If there is one thing we know for sure about obesity management, it is the sad fact, that no diet, exercise, medication, not even bariatric surgery, will permanently reset the body’s tendency to defend and regain its body weight to its set point – this generally being the highest weight that has been achieved and maintained for a notable length of time.
Thus, any effective long-term treatment has to offset the complex neurobiology that will eventually doom every weight-loss attempt to “failure” (no, anecdotes don’t count!).
Just how complex and overpowering this biological system that regulates body weight is, is described in a comprehensive review by the undisputed leaders in this field (Michael Schwartz, Randy Seeley, Eric Ravussin, Rudolph Leibel and colleagues) published in Endocrine Reviews. Indeed the paper is nothing less than a “Scientific Statement” from the venerable Endocrine Society, or, in other words, these folks know what they’re talking about when it comes to the science of energy balance.
As the authors remind us,
“In its third year of existence, the Endocrine Society elected Sir Harvey Cushing as President. In his presidential address, he advocated strongly in favor of adopting the scientific method and abandoning empiricism to better inform the diagnosis and treatment of endocrine disease. In doing so, Cushing helped to usher in the modern era of endocrinology and with it, the end of organo-therapy. (In an interesting historical footnote, Cushing’s Energy Homeostasis and the Physiological Control of Body-Fat Stores presidential address was given in , the same year that insulin was discovered.)”
Over 30 pages, backed by almost 350 scientific citations, the authors outline in excruciating detail just how complex the biological system that regulates, defends, and restores body weight actually is. Moreover, this system is not static but rather, is strongly influenced and modulated by environmental and societal factors.
Indeed, after reading this article, it seems that the very notion, that average Jane or Joe could somehow learn to permanently overcome this intricately fine-tuned system (or the societal drivers) with will power alone is almost laughable (hats off to the very few brave and determined individuals, who can actually do this – you have climbed to the top of Mount Everest and decided to camp out there for the foreseeable future – I wish you all the best!).
Thus, the authors are confident that,
“The identification of neuromolecular mechanisms that integrate short-term and long-term control of feeding behavior, such that calorie intake precisely matches energy expenditure over long time intervals, will almost certainly enable better preventive and therapeutic approaches to obesity.”
Sadly, despite all we have learnt about this system, we are still far from fully understanding it. Thus, the canonical molecular/ cellular signaling pathway: LEP → LEPR → POMC, AgRP → PC → MC4R is just one pathway in a complex network of multiple interacting and sometimes redundant pathways that involve virtually every part of the brain.
Also, the effect of environmental factors appears to be far more complex than most people think. Thus,
“During sensitive periods of development, ontogenic processes in both brain and peripheral organs can be modified so as to match anticipated environmental conditions. Although many exposures during development could potentially predispose to obesity in adulthood, we focus here on two that some researchers think contribute to the secular trends in obesity: parental obesity and exposure to endocrine disrupting chemicals (EDCs).”
Throw in the role of gut bugs, infections, and societal factors, and it is easy to see why no simple solution to the obesity epidemic are in sight (let alone a range of effective long-term treatments like we have for most other common chronic diseases).
As for solutions,
“To be viable, theories of obesity pathogenesis must account not only for how excess body fat is acquired, but also for how excess body fat comes to be biologically defended. To date, the preponderance of research has focused on the former. However, we must consider the possibility that some (perhaps even most) mechanisms underlying weight gain are distinct from those responsible for the biological defense of excess fat mass. A key question, therefore, is how the energy homeostasis system comes to defend an elevated level of fat mass (analogous to the defense of elevated blood pressure in patients with hypertension). Answering this question requires an improved understanding of the neuro-molecular elements that underlie a “defended” level of body fat. What are the molecular/neuroanatomic predicates that help establish and defend a “set point” for adiposity? How do these elements regulate feeding behavior and/or energy expenditure, so as to achieve long-term energy balance? By what mechanisms is an apparently higher set point established and defended in individuals who are obese?” [sic]
“Given that recovery of lost weight (the normal, physiological response to weight loss irrespective of one’s starting weight) is the largest single obstacle to effective long-term weight loss, we cannot overstate the importance of a coherent understanding of obesity-associated alterations of the energy homeostasis system.”
There is much work to be done. Whether or not, in this climate of anti- and pseudo-science, funding for such fundamental work will actually be made available, is anyone’s guess.
Regular readers may recall previous posts on the novel anti-obesity compound belanorib, a MetAP2 inhibitor that showed remarkable weight loss efficacy both in patients with Prader-Willi Syndrome as well as hypothalamic obesity.
Unfortunately, as noted before, several cases of venous thromoboembolisms led to a halt of ongoing trials during which the company (Zafgen) sought to better understand the possible mechanism for this serious adverse effect and explore the possibility of implementing a risk mitigation strategy.
As announced by the company in a press release earlier this week,
“Following its discussions with the FDA and review of other considerations, Zafgen has determined that the obstacles, costs and development timelines to obtain marketing approval for beloranib are too great to justify additional investment in the program, particularly given the promising emerging profile of ZGN-1061. The Company is therefore suspending further development of beloranib in order to focus its resources on ZGN-1061.”
The press release also describes the new compound ZGN-1061 as a,
“…fumagillin-class, injectable small molecule second generation MetAP2 inhibitor that was discovered by Zafgen’s researchers and has been shown to have an improved profile relative to previous inhibitors in the class. Like other MetAP2 inhibitors that have shown promise in the treatment of metabolic diseases including severe and complicated obesity, ZGN-1061 modulates the activity of key cellular processes that control the body’s ability to make and store fat, and utilize fat and glucose as an energy source. ZGN-1061 is also anticipated to help reduce hunger and restore balance to fat metabolism, enabling calories to once again be used as a productive energy source, leading to weight loss and improved metabolic control. ZGN-1061 has an emerging safety profile and dosage form that are believed to be appropriate for the treatment of prevalent forms of severe and complicated obesity, and is currently in Phase 1 clinical development. Zafgen holds exclusive worldwide rights for the development and commercialization of ZGN-1061.”
According to the press release,
“The compound has similar efficacy, potency, and range of activity in animal models of obesity as beloranib, but displays highly differentiated properties and a reduced potential to impact thrombosis, supporting the value of the compound as a more highly optimized MetAP2 inhibitor.”
Screening of patients for a Phase 1 clinical trial evaluating ZGN-1061 for safety, tolerability, and weight loss efficacy over four weeks of treatment is currently underway.
Disclaimer: I have served as a consultant to Zafgen.
That said, fructose has also been implicated in non-caloric metabolic effects including promoting insulin resistance and systemic inflammation.
Now a study by Jessica Kuzma and colleagues from the Fred Hutchinson Cancer Research Center, Seattle, WA, published in the American Journal of Clinical Nutrition, specifically addresses the hypothesis that fructose-sweetened beverages can promote systemic inflammation.
For their study, they randomised 24 otherwise healthy participants to three 8 day periods during which participants consumed 4 daily servings of fructose-, glucose-, or HFCS-sweetened beverages accounting for 25% of estimated calorie requirements while consuming a standardized diet ad libitum.
During the study subjects consumed 116% of their estimated calorie requirement while drinking the beverages with no difference in total energy intake or body weight.
Neither fasting plasma concentrations of C-reactive protein or IL-6 changed during the study.
Furthermore, there were no consistent changes in measures of adipose tissue inflammation or in intestinal permeability.
Overall, the researchers conclude that consuming an excessive amount of fructose, HFCS, and glucose derived from SSBs consumed, at least in the short term (8 days), does not appear to promote systemic inflammation in otherwise healthy adults.
Obviously, this study does not address the issue of wether or not overconsumption of sugar-sweetened beverages can promote obesity or whether cutting out such beverages has any other advantages short of lowering caloric consumption.
Continuing in my miniseries on reasons why obesity should be considered a disease, I turn to the idea that obesity is largely driven by biology (in which I include psychology, which is also ultimately biology).
This is something people dealing with mental illness discovered a long time ago – depression is “molecules in your brain” – well, so is obesity!
Let me explain.
Humans throughout evolutionary history, like all living creatures, were faced with a dilemma, namely to deal with wide variations in food availability over time (feast vs. famine).
Biologically, this means that they were driven in times of plenty to take up and store as many calories as they could in preparation for bad times – this is how our ancestors survived to this day.
While finding and eating food during times of plenty does not require much work or motivation, finding food during times of famine requires us to go to almost any length and risks to find food. This risk-taking behaviour is biologically ensured by tightly linking food intake to the hedonic reward system, which provides the strong intrinsic motivator to put in the work required to find foods and consume them beyond our immediate needs.
Indeed, it is this link between food and pleasure that explains why we would go to such lengths to further enhance the reward from food by converting raw ingredients into often complex dishes involving hours of toiling in the kitchen. Human culinary creativity knows no limits – all in the service of enhancing pleasure.
Thus, our bodies are perfectly geared towards these activities. When we don’t eat, a complex and powerful neurohormonal response takes over (aka hunger), till the urge becomes overwhelming and forces us to still our appetites by seeking, preparing and consuming foods – the hungrier we get, the more we seek and prepare foods to deliver even greater hedonic reward (fat, sugar, salt, spices).
The tight biological link between eating and the reward system also explains why we so often eat in response to emotions – anxiety, depression, boredom, happiness, fear, loneliness, stress, can all make us eat.
But eating is also engrained into our social behaviour (again largely driven by biology) – as we bond to our mothers through food, we bond to others through eating. Thus, eating has been part of virtually every celebration and social gathering for as long as anyone can remember. Food is celebration, bonding, culture, and identity – all features, the capacity for which, is deeply engrained into our biology.
In fact, our own biology perfectly explains why we have gone to such lengths to create the very environment that we currently live in. Our biology (paired with our species’ limitless creativity and ingenuity) has driven us to conquer famine (at least in most parts of the world) by creating an environment awash in highly palatable foods, nutrient content (and health) be damned!
Thus, even without delving any deeper into the complex genetics, epigenetics, or neuroendocrine biology of eating behaviours, it is not hard to understand why much of today’s obesity epidemic is simply the result of our natural behaviours (biology) acting in an unnatural environment.
So if most of obesity is the result of “normal” biology, how does obesity become a disease?
Because, even “normal” biology becomes a disease, when it affects health.
There are many instances of this.
For example, in the same manner that the biological system responsible for our eating behaviour and energy balance responds to an “abnormal” food environment by promoting excessive weight gain to the point that it can negatively affect our health, other biological systems respond to abnormal environmental cues to affect their respective organ systems to produce illnesses.
Our immune systems designed to differentiate between “good” and “bad”, when underexposed to “good” at critical times in our development (thanks to our modern environments), treat it as “bad”, thereby creating debilitating and even fatal allergic responses to otherwise “harmless” substances like peanuts or strawberries.
Our “normal” glucose homeostasis system, when faced with insulin resistance (resulting from increasingly sedentary life circumstances), provoke hyperinsulinemia with ultimate failure of the beta-cell, resulting in diabetes.
Similarly, our “normal” biological responses to lack of sleep or constant stress, result in a wide range of mental and physical illnesses.
Our “normal” biological responses to drugs and alcohol can result in chronic drug and alcohol addiction.
Our “normal” biological response to cancerogenous substances (including sunlight) can result in cancers.
The list goes on.
Obviously, not everyone responds to the same environment in the same manner – thanks to biological variability (another important reason why our ancestors have made it through the ages).
But, you may argue, if obesity is largely the result of “normal” biology responding to an “abnormal” environment, then isn’t it really the environment that is causing the disease?
That may well be the case, but it doesn’t matter for the definition of disease. Many diseases are the result for the environment interacting with biology and yes, changing the environment could indeed be the best treatment (or even cure) for that disease.
Thus, even if pollution causes asthma and the ultimate “cure” for asthma is to rid the air of pollutants, asthma, while it exists, is still a disease for the person who has it.
All that counts is whether or not the biological condition at hand is affecting your health or not.
The only reason I bring up biology at all, is to counter the argument that obesity is simply stupid people making poor “choices” – one you consider the biology, nothing about obesity is “simple”.
Next, 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.