I am currently in Rio de Janeiro, speaking at the 21st World Congress of the International Federation for the Surgery of Obesity & Metabolic Disorders – IFSO 2016.
As Lee Kaplan from Harvard University reminded the audience, obesity is a disease of energy homeostasis, where everything seems to be working just fine, except that the “setpoint” of the system is set too high.
Kaplan used the analogy of the temperature in a room, where the thermostat is set too high – say to 30 Centigrade.
Everything else in the room works just fine: nothing wrong with the heater, or the air-conditioning, or the ventilation system, or the isolation. In fact, even the thermostat is working just fine doing its job – except that it is set too high!
Dieting would be like tearing open a window to lower the temperature in the room. Yes, if you open the window, things may cool down, but the thermostat will only make the heating work extra hard trying to heat the room and, once you close the window, the thermostat will rapidly bring the temperature back to 30 Centigrade (or come off your diet).
So how do we reset the set point?
Well, that appears to be exactly what bariatric surgery does to the system – it somehow manages to lower the set point, allowing the body to regulate its weight at a lower level than before (something that does not happen when you lose weight simply with diet and exercise).
How exactly surgery does this, remains unclear, but there is no doubt that this happens and there are a lot of experiments showing that after sugery, the body actively regulates body weight at a lower “setpoint”.
Unfortunately, this “resetting” is not permanent.
If you reverse the surgery, the body goes right back to regulating its weight at the higher level, resulting in the rapid weight regain, which is why I consider obesity surgery a “treatment” rather than a “cure”.
Kaplan went on to talk about the role of the bacteriome and bile acid metabolism (both dramatically changes with bariatric surgery – but very little with diet and exercise).
Figuring out how bariatric surgery changes the setpoint (even temporarily) will hopefully lead to new medical treatments for obesity.
Till then, anyone losing weight (no matter what diet, exercise, or medication) needs to remember that they stand to regain the weight, the minute they stop the “treatment”.
Rio de Janiero
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.
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.
Disclaimer: I have received consulting honoraria from Zafgen
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.
Disclaimer: I have received consulting and speaking honoraria from Novo Nordisk, the makers of liraglutide and semaglutide
However, for many dietitians, keeping up to date with the many issues related to obesity – from our evolving understanding of the complex neurobiology of energy homeostasis that make obesity a chronic disease to the issues of emerging pharmacotherapy and nutritional care for the bariatric surgery patient – is always a challenge.
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