart and metabolic health. At least some members of this group seemed to have an influence on where the fat was deposited (less around the intestines). People with many of these variants tended to have less lean mass and, oddly, were taller.

Another group – the largest with 31 digits – appeared to be involved in fat regulation as it was linked to better good to bad cholesterol ratios and lower triglycerides. There was no evidence that body fat distribution was more favorable in those who have many of these variants. Finally, the third group appeared to be associated with an overall increase in fat content and a decrease in signs of diabetes risk without focusing on any particular aspect. Consistent with this, people with an abundance of these variants tended to have changes in glucose levels.

What is there?

In many cases, these variants are within (or very close to) genes so we can study what the genes linked to these variants are actually doing. A look at previous research on these genes showed that the genes were often associated with processes that affect adipose tissue, as expected, including changing the activity of other genes in adipose cells. There was also evidence that the genes might be involved in metabolism, with associations with the adrenal cortex, liver, and pancreas.


Some of the variants appear to be in DNA, which helps control the genes around it. This makes it a challenge to know which gene is affected by the genetic differences. However, the researchers use a variety of criteria (which genes are active in fat cells, etc.) to get a feel for the relevant genes.

Overall, the researchers suggest that these 62 genes influence a variety of relevant processes. Some of them precede fat deposition, such as B. Insulin Signaling and Glucose Control. And others seem to regulate the process of breaking down fats. Still others seem to control how adipose tissue develops, how to switch between white and brown fat, and where fat forms. Neither of these are particularly surprising, but it’s not necessarily predictable that they would affect things in ways that appear to limit the damage associated with fat accumulation.

While some people consider wearing these variants a license to carry a few extra pounds, the work doesn’t really go into how much of an impact each of these factors has on any of the things it was looking at, either in relation to obesity or Health. If the variations are typical of other factors affecting complex traits, the individual impact of any of those factors is extremely small.

The value of this type of study really lies elsewhere. Although we know that obesity is linked to a variety of health risks, these relationships are currently complex and poorly understood. Research like this could narrow down the unknowns and help us find ways we can separate obesity, which doesn’t seem to go away, from some of its consequences.

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

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