Published on September 6, 2023
As part of our series on the regulation of blood sugar levels, this blog post discusses the science of how excess body weight and fat mass are major causes of insulin resistance. Specifically, we will discuss a critically important concept called the personal fat threshold hypothesis.
Body Weight and Fat Mass Are Associated With Insulin Resistance
In observational studies, we see that there is a very strong association between the body mass index (BMI) and the risk of developing type 2 diabetes. In the Nurses Health Study, for example, more than 114,000 nurses without diabetes at baseline were studied. Over 14 years, the risk of developing diabetes was strongly linked to the baseline BMI (see figure below). And in the highest BMI category, for those who had a baseline BMI of 35 or higher, their risk of developing diabetes was 93-fold higher than that of those in the lowest BMI category. Not 93% higher, but 93-FOLD higher. And that is even though we should acknowledge that BMI is not a perfect measure of body fat mass, as we’ll discuss later in this blog post. We also need to acknowledge that an association in an observational study does not prove that having more body fat mass causes type 2 diabetes. But seeing such a strong association, and seeing it consistently across numerous studies, as is the case for this relationship here, does provide a higher level of confidence that a cause-and-effect relationship may be underlying the observed association.
What we would like to know, though, is what it is about carrying extra body weight and particularly fat mass that so dramatically raises our risk of developing type 2 diabetes.
As I discussed in more detail in my blog post about the regulation of blood sugar, diabetes is a disease in which the body loses its ability to keep blood sugar levels in the normal range. How good our glucose tolerance is depends on three factors: insulin sensitivity, the ability of our pancreatic beta-cells to produce insulin, which we often call beta-cell function, and insulin-independent glucose disposal, of which glucose effectiveness and exercise-induced uptake of glucose into muscle cells are probably the two most important ones.
In general, as someone gains weight, we do tend to see worsening in beta-cell function and glucose effectiveness as well, but the most profound shift that we also have the most evidence for is that weight gain is very commonly associated with an increase in insulin resistance. My objective with this blog post is to discuss that link between body weight and insulin resistance, and what actually happens inside the body when we gain weight that can make us insulin resistant.
So let’s start by looking at how weight gain is associated with an increase in insulin resistance.
Let’s say we had a group of men, and we wanted to look at the relationship between BMI, on the x-axis in the figure below, and insulin resistance on the y-axis. At normal body weight, with a BMI between 20 and 25, most people would have fairly good to very good insulin sensitivity, or expressed the other way around, low insulin resistance. Note that there is some variability here, though, so even at the exact same low BMI, some people are more insulin resistant than others.
As BMI now increases, so does insulin resistance, at least on average. Among obese people, those with a BMI greater than 30, most are at least somewhat insulin resistant, and some are very insulin resistant. Note again, however, how some people remain pretty insulin sensitive even with a BMI in the obese category.
That brings us to the first important point I’d like to make, and that is that BMI has one major limitation. Remember that we calculate BMI as the body weight in kg divided by the height in meters squared. So this is a measure of weight in relation to height. However, it tells us little about why body weight is elevated in any given individual. The person marked in orange, for example, is a very lean bodybuilder who is heavy relative to his height, simply because he carries a lot of muscle mass. At the same time, this man marked in green appears to be overweight by BMI, but he has very little muscle mass and a high body fat percentage, so that’s why he is pretty insulin resistant for his BMI level.
A better measure to look at would be body fat percentage. So let’s change the x-axis from BMI to body fat percentage, and see how the position of our two gentlemen on the graph change. Play the short video clip below and watch how our bodybuilder in orange, who has a high BMI but a low body fat percentage, moves quite a bit to the left, and now he is no longer an outlier. In fact, we would predict good insulin sensitivity in someone with such a low body fat percentage. And our under-muscled overweight man in green is now shifting to the right because even though his BMI was not all that high, he has a high body fat percentage, and that now is very much in line with the high level of insulin resistance he has.
What I am hoping you can appreciate is that body fat percentage is a bit more strongly associated with insulin resistance than BMI. So again, in general, people who are lean, with a low body fat percentage, usually have low insulin resistance. And people with higher body fat percentage, as is common in those with overweight or obesity, tend to be more insulin resistant. And so, maybe not unexpectedly, someone who is lean and insulin sensitive tends to become more insulin resistant if they gain weight. And losing weight often reduces insulin resistance.
A few additional important points:
First, I mentioned that this graph is based on men. The relationship is very similar for women. The reason to talk about men and women separately is that women have a higher body fat percentage at the same level of BMI, and so it’s important to look at these graphs separately.
Second, you can see that there is still a wide spread in insulin resistance at any given level of body fat percentage. One potential reason for this is that there are many other reasons that have nothing to do with body fat that can cause insulin resistance. As we will discuss in more detail in a later blog post, there are certain medical conditions or medications, for example, that can cause insulin resistance.
And third, still, even if we created this graph from a population in which we had excluded anyone who is insulin resistant because of another illness, medication intake, chronic stress etc. we would still have variability at any given level of body fat percentage. And the reason for this is that people store fat in different places, and it matters quite a lot for insulin sensitivity where the extra fat is stored.
Let me explain.
How Fat Can Safely be Stored in the Body
To understand this, we need to take a look at how fat can safely be stored in the body.
Let’s consider the gentleman marked in red in the clip below, Mark. In his 20s, Mark is a very lean and athletic young man, but then he gets injured, starts a busy career with lots of travel, and has a couple of kids. And we all know how it goes: not enough time for sleep, exercising regularly, or preparing meals. He has many meals on the road in fast food restaurants, and over the next 20 years, he gains 40 pounds. Play the clip to see how his body fat mass and insulin resistance change during this time.
Well, in his case, he gained 40 pounds of body fat, but he remained quite insulin sensitive. That is because his body was able to store the extra body fat away safely in his subcutaneous fat tissue. That’s the fat tissue right under the skin, all over the body. So we would expect that 45-year old Mark would have a bit more fat stored in the subcutaneous fat depots in his hands, his arms, his face, really anywhere, but particularly in the subcutaneous fat depots on the outside of his belly and thighs. If he took an MRI scan, right through the middle of his belly, let’s say around the area of the belly button, the figure below shows what this may look like.
In this MRI scan image, fat is white, and bones, muscles, and inner organs are grey. The fat on the outside, just under his skin, is what we call subcutaneous fat. The fat deep within his belly, surrounding the inner organs, that’s what we call intra-abdominal or visceral fat
And what we can see readily is that Mark has most of his belly fat stored on the outside. He has a lot of subcutaneous fat and very little visceral fat. And actually, most of his body fat cannot be seen here in this image, because it isn’t even stored around his belly, but in the subcutaneous fat tissues of his thighs, legs, arms, shoulders etc.
Now, if Mark could gain this much body fat and barely become any more insulin resistant, why is body fat mass then so strongly associated with insulin resistance?
The Type of Body Fat that Triggers Insulin Resistance
Well, let’s take a look at the type of body fat that does trigger insulin resistance.
For these purposes, let’s look at another example: Jim, marked in blue in the clip below. Like Mark, he was very lean and athletic in his 20s, and like Mark, he also gained 40 pounds of fat mass over the next 20 years of his life. So in their 40s, Jim and Mark have exactly the same body fat percentage. But while Mark is still pretty insulin-sensitive, Jim is now very insulin-resistant. What is going on here?
Well, let’s take a look at an MRI image across Jim’s belly. Jim also has a lot of fat stored in his subcutaneous fat tissue, but he also has way more fat stored in the visceral fat depots around his inner organs. Actually, if we quantified it, he has three and a half times as much as Mark, even though both have the same total body fat percentage. What this means is that Jim overall has a lower percentage of fat stored in the subcutaneous fat depots around his body. His thighs, for example, may still look pretty lean.
These differences in how these two men store fat would be apparent already from the outside. Mark would have a body shape more like a pear, because he has stored a lot of his excess fat in the subcutaneous fat tissue in the lower part of the body, particularly his buttocks and thighs. Jim, by contrast, would have a shape more similar to an apple, because he stores most of his excess fat in his belly and particularly in the visceral fat depots deep inside of his belly.
Now, why does storing fat in the visceral fat depots trigger insulin resistance while storing it in the subcutaneous fat depots does not?
The picture that is emerging, with lots of support from different lines of evidence from experiments done in both animals and humans, suggests that it isn’t really the visceral fat that causes insulin resistance, at least not by itself. Instead, what it looks like is that having a lot of visceral fat indicates that the subcutaneous fat tissue is filled to capacity and can no longer store more fat. And once fat can no longer safely be stored in our subcutaneous fat depots, a whole host of things change that contribute to insulin resistance.
What is that supposed to mean now: the subcutaneous fat tissue is filled to capacity and can no longer store more fat?
How Fat Tissue Works
Well, let me share the basics of how fat tissue works, and how that is linked to what has now become known as the personal fat threshold hypothesis.
Let’s assume we had a very good microscope, and were able to observe the changes in subcutaneous fat tissue in someone like Jim as he is gaining 40 pounds of fat mass over 20 years.
So we start this journey with Jim when he is 25. He has a fairly low body fat percentage and is very insulin-sensitive. If we look at his subcutaneous fat tissue at this time, it consists of many fat cells that are mostly small. Now, when I say small, that’s actually incorrect. Fat cells, or adipocytes, are some of the largest cells in the human body, so when I say small, these are still many-fold larger than most other cell types. But, as far as fat cells go, those in young Jim are small. What you see in the cartoon below is that these fat cells are largely filled by a fat droplet. These are triglycerides, the same type of fat that you’ll find in butter or olive oil. That’s the long-term storage form of fat and energy in the human body.
Fat tissue does consist of many other cell types as well. I don’t want to go into too much unnecessary detail here, but let me emphasize two types. One are endothelial cells that make up the small blood vessels that provide nutrients and oxygen to the fat cells. I have drawn these in red in the cartoon. Another, in blue, are cells called preadipocytes. As I said earlier, fat cells are also called adipocytes, so preadipocytes, you can imagine are like fat cells in-waiting. They are not ready to store fat yet, but they will become mature fat cells should they be called upon. For now, they are just hanging out.
If we were able to look at this during a typical day of Jim’s life (see cartoon above), we would see that in the fasting state, for example, when he is sleeping, the fat cells release a small trickle of the fat they have stored. What they release are individual fatty acids that then float through the blood to provide tissues all over the body with energy. This changes when Jim eats a meal. After each meal, his blood levels of glucose, fatty acids, and insulin are high, and then the flow of nutrients changes. Under the influence of the elevated insulin – insulin being the little red triangle in the cartoon – the fat cell changes in three key ways: for one, it stops the release of fatty acids by the cell. That makes sense, right? Insulin is a signal that food was just consumed, and that means nutrients are going to be available to tissues from that food. Because it’s no longer necessary for fat cells to provide energy to other cells in the body, insulin stops the breakdown and release of fat stored in the fat cells.
Insulin also enables the cells to take up glucose as well as fatty acids from the blood. Glucose is then converted to fatty acids, and the fatty acids get stored as triglycerides.
So, keep this in mind: insulin binding to the fat cell, and the fat cell responding to it, are crucial processes not just in clearing glucose from the blood, but in enabling the fat cell to take up and store fat as well. This process, where the fat cell stores fat right after the meal, and then releases it again while we are fasting, happens several times throughout the day. And if we eat as many calories as we are burning, the total amount of fat stored in the body stays about the same over time, with just a small fluctuation up and down throughout the day.
However, this is not the case with Jim. He is actively gaining weight. See in the figure below, by the time he is 38 years old, his body fat percentage has increased quite a bit, which means that over these years, he needed to store more and more fat in his fat tissue. Now, what you can appreciate is that even though Jim gained quite a bit of fat, his insulin resistance didn’t change all that much. That is because he was able to store the additional fat largely in his subcutaneous fat tissue, which expanded by recruiting new preadipocytes and making them into mature fat cells. In other words, the number of fat cells in his subcutaneous fat tissue increased. But the size of his fat cells did not increase. He now has more small fat cells. We call this increase in the number of cells hyperplasia. And usually, when the subcutaneous fat tissue is able to expand by hyperplasia, insulin sensitivity does not change much. So if we were to take another MRI scan here when Jim is 38, we would expect him to have more subcutaneous fat, but not much more visceral fat.
But subcutaneous fat tissue can not expand through hyperplasia forever, because the tissue is limited in the number of preadipocytes it can recruit. It does seem clear that older individuals have a more limited ability to recruit new preadipocytes. That is because with age, we seem to partially lose the stem cells that are needed to make new preadipocytes. There probably is also a genetic component to how much we can expand the subcutaneous fat tissue by hyperplasia.
Whatever the reasons are, there is a limit to how many more small fat cells we can recruit. That limit has been reached in Jim roughly by the time he is 38. Over the next few months as his body fat percentage continues to increase, the subcutaneous fat cells start to increase in size. That is because his subcutaneous fat cannot recruit more new fat cells, so the existing ones need to store more. This process we now call hypertrophy. Jim now has more fat cells than when he was young, and all of these are now also gradually getting larger and larger. This has several negative consequences.
For one, fat cells that get too big move further and further away from the blood vessels that provide nutrients and oxygen. The expansion of the cells and the tissue as a whole creates pockets of cells that lack enough oxygen, a condition we call hypoxia. Getting too large and not getting enough oxygen creates a state that threatens the very survival of individual cells, and actually, some die. As a result, you suddenly have globs of fat and cell debris lying around in between the healthy cells. You don’t need to be a cell biologist to understand that this is not a healthy thing.
The second thing that happens is that fat cells that get too big and that lack oxygen call for help. They do this by secreting messenger molecules that attract certain other cells from the blood stream. A specific type of white blood cell called a monocyte is one of the first to respond, and these monocytes move from the blood into the fat tissue. In the tissue, the monocytes change to become specialized cells called macrophages that are ready for whatever task is at hand. These macrophages are seriously amazing kinds of cells. They get the message that the huge fat cells are overwhelmed, and they also see the globs of fat and tissue debris from the dead cells lying around. So they do a number of things. For one, they clean up the mess from the dead fat cells. They also help build new blood vessels, to make sure that all cells within the expanded fat tissue receive enough nutrients and oxygen. And they secrete mediators of inflammation. And these mediators, we call them cytokines, come to the aid of the very large fat cells – by making them insulin resistant. Now, usually, inflammatory cytokines induce insulin resistance in a tissue because they want to preserve a solid supply of glucose for themselves, as they are – typically – fighting an infection in that tissue. By making surrounding tissue cells insulin resistant, these cells stop taking up glucose from the blood, and more glucose is available to the immune cells that are fighting invading pathogens.
So what is the role of inflammatory cytokines in fat tissue? Here, triggering the release of inflammatory cytokines, and their effect to make fat cells insulin resistant, also makes sense. Because imagine that these super big fat cells are so large that they can barely survive. If they had to take up any more glucose or fatty acids from the circulation, they would burst (more or less literally). By becoming insulin resistant, their growth is basically stopped. Because if now, after a meal, sugar and fatty acids come by along with insulin, insulin is no longer able to effectively shuttle sugar and fatty acids into the large fat cell. And insulin is also less able to inhibit the release of fatty acids by the fat cells during the fasting state. As a result, the large fat cell continues to secrete fatty acids into the blood rather than taking up sugar and fatty acids from the blood. Locally, and specifically for this huge fat cell, that is a win, because it prevents the fat cell from dying. But, as you can probably guess, it comes at a cost.
For one we now have insulin resistance in our subcutaneous fat tissue. And because subcutaneous fat tissue is one place that can remove sugar from the blood after a meal, this is not a good thing. It’s basically like we had team of different tissues working together to keep blood sugar in the normal range at all times, and by making the subcutaneous fat tissue insulin resistant, we are one player down.
But the bigger issue is that the glucose and the fat from the blood now need to go elsewhere. And where do they go: they get stored in the visceral fat depots, and also in muscle and inner organs, such as the liver and the pancreas. And so, as the fat content in the visceral depots increases, and the fat content in liver and muscle increase, so does overall insulin resistance. One way to think about this is exergy toxicity. The cells in liver and muscle and also the subcutaneous and visceral fat tissues, these are among the major cell types that take up glucose after meals. And now, they are increasingly stuffed already with sugar and fat. And just like you are stuffed and unable to eat more once you’ve had a few pieces of cake, the liver cells and the muscle cells and the fat cells increasingly say: enough, and they reduce their sensitivity to insulin. And less sensitivity to insulin is what we call insulin resistance.
Now, as we have discussed repeatedly, insulin resistance does not automatically lead to glucose intolerance. For a while, the body can simply make more insulin. However, I just mentioned that fat also accumulates in the pancreas when the subcutaneous fat tissue is filled to capacity. And such pancreatic fat is now also thought to reduce the ability of the pancreatic beta-cells to produce insulin. That’s something we’ll talk about in a separate blog post.
So, I mentioned earlier the term personal fat threshold. What does that mean? The personal fat threshold is the amount of fat that can safely be stored in small fat cells within the subcutaneous fat tissue. So, for Jim, his personal fat threshold would be about when he is around 38 years old, because what we can see clearly is that beyond this point, even small amounts of additional fat that need to be stored trigger major increases in insulin resistance, strongly suggesting that from this point on more and more of the additional fat needs to get stored in unsafe places. We call these unsafe places ectopic fat depots, ectopic meaning untypical or not made for this purpose. Traditionally, we call fat stored in liver, muscle, and pancreas ectopic fat, because these are not fat storage tissues. However, I and some of my colleagues would also call visceral fat depots ectopic, because, for optimal health, we really shouldn’t be storing a lot of fat there. So when Jim is 45, he now is insulin resistant because he now has quite a lot of fat stored in his visceral fat depots, he has excess fat in his liver and muscle, and he has low-grade chronic inflammation, in his tissues, but also measurable in his blood. We’ll talk about this later.
Because it’s such an important point, let’s be clear again that how Jim’s body has stored excess body fat is in direct contrast to Mark, our earlier example. Remember that Jim and Mark at this time point when these MRI scans in the figure above were taken are both in their 40s, and they have an identical body fat percentage. The big difference is that Mark is lucky in that he is able to store most of his body fat in his subcutaneous fat depots. He does not store much fat in his visceral depots, or his liver and muscle, and because his subcutaneous fat isn’t overwhelmed yet, he also doesn’t suffer from low-grade chronic inflammation in his fat tissue. And as a result, he remains quite insulin-sensitive.
Now, don’t forget that I have picked two extreme examples here, but they do illustrate nicely that an increase in body fat does not per se trigger an increase in insulin resistance, even though body fat percentage is associated with insulin resistance. That is because only certain types of body fat, namely that stored in visceral and ectopic depots, cause insulin resistance, while fat stored in subcutaneous depots does not. One way to think about the relationship between body fat percentage and insulin resistance is simply that as the body fat percentage increases, it becomes more and more likely that any given individual will cross their personal fat threshold and start accumulating fat in their visceral and ectopic depots.
What Is The Evidence Supporting the Personal Fat Threshold Hypothesis?
So far, I have outlined a series of events leading from failure of subcutaneous fat tissue to store fat to visceral and ectopic fat storage to whole body insulin resistance. What is the actual evidence suppporting this model? And specifically, how do we know that this is what happens and that there couldn’t be another explanation for why people with excess fat mass tend to be more insulin resistant?
Well, in science, it’s close to impossible to ever be 100% certain. There can always be other explanations, and as scientists, we should remain open to new ideas and new data, and – in fact – there may well be additional factors that happen as we eat and gain weight that could contribute to insulin resistance. We’ll talk about these additional factors in future blog posts. The model that I have outlined here simply is the one that – in my opinion and that of many of my colleagues – is most consistent with the cumulative evidence. So let me share a few more pieces of evidence that support this model and that has made me fairly convinced that this personal fat threshold hypothesis holds value.
A key piece of evidence supporting the personal fat threshold hypothesis is what we just discussed: that people with obesity who are insulin sensitive tend to have more fat stored in their subcutaneous fat depots, they tend to have less visceral fat, less fat in liver and muscle, and lower levels of inflammation. In contrast, those people who are the most insulin resistant have much more fat stored in visceral depots, they tend to have non-alcoholic fatty liver disease, or NALFD, which means excessive fat storage in the liver; they tend to have fat in their muscle tissue, and they tend to have high levels of inflammation markers in their tissues and in their blood. We summarized the very extensive literature on this topic a few years ago in a comprehensive review article.
There is another line of research that strongly suggests that there is a special benefit to storing fat in subcutaneous fat depots and not in visceral fat depots or even liver and muscle. And that is research on a medical condition called lipodystrophy. Lipodystrophy can be genetic or acquired, for example, in some people taking antiretroviral drugs for HIV infection. What they have in common is that in all cases, the subcutaneous fat tissue is more or less unable to recruit preadipocytes to store fat safely, and so these people often have very thin arms and legs, with very little subcutaneous fat tissue, and most of their body fat is stored in visceral depots as well as in liver and muscle. And that kind of picture clinically often comes with more or less pronounced insulin resistance and often manifest type 2 diabetes.
In mice that have been genetically changed to have lipodystrophy, we see the same thing: lack of subcutaneous fat tissue leads to accumulation of fat in ectopic depots and the development of – often severe – insulin resistance. And then, if some functional subcutaneous fat tissue is transplanted to them, the whole condition, including the insulin resistance, is to some degree reversible.
Some investigations have also studied the effect of inhibiting the inflammation in fat tissue (and potentially also in liver and even muscle) that comes from crossing the personal fat threshold. Generally, these studies show a modest improvement in insulin sensitivity when inflammation pathways are inhibited, even if body fat mass or fat distribution are not changed. This suggests that inflammation plays a causal role in the development of insulin resistance with fat mass gain. That in these studies insulin sensitivity is only slightly improved and not completely normalized also suggests that low-grade chronic inflammation is only partly responsible for insulin resistance in individuals who have crossed the personal fat threshold. Even though these data may sound promising, I admit that I am a bit skeptical of anti-inflammation approaches to insulin resistance and type 2 diabetes, because I see the role of the immune system and activation of inflammation pathways in tissues overwhelmed by nutrient excess as protective. Without a proper immune response, many more cells in the subcutaneous fat tissue, for example, may die, and in the long run, we may well be worse of. So maybe it’s not surprising that even though some small-scale anti-inflammation trials were published, we don’t have anti-inflammatory drugs to treat type 2 diabetes.
The last major piece of evidence supporting the personal fat threshold hypothesis comes from weight loss studies. Whenever people lose weight, their insulin sensitivity tends to improve, but we see the greatest improvements in people whose liver fat, muscle fat, and visceral fat drop the most. So again, that strongly supports the idea that storing fat in these depots contributes strongly to insulin resistance.
Why is the Personal Fat Threshold Hypothesis Relevant?
Why is the personal fat threshold hypothesis relevant?
Once someone gains body fat that can no longer be safely stored in small fat cells in subcutaneous fat tissue, that’s when a lot of health risks manifest. For one, as we discussed here, storage of fat in visceral fat depots as well as liver and muscle, is almost certainly a key contributor to insulin resistance, and a major reason why people with high BMIs tend to have a massively elevated risk of developing type 2 diabetes.
Storing a lot of fat in ectopic depots is bad for other reasons as well, though.
Let’s look at the liver first. Storing a lot of fat in the liver is called non-alcoholic fatty liver disease, or NAFLD, and NAFLD is a risk factor for hepatic fibrosis and cirrhosis. Liver cirrhosis is a pretty bad condition in its own right. However, liver cirrhosis also substantially increases the risk of developing liver cancer. And, less well known, NAFLD is also a major risk factor for the development of cardiovascular disease.
Then the heart. It’s now recognized that storing excessive amounts of fat in one of the visceral fat depots, the epicardial fat depot that is surrounding the heart, is a risk factor for coronary heart disease. While the mechanisms underlying this relationship are not entirely clear yet, that is probably particularly true if chronic low-grade inflammation is present in the epicardial fat tissue.
Similarly, a visceral fat tissue surrounding the gastrointestinal tract called the mesenteric fat is thought to play a role in cancers of the digestive system, particularly colon cancer.
And lastly, we do know that expansion of visceral fat and inflammation in visceral fat is associated with decreased kidney function.
So, all that said, we have very good reasons to try hard to stay below our personal fat threshold. I do think knowing about this hypothesis can be useful because it suggests that negative health consequences of weight gain do not scale in a linear fashion. Most of us probably can gain quite a few pounds before we cross the personal fat threshold. Not that I want to encourage weight gain, but it may be helpful to know that not every extra pound we gain throughout our life necessarily has negative health consequences. And even if we are overweight or obese, the existing data do suggest that major health benefits can result from losing just a few extra pounds if that weight comes right out of the liver and the visceral fat depots. Jim, from our earlier example, would just need to lose a few pounds of the extra fat mass, and his insulin sensitivity would improve pretty dramatically. He wouldn’t need to go back all the way to the body weight he had in his 20s.
How Do We Know Whether We Have Crossed Our Own Personal Fat Threshold?
I am sure many of you are wondering now: How do we know whether we have crossed our own personal fat threshold?
The best way to find out is to have an abdominal MRI scan to directly measure the visceral fat mass and the fat in the liver. This is not routinely done in clinical care, but you could certainly pay for the scan yourself if you really need to know. Personally, I don’t think this is necessary for most people.
So unless you have a few hundred or thousand dollars to spare, using some indirect measures will be the better choice.
One option is to estimate visceral fat mass from a DEXA-scan. DEXA-scans are commonly done to measure bone mineral density, but the software can usually also provide a pretty good measure of total body fat mass and an estimate of visceral fat, at least with newer DEXA-scanner models.
Liver fat can also be estimated by specific ultrasound methods.
Another option is to consider your BMI together with a measure of insulin resistance such as HOMA-IR, which I discussed in the last blog post, a measure of inflammation such as C-reactive protein (CRP), and fasting blood triglycerides.
If you have an elevated BMI, elevated HOMA-IR, elevated CRP, and elevated fasting triglycerides, it is likely that your body has increased visceral and ectopic fat depots. For CRP, it is important to get the high-sensitivity CRP test done; the normal one is not sensitive enough.
Note that in most people who have excessive visceral and ectopic fat, most or all of these markers will be at least slightly elevated. So consistent elevation in at least 2 or 3 of these markers is what we are looking for, not a single elevated one. That is particularly important to remember because these markers could be elevated for reasons other than excessive visceral and ectopic fat. CRP, for example, could be massively elevated in someone who is acutely ill, or who has just had major surgery. That’s not what we are looking for here. Instead, what we are interested in is detecting the chronic low-grade inflammation in fat tissue or liver that results from these tissues being overwhelmed with nutrient excess. So it’s important to get blood drawn for these tests in the fasting state, and only if you are not acutely ill and haven’t had surgery in the last month.
Also, these cut-offs shown in the table above are my estimates, obviously based on the scientific literature, but they are not firmly established clinical cut-offs, so please use these only to get a rough idea of how likely it is that you may have elevated visceral and ectopic fat. Do not self-diagnose here, and make sure to discuss this issue with your doctor. I personally do think these measures hold value in the absence of direct measurements, such as an MRI scan, because these are all closely linked to increased visceral and ectopic fat deposition. And, these lab measures could also be used to track progress if we are trying to lose ectopic and visceral fat, whereas we probably would not want to pay out of pocket for repeated MRI scans.
Summary of the Personal Fat Threshold Hypothesis
To summarize the personal fat threshold hypothesis:
BMI and particularly body fat percentage are associated with insulin resistance.
However, at any given level of adiposity, there is quite a bit of variability in insulin resistance.
This is because not all body fat causes insulin resistance. In fact, storing fat safely in small fat cells in subcutaneous fat depots is somewhat protective against insulin resistance.
Insulin resistance develops mostly after the personal fat threshold has been crossed. At that threshold, the person’s subcutaneous fat tissue can no longer expand by recruiting new fat cells (called hyperplasia) and instead expands by growth of existing fat cells (called hypertrophy).
Hypertrophy of fat cells leads to inflammation and insulin resistance in subcutaneous fat cells.
Insulin resistance in subcutaneous fat cells reduces the ability of the body to store fat there safely, and gradually more fat needs to be stored in ectopic locations such as the visceral fat depots surrounding the inner organs, muscle, liver, and pancreas. Excessive storage of fat in these depots also causes inflammation and insulin resistance in these tissues.
The end result is whole-body insulin resistance, because all of the tissues that usually take up glucose after a meal rich in carbohydrates are already full to the brim with nutrients. In other words, the ability of these tissues to do their job and participate in normal blood sugar regulation is impaired because of what we may call energy toxicity.
In the coming weeks, as we discuss other causes of insulin resistance and different ways to improve insulin sensitivity, it will be very useful to have a solid understanding of the personal fat threshold hypothesis. Please leave a comment below to provide feedback, or to ask any questions.
Take care.
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6 Responses
It is very interesting that the person who coined the term “personal fat threshold”, that is Dr. Roy Taylor (Newcastle, UK) is not mentioned among the references.
great lay down of this topic. i much appreciate how you explain it in easy to understand terms. Have you or can you explain why elevated glucose is dangerous and what’s more damaging, glucose spikes or long term elevated glucose or both? thanks
Thank you for your kind feedback.
I’d say that the evidence is pretty clear that chronically elevated blood sugar is worse than occasional spikes, simply because people with chronic hyperglycemia also tend to have spikes when they eat a large carb-rich meal.
The question is also complex, for one reason: we cannot really isolate the impact of blood sugar on chronic disease endpoints in most studies, because the factors that underly glucose intolerance (ectopic fat, insulin resistance, beta-cell dysfunction, low-grade chronic inflammation etc.) could also contribute themselves to an increased risk of other chronic diseases. In large cohorts in which we can assess the risk of developing a chronic disease, most of these factors are never measured, because their measurement is too involved or too expensive. However, it’s clear that if someone is very glucose intolerant, with a HbA1c of, say, 9%, they will have an increased risk of heart disease or kidney disease partly because of their very high and probably spiking blood glucose levels, but also because they almost certainly have a lot of visceral and ectopic fat, they suffer from insulin resistance, they have chronic low-grade inflammation etc. etc.
Hope this makes sense.
Cheers
Mario
Wow, how did you manage never to mention FFA? FFA is crucial in this question. More fat – higher FFA levels. More visceral fat – higher FFA. Higher FFA – more intracellular fatty acids metabolites. And therefore also insulin resistance.
I agree with you, and I talk about the release of fatty acids from fat tissue, and the role of insulin resistance in uninhibited flow of fatty acids to visceral and ectopic depots.
FFA is also dependent on fat intake. 1000+ nM is nothing unusual on a high-fat diet.