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What Is “Abnormal” Body Fat?

sharma-obesity-fatty-liver-diseaseThe WHO defines obesity as the accumulation of excess or abnormal body fat that impairs health.

While many folks have no problem seeing how “excess” body fat can often lead to health problems, they may wonder what exactly is meant by “abnormal” body fat and are perhaps unsure as to why this would be included in the definition of obesity.

This is where we need to take a moment to remind ourselves that fat tissue is actually a vital organ, without which, we would experiences all kinds of health problems. Not only, is our ability to store excess calories vital to prepare for the next major illness or famine, it is also a vital organ for reproduction (women stop having periods when their fat stores get too low).

That said, the safest place to store all those excess calories is in your fat tissue, especially the fat tissue directly underneath your skin. This is where the excess calories cause the least trouble, not affecting the functioning of other organs or clogging up your blood stream, and where they can sit for decades, until they are perhaps one-day called upon in a time of need.

It is also “normal” to have a small amount of fat in other depots such as around the gastrointestinal tract, the heart, or the kidneys – here the fat serves both a mechanical and immunological function – again, the fat here generally does not cause any health problems (indeed, lack of fat in these locations may).

All of this is not very interesting from a medical or health perspective, as this kind of fat generally does not cause any real health problems, unless, it perhaps expands to a size that causes mechanical issues simply due to its sheer mass.

In contrast, the term “abnormal” refers to fat accumulation in parts of the body where you would not normally find fat in a “healthy” person. This, is commonly referred to as “ectopic” fat and refers to fat accumulation within organs like the liver, pancreas, heart, skeletal muscle or other organs, where you would rather not have any fat.

These “abnormal” fat accumulations can substantially disrupt organ function, leading to all kinds of metabolic problems.

Interestingly enough, there is not a very strong relationship between the total amount of body fat and the location of that body fat.

The extreme example of this is seen in patients with lipodystrophy, who, being unable to store excess calories in “normal” subcutaneous fat depots, deposit their fat in the liver and other organs, thus presenting with all of the problems generally associated with obesity.

Exactly why some people are more prone to “ectopic” fat deposition that others, who can apparently tuck away all their extra calories underneath their skin with little, if any, impact on their health, remains largely unknown, except that genetics appears to play a very substantial role.

But, whatever the reason, the bottom line remains that even very little extra body fat, if stored in the wrong location, can cause all of the metabolic problems generally associated with obesity.

In contrast, even large amounts of body fat, if safely sequestered away in subcutaneous depots may have little (if any) impact on health.

This is why the WHO included both the presence of “excess” as well “abnormal” body fat in their definition of obesity.

Again, none of this can be measured by stepping on a scale or looking at a BMI chart.

If your excess or abnormal body fat affects your health – you have obesity – if it doesn’t, you don’t.

@DrSharma
Edmonton, AB

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Non-Smokers Die of Lung Cancer and Teetotalers Die of Liver Cirrhosis

cause-effectIn all of my interactions with people who believe that the obesity epidemic is vastly overblown and that the links between excess body fat are imagined, I often hear the argument that obesity cannot “cause” [chose your health problem here] because “normal-weight” people can have [same health problem] too!

This is a rather naive argument, pretty much along the lines of, “Tobacco cannot cause lung cancer because non-smokers can get lung cancer too, or alcohol cannot cause liver cirrhosis because teetotalers get cirrhosis too”.

Or, “Drunk driving cannot cause road accidents, because non-drunk drivers get into accidents too”.

Or, “Flu vaccines don’t work, because vaccinated people get the flu too”.

I could go on….

What is missing in this perspective, is a very basic understanding of multiple cause and effect, as well as a fundamental understandings of probability and risk.

Firstly, almost all medical conditions can have more than one cause. Thus, although most lung cancer is by far attributable to smoking, it is also seen with exposure to asbestos, other environmental toxins, and of course sporadic mutagenesis.

Similarly, there are a multitude of reasons why someone may get liver cirrhosis, but, at least in Western societies, alcohol consumption is by far the number one cause of this problem.

And yes, some vaccinated people do catch the flu, but most vaccinated people don’t and when they do, it turns out to be less severe than it would have been without the vaccine.

So, just because “normal-weight” people can also have hypertension, diabetes, fatty liver disease, sleep apnea, osteoarthritis, gastroesophageal reflux, urinary incontinence, plantar fasciitis, and a host of other conditions, does not “prove” that excess weight does not also “cause” all of these conditions.

Yes, skinny people can have sleep apnea too but the overwhelmingly vast majority of sleep apnea is seen in people with excess weight – the same goes for virtually every obesity related health problem.

The other argument I often hear is that obesity cannot be the cause of [chose your health problem here] because not all people with obesity have [same health problem].

This argument is likewise stupid!

The fact that not every smoker dies of lung cancer, in no way “proves” that smoking does not cause cancer.

The fact that not everyone who regularly drinks a lot of alcohol gets a cirrhotic liver, does not disprove the link between alcohol and cirrhosis.

This is where we need to understand the basic concept of risk and probability.

When a certain factor (e.g. excess body fat) increases the risk of a certain condition, it does not mean that everyone exposed to that factor ends up with the condition. It just means that the risk for that condition is vastly higher.

Now let’s add a further level of complexity to the concept of risk, because, as we know, body fat is not body fat is not body fat is not body fat!

Whether or not my body fat actually causes any health problem, depends on a wide range of factors ranging from my underlying genetic predisposition (e.g. for diabetes, hypertension, etc.), my fat location (subcutaneous vs. ectopic), the cellular structure of my fat (hypertrophic vs. hyperplastic), fat-tissue inflammation, and probably countless other factors.

Add to this, that risk for obesity related conditions can be substantially modified by other factors including physical fitness, healthy diets, positive body image, good mental health – it is easy to understand why defining “sick” and “healthy” simply based on a measurement (direct or indirect) of body fat makes no sense.

Thus, we need to ensure that the medical term “obesity” is not used to label everyone above a certain (arbitrary) BMI cutoff.

Rather, we should reserve the medical term “obesity” only for the condition where excess or abnormal body fat directly impairs the health of a given individual (the actual WHO definition of obesity!).

Someone with the exact same amount of body fat (or even more), who does not experience any health impairment should not be referred to as having “obesity” – that person is just “fat” (a word that really needs to be destigmatised!).

Personally, I couldn’t care less about how “fat” anyone is. Only when “fat” becomes “obesity” does it become a medical issue.

@DrSharma
Edmonton, AB

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MetAP2 Inhibitors For Obesity – Take Two

Regular readers may recall that Zafgen, a Boston-based biopharmaceutical company, recently abandoned its development program for belanorib, a MetAP2 inhibitor. The program had to be abandoned, despite substantial weight loss in indiviuals with Prader-Wili syndrome, hypothalamic obesity, as well as “garden-variety” obesity, due to serious thrombotic adverse events.

Now, Zafgen reports that they have initiated a new round of Phase 1 studies of their 2nd generation MetAP2 inhibitor (ZGN-1061), which despite similar MetAP2 inhibition, appears to have much more favourable effects on coagulation.

The Phase 1 trial, designed to evaluate safety, tolerability, and weight loss efficacy over four weeks will enroll up to 48 healthy subjects across up to six cohorts of single escalating doses of ZGN-1061. The clinical trial also includes a multiple-ascending dose portion, which is evaluating twice-weekly ZGN-1061 over four weeks in up to 24 obese subjects.

The Company expects that top-line data from this clinical trial will be available by the end of the first quarter of 2017.

Given the rather spectacular weight loss seen with belanorib, this 2nd generation MetAP2 inhibitor study certainly warrants our attention.

@DrSharma
Edmonton, AB

Disclaimer: I have received consulting honoraria from Zafgen

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How Far Are We From Once-Weekly Medications For Obesity?

Anyone who follows these pages is aware of the fact that we desperately lack better medical treatments for obesity.

Last year, Health Canada approved the glucagon-like peptide 1 (GLP-1) analogue liraglutide (Saxenda(R)) for obesity treatment, which although effective and generally well-tolerated, has to be administered by daily injections.

Now, the results of the SUSTAIN-6 trial, published in the New England Journal of Medicine, show that the once weekly injection of the GLP-1 analogue semaglutide, not only decreases cardiovascular events, but also significantly lowers body weight, a promising finding for future obesity treatment with this drug.

The SUSTAIN 6 trial randomised 3297 patients with type 2 diabetes to once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks.

At baseline, 2735 of the patients (83.0%) had established cardiovascular disease, chronic kidney disease, or both.

The primary outcome (MACE) occurred in 108 of 1648 patients (6.6%) in the semaglutide group and in 146 of 1649 patients (8.9%) in the placebo group (hazard ratio, 0.74).

Nonfatal myocardial infarction occurred in 2.9% of the patients receiving semaglutide and in 3.9% of those receiving placebo (hazard ratio, 0.74); nonfatal stroke occurred in 1.6% and 2.7%, (hazard ratio, 0.61).

While average body weight at week 104 remained stable in the placebo group, it decreased by 3.6 kg in the semaglutide 0.5 mg group and and 4.9 kg in the semaglutide 1.0 mg group.

While this may not seem spectacular, it is important to remember that weight loss is notoriously difficult in patients with type 2 diabetes and that this was a diabetes and not an obesity trial, in which case participants would have also been counselled to change their diet and activity levels to achieve weight loss.

Thus, one can only speculate on what the differences in body weight would have been had the participants been actually trying to lose weight.

That said, it was perhaps surprising to note that fewer serious adverse events occurred in the semaglutide group, although more patients discontinued treatment because of adverse events, mainly gastrointestinal.

It will be interesting to see how well semaglutide fares in studies in which this treatment is assessed for the obesity indication, which will hopefully bring us closer to a once-weekly medication for obesity.

In the meantime, once-daily liraglutide 3.0 mg is certainly a welcome addition to medical management of obesity, but clearly there is more to come in terms of harnessing GLP-1 for obesity management.

@DrSharma
Edmonton, AB

Disclaimer: I have received consulting and speaking honoraria from Novo Nordisk, the makers of liraglutide and semaglutide

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Arguments Against Obesity As A Disease #9: Its Just A Risk Factor

sharma-obesity-blood-pressure4Next, in my miniseries on arguments I commonly hear against the notion of calling obesity a disease, is that it is “just a risk factor” for other diseases.

This may be true, if you just (wrongly) considered elevated BMI as your definition of obesity, because no doubt, people with higher BMI levels carry a higher risk for obesity related complications including type 2 diabetes, sleep apnea, fatty liver disease, hypertension – just to name a few. (Note that increased risk is not the same as actually having the condition!).

However, when you use the actual WHO definition of obesity, namely, “accumulation of excess or abnormal fat that impairs health”, obesity is no longer just a risk factor – it is now (by definition) impairing your health, which makes it far more than just a risk factor.

So while someone with a BMI of 35 may be at risk of developing obesity (not the same as having it), when their excess fat actually starts impairing their health, it de facto becomes a disease in its own right.

Even then, one might argue that obesity itself is not the disease, rather the complications of obesity are the real disease.

This notion is both right and wrong.

There are many conditions that are both diseases in their own right as well as risk factors for other diseases or complications.

Take type 2 diabetes for instance – it is both a disease in itself but also a risk factor for coronary heart disease or end-stage kidney disease.

Take hypertension – a disease in its own right but also a risk factor for strokes and heart attacks.

Take gastro-oesophageal reflux disease, which is also a risk factor for Barrett’s disease and oesophageal cancer.

Take fatty liver disease, which is also a risk factor for cirrhosis.

Gall bladder stones, which is also a risk factor for pancreatitis.

Multiple sclerosis, which is also a risk factor for neurogenic bladder and pyelonephritis.

The list goes on and on.

So just because obesity is also a risk factor for a wide range of other medical problems, it does not make obesity any less of a disease in its own right.

When excess or abnormal body fat affects health – it’s a disease. When it doesn’t, it’s at best a risk factor.

That, is perhaps a subtle but important distinction.

@DrSharma
Toronto, ON

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