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.

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.

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 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. 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.

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.

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.

And as a result, he remains quite insulin-sensitive. 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.

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? 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.

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.

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. 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. 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. 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. 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.

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. 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.

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.

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.

Essential body fat is necessary to maintain life and reproductive functions. The percentage of essential body fat for women is greater than that for men, due to the demands of childbearing and other hormonal functions.

Storage body fat consists of fat accumulation in adipose tissue , part of which protects internal organs in the chest and abdomen. A number of methods are available for determining body fat percentage, such as measurement with calipers or through the use of bioelectrical impedance analysis.

The body fat percentage is a measure of fitness level, since it is the only body measurement which directly calculates a person's relative body composition without regard to height or weight. The widely used body mass index BMI provides a measure that allows the comparison of the adiposity of individuals of different heights and weights.

While BMI largely increases as adiposity increases, due to differences in body composition, other indicators of body fat give more accurate results; for example, individuals with greater muscle mass or larger bones will have higher BMIs. As such, BMI is a useful indicator of overall fitness for a large group of people, but a poor tool for determining the health of an individual.

Epidemiologically , the percentage of body fat in an individual varies according to sex and age. Different authorities have consequently developed different recommendations for ideal body fat percentages.

This graph from the National Health and Nutrition Examination Survey NHANES in the United States charts the average body fat percentages of Americans from samples from to Essential fat is the level at which physical and physiological health would be negatively affected, and below which death is certain.

Bodybuilders may compete at essential body fat range. Certified personal trainers will suggest competitors keep that extremely low level of body fat only for the contest time. Irrespective of the location from which they are obtained, the fat cells in humans are composed almost entirely of pure triglycerides with an average density of about 0.

Most modern body composition laboratories today use the value of 1. With a well engineered weighing system, body density can be determined with great accuracy by completely submerging a person in water and calculating the volume of the displaced water from the weight of the displaced water. A correction is made for the buoyancy of air in the lungs and other gases in the body spaces.

If there were no errors whatsoever in measuring body density, the uncertainty in fat estimation would be about ± 3. Whole-body air displacement plethysmography ADP is a recognised and scientifically validated densitometric method to measure human body fat percentage. Air-displacement plethysmography offers several advantages over established reference methods, including a quick, comfortable, automated, noninvasive, and safe measurement process, and accommodation of various subject types e.

A beam of infra-red light is transmitted into a biceps. The light is reflected from the underlying muscle and absorbed by the fat. The method is safe, noninvasive, rapid and easy to use. Dual energy X-ray absorptiometry, or DXA formerly DEXA , is a newer method for estimating body fat percentage, and determining body composition and bone mineral density.

X-rays of two different energies are used to scan the body, one of which is absorbed more strongly by fat than the other. A computer can subtract one image from the other, and the difference indicates the amount of fat relative to other tissues at each point. A sum over the entire image enables calculation of the overall body composition.

There are several more complicated procedures that more accurately determine body fat percentage. Some, referred to as multicompartment models, can include DXA measurement of bone, plus independent measures of body water using the dilution principle with isotopically labeled water and body volume either by water displacement or air plethysmography.

Various other components may be independently measured, such as total body potassium. In-vivo neutron activation can quantify all the elements of the body and use mathematical relations among the measured elements in the different components of the body fat, water, protein, etc.

to develop simultaneous equations to estimate total body composition, including body fat. Prior to the adoption of DXA, the most accurate method of estimating body fat percentage was to measure that person's average density total mass divided by total volume and apply a formula to convert that to body fat percentage.

Since fat tissue has a lower density than muscles and bones, it is possible to estimate the fat content. This estimate is distorted by the fact that muscles and bones have different densities: for a person with a more-than-average amount of bone mass, the estimate will be too low.

The bioelectrical impedance analysis BIA method is a lower-cost from less than one to several hundred US dollars in [16] but less accurate way to estimate body fat percentage.

The general principle behind BIA: two or more conductors are attached to a person's body and a small electric current is sent through the body. The resistance between the conductors will provide a measure of body fat between a pair of electrodes, since the resistance to electricity varies between adipose , muscular and skeletal tissue.

Factors that affect the accuracy and precision of this method include instrumentation, subject factors, technician skill, and the prediction equation formulated to estimate the fat-free mass. Each bare foot may be placed on an electrode, with the current sent up one leg, across the abdomen and down the other leg.

For convenience, an instrument which must be stepped on will also measure weight. Alternatively, an electrode may be held in each hand; calculation of fat percentage uses the weight, so that must be measured with scales and entered by the user.

The two methods may give different percentages, without being inconsistent, as they measure fat in different parts of the body. More sophisticated instruments for domestic use are available with electrodes for both feet and hands.

There is little scope for technician error as such, but factors such as eating, drinking and exercising must be controlled [16] since hydration level is an important source of error in determining the flow of the electric current to estimate body fat.

The instructions for use of instruments typically recommended not making measurements soon after drinking or eating or exercising, or when dehydrated.

Instruments require details such as sex and age to be entered, and use formulae taking these into account; for example, men and women store fat differently around the abdomen and thigh region. Different BIA analysers may vary. Population-specific equations are available for some instruments, which are only reliable for specific ethnic groups, populations, and conditions.

Population-specific equations may not be appropriate for individuals outside of specific groups. There exist various anthropometric methods for estimating body fat. The term anthropometric refers to measurements made of various parameters of the human body, such as circumferences of various body parts or thicknesses of skinfolds.

Most of these methods are based on a statistical model. Some measurements are selected, and are applied to a population sample.

For each individual in the sample, the method's measurements are recorded, and that individual's body density is also recorded, being determined by, for instance, under-water weighing, in combination with a multi-compartment body density model.

From this data, a formula relating the body measurements to density is developed. Because most anthropometric formulas such as the Durnin-Womersley skinfold method, [18] the Jackson-Pollock skinfold method, and the US Navy circumference method, actually estimate body density, not body fat percentage, the body fat percentage is obtained by applying a second formula, such as the Siri or Brozek described in the above section on density.

Consequently, the body fat percentage calculated from skin folds or other anthropometric methods carries the cumulative error from the application of two separate statistical models. These methods are therefore inferior to a direct measurement of body density and the application of just one formula to estimate body fat percentage.

One way to regard these methods is that they trade accuracy for convenience, since it is much more convenient to take a few body measurements than to submerge individuals in water.

The chief problem with all statistically derived formulas is that in order to be widely applicable, they must be based on a broad sample of individuals.

What seemed interesting was the blood sugar levels after eating were similar to what he had during his 7 day fast.

Interested in your take on this study which shows hyperinsulinemia precedes diabetes and it is not correlated with obesity. Thank you for this article. I lost 70 pounds on a commercial PSMF program before conceiving my first child.

After that pregnancy I started more of a traditional Keto diet with high fat and moderate protein. My weight was stable at about 50 pounds down from my highest, but I never reached my pre-pregnancy weight and I noticed that I seemed to be gaining size around my midsection despite no change in weight.

If this is successful I will certainly have anecdotal support for this theory. Thank you for helping me to understand. Congratulations on your success.

You may be interested in this post on the PSMF approach. PSMF is essentially what is prescribed after weight loss surgery. People keep saying weight loss surgery is forced fasting but at most it is intermittent fasting with emphasis on protein first.

I am 5 years post sleeve and working back from regain by going back to the basics of the plan of no snacking and protein first. I do not regret the surgery. It has taught me how to eat properly and my experience was very smooth with an excellent surgeon with proper diet and support post surgery.

So PSMF works very well especially with IF. But even without surgery it should be very effective and less expensive! A google search comes up empty. a hardcore PSMF is hard to maintain long term because it ends up being extreme calorie restriction.

but any diet that works long term provides greater satiety. adequate dietary protein preserves LBM and helps to maintain BMR. Marty, This is auch a lovely article. Could this be one of the reasons why your fasting glucose reads higher than Post prandial?

I have an HbA1c: 5. I have been trying Keto and strength training, My fasting glucose had dropped to 84 when I was on strict keto and fasting insulin has dropped from 24 to Thank you so much Marty! Such continuing clarity! What an amazing change from the years of being alone in the blame ridden wilderness!

So appreciate your work and the generosity w which you share. after all these years. How is that even possible? This article was so enlightening for me.

Thank you! I could not figure out what the issue was as I kept zeroing in on my macros and getting my carbs really low 10 grams. I had a really bad experience on a low-fat diet years ago so I thought more fat was nourishing and helpful.

Your article explained WHY my weight loss is so little while my weight is still so high. Started PSMF 5 days ago and have dropped 5 pounds. Feeling very excited with this information and a solution!

The metabolic pathway for dietary fat does not depend on insulin for storage so how can it raise basal insulin levels?

Are you saying an excess of energy from too much dietary fat creates a calorie surplus that increase basal insulin levels? The more fat we have to hold in storage the harder our pancreas needs to work to produce basal insulin. for me I tried every diet in teh book I have high fat threshold apparently keto started me out but I wasnt really losing that much weight, or feeling better, well maybe some better but I listend to a doctor about addictions i was not planning on fasting I get to hungry well I was trying to follow the insulin index diet, finding out that milk has variable numbers and what the doctor said about addictions decided to stop drinking milk cheese doesnt give me problems I can eat a slice inmy salad and be okay and realized that some meats have some affect on insulin but it has high satiety for me.

one guy was saying fasting helps you regain your true hunger, but I ended up falling into intermitten fast because I was losing my appetite over time. when I got h ungry I realized that guy was right.

that hunger was different then the nawing feeling in my stomach and feeling. anyway I can actually stick to a diet now and be satiated if I eat the right foods. and avoid the wrong ones that triggor to much insulin.

you need to watch this video from Professor Roger Unger. His theory and experimental data matched perfectly to yours. this is a brilliant lecture. he has a really profound understanding of how everything actually works.

this was a real inspiration for me when it came out back in the day.