Melanocyte-stimulating hormone (a-MSH), which is produced from the hormone precursor proopiomelanocortin (POMC) and acts on the hypothalamic melanocortin-4 receptor, plays a key role in the regulation of satiety and energy expenditure.
In very rare instances, mutations of the gene coding for POMC can cause severe early onset obesity characterised by increased appetite. Due to other effects of POMC deficiency, patients will present with pale skin, red hair and clinical signs of hypocortisolism.
Now, a paper by Peter Kühnen and colleagues published in the New England Journal of Medicine, shows that treating patients with the melanocortin-4 receptor agonist, setmelanotide, can result in significant reduction in appetite and body weight.
The open-label study was performed in two adult patients with POMC deficiency, in cooperation with Rhythm Pharmaceuticals, which provided the study medication and regulatory support.
Both patients weighed around 150 Kg with marked hyperphagia and both responded to treatment with a substantial reduction in appetite and dramatic weight loss of over 20 Kg over 12-13 weeks.
After a brief interruption, one patient was again treated for 42 weeks, ultimately losing 51 kg (32.9% of her initial body weight).
As the authors note,
“Setmelanotide appeared to completely reverse hyperphagia, leading to impressive weight loss and normalization of insulin resistance. More important, both patients reported a dramatic improvement in their quality of life after the initiation of setmelanotide therapy. Moreover, the substantial and ongoing reduction in body weight was similar to the changes observed after leptin administration in patients with leptin deficiency.”
Over all the treatment was well tolerated with no major adverse effects.
While these observations were made in very rare patients with documented POMC deficiency, these findings may have broader implications for individuals with more common “garden-variety” obesity.
“Both patients described here had very high leptin levels before treatment, suggesting leptin resistance. In patients with proopiomelanocortin deficiency, the leptin signal is probably not properly transduced into anorexigenic responses, given the lack of melanocyte-stimulating hormone. Setmelanotide substitutes for melanocyte-stimulating hormone and binds at its receptor, thus overcoming leptin resistance. On the basis of the observation that obese patients without known genetic abnormalities have severe leptin resistance and regain weight owing to a post-dieting increase in appetite, we speculate that setmelanotide may also be effective in nongenetic forms of obesity.”
Appropriate studies in patients with non-POMC deficient obesity are currently underway.
A popular narrative by proponents of low-glycemic index foods is the notion that high-glycemic index foods lead to a surge in plasma glucose, which in turn stimulates a spike in insulin levels, resulting in a rapid drop in blood glucose levels and an increase in appetite (“crash and crave”).
While this narrative is both biologically plausible and has been popularised by countless low-GI diets and products, the actual science of whether this story really holds true is less robust that you may think.
Now, a study by Bernd Schultes and colleagues, published in Appetite, seriously challenges this narrative.
The study was specifically designed to test the hypothesis that inducing glycemic fluctuations by intravenous glucose infusion is associated with concurrent changes in hunger, appetite, and satiety.
Using a single blind, counter-balanced crossover study in 15 healthy young men, participants were either given an i.v. infusion of 500 ml of a solution containing 50 g glucose or 0.9% saline, respectively, over a 1-h period.
On each occasion, the infusions were performed one hour after a light breakfast (284 kcal).
I.v. glucose markedly increased glucose and insulin concentrations (peak glucose level: 9.7 vs. 5.3 mmol/l in the control group); peak insulin level: 370 vs. 109) followed by a sharp decline in glycaemia to a nadir of 3.0 in the glucose study vs. 3.9 mmol/l at the corresponding time in the control condition.
Despite this wide glycemic fluctuation in the glucose infusion condition, the subjective feelings of hunger, appetite satiety, and fullness did not differ from the control condition throughout the experiment.
Clearly, these findings speak against the conventional narrative that fluctuations in glycemia and insulinemia represent major signals in the short-term regulation of hunger and satiety.
Or, as the authors put it,
Our findings might also challenge the popular concept of low glycemic index diets to lose body weight. Advocates of this dietary approach often argue that large glycemic (and concurrent insulinemic) fluctuations induced by the intake of high glycemic index foods can trigger feelings of hunger and, thus, on the long run favor weight gain. Our results argue against this notion since the sharp drop in circulating glucose after the end of the glucose infusion remained without effect on hunger ratings, at least within the time period covered by our experiment.
As they further note, these findings may explain why,
“…several clinical dietary intervention trials have failed to show an advantage of low glycemic index dietary approaches for weight loss in overweight/obese subjects in comparison with other dietary approaches.”
The lesson here, I guess is that, just because there is a seemingly compelling narrative to support an idea, it does not mean that that’s how biology in real life actually works.
Next, in this miniseries on arguments for and against calling obesity a disease, I turn to the issue of stigma.
One of the biggest arguments against calling obesity, is the fear that doing so can increase stigma against people living with obesity.
This is nonsense, because I do not think it is at all possible for anything to make stigma and the discrimination of people living with obesity worse than it already is.
If anything, calling obesity a disease (defined as excess or abnormal body fat that impairs your health), could well serve to reduce that stigma by changing the narrative around obesity.
The current narrative sees obesity largely as a matter of personal choice involving poor will power to control your diet and unwillingness to engage in even a modest amount of regular physical activity.
In contrast, the term ‘disease’ conjures up the notion of complex biology including genetics, epigenetics, neurohormonal dysregulation, environmental toxins, mental health issues and other factors including social determinants of health, that many will accept are beyond the simple control of the individual.
This is not to say that other diseases do not carry stigma. This has and remains the case for diseases ranging from HIV/AIDS to depression – but, the stigma surrounding these conditions has been vastly reduced by changing the narrative of these illnesses.
Today, we are more likely to think of depression (and other mental illnesses) as a problem related to “chemicals in the brain”, than something that people can pull out of with sheer motivation and will power.
Perhaps changing the public narrative around obesity, from simply a matter of motivation and will power, to one that invokes the complex sociopsychobiology that really underlies this disorder, will, over time, also help reduce the stigma of obesity.
Once we see obesity as something that can affect anyone (it can), for which we have no easy solutions (we don’t), and which often requires medical or surgical treatment (it does) best administered by trained and regulated health professionals (like for other diseases), we can perhaps start destigmatizing this condition and change the climate of shame and blame that people with this disease face everyday.
Continuing in my miniseries on arguments that support calling obesity a disease, is the simple fact that, once established, it behaves like a chronic disease.
Thus, once people have accumulated excess or abnormal adipose tissue that affects their health, there is no known way of reversing the process to the point that this condition would be considered “cured”.
By “cured”, I mean that there is a treatment for obesity, which can be stopped without the problem reappearing. For e.g. we can cure an ear infection – a short course of antibiotics and the infection will resolve to perhaps never reappear. We can also cure many forms of cancer, where surgery or a bout of chemotherapy removes the tumour forever. Those conditions we can “cure” – obesity we cannot!
For all practical purposes, obesity behaves exactly like every other chronic disease – yes, we can modify the course or even ameliorate the condition with the help of behavioural, medical or surgical treatments to the point that it may no longer pose a health threat, but it is at best in “remission” – when the treatment stops, the weight comes back – sometimes with a vengeance.
And yes, behavioural treatments are treatments, because the behaviours we are talking about that lead to ‘remission’ are far more intense than the behaviours that non-obese people have to adopt to not gain weight in the first place.
This is how I explained this to someone, who recently told me that about five years ago he had lost a substantial amount of weight (over 50 pounds) simply by watching what he eats and maintaining a regular exercise program. He argued that he had “conquered” his obesity and would now consider himself “cured”.
I explained to him, that I would at best consider him in “remission”, because his biology is still that of someone living with obesity.
And this is how I would prove my point.
Imagine he and I tried to put on 50 pounds in the next 6 weeks – I would face a real upward battle and may not be able to put on that weight at all – he, in contrast, would have absolutely no problem putting the weight back on.
In fact, if he were to simply live the way I do, eating the amount of food I do, those 50 lbs would be back before he knows it.
His body is just waiting to put the weight back on whereas my biology will actually make it difficult for me simply put that weight on.
This is because his “set-point”, even 5 years after losing the weight, is still 50 lbs higher than my “set-point”, which is around my current weight (the heaviest I have ever been).
Whereas, he is currently working hard against his set-point, by doing what he is doing (watching what he eats, following a strict exercise routine), I would be working against my set-point by having to force myself to eat substantially more than my body needs or wants.
That is the difference! By virtue of having had 50 lb heavier, his biology has been permanently altered in that it now defends a weight that is substantially higher than mine.
His post-weight loss biology is very different from mine, although we are currently at about the same weight.
This is what I mean by saying he is in “remission”, thanks to his ongoing behavioural therapy.
Today, we understand much of this biology. We understand what happens when people try to lose weight and how hard the body fights to resist weight loss and to put the weight back on.
This is why, for all practical purposes, obesity behaves just like every other chronic disease and requires ongoing treatment to control – no one is ever “cured” of their obesity.
Not even people who have bariatric surgery – reverse the surgery and before you know it, the weight is back.
So, if for all practical purposes, obesity behaves like a chronic disease, why not just call a spade a spade?
For an illustration on why obesity acts like a chronic disease watch this short TEDx talk
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”.