POMC Mutation Obesity Responds To Melanocortin-4 Receptor Agonist
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. @DrSharma Atlanta, GA
Does Glycemic Response to Food Really Affect Appetite?
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… Read More »
Arguments For Calling Obesity A Disease #3: Once Established It Becomes A Lifelong Problem
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… Read More »
Arguments Against Obesity As A Disease #7: Medicalizes A Behaviour
Continuing in my miniseries on objections I have heard against calling obesity a disease, I now address the argument that, doing so “medicalizes a behaviour”. This argument is of course based on the underlying assumption that the root cause of obesity is a behaviour. This is perhaps true at the most superficial level of understanding of obesity – yes, there are behaviours that can promote weight gain like eating too much, sedentariness and working shifts. Note however, that nowhere in the WHO definition of obesity as a “disease that results from excess or abnormal body fat that impairs health”, is there any mention of behaviour whatsoever. This is because for many people, the relationship between behaviour and weight gain is not at all as straightforward as many think. Take for example physical activity – although over 95% of Canadians do not meet even the minimum criteria for daily physical activity (a behaviour), only 20% of Canadians have obesity (using the BMI 30 cutoff for the sake of argument). So if behaviour (not moving enough) is touted as one of the root causes of obesity, why does not 95% of the population have obesity? The simple answer is that for any given level of physical activity (or rather lack of it), some people gain weight while others don’t. Similarly, if you believe that eating a lot of junk food (a behaviour) is the root cause of obesity, you will have to explain why not everyone who eats a lot of junk food has obesity and why a lot of people have obesity despite never touching the stuff. No matter what behaviour you pick, it will never explain all (or even most) of obesity and there will always be plenty of people with those exact same behaviours, who manage to maintain a “normal” weight with no additional effort. As I have previously outlined in blog posts and articles. “behaviours” leading to obesity, if anything, are no more than a symptom of underlying root causes of energy imbalance that can be related to a wide range of psychological, social and/or biological factors, with the precise cause varying widely from one person to the next. Thus, equating “behaviour” with “obesity” only happens in the minds of people who fail to see obesity for what it actually is – a complex heterogenous often multifactorial disease characterized by excess or abnormal fat tissue that impairs health. Thus, all that declaring… Read More »
Is ADHD Sabotaging Your Weight Management Efforts?
Are you an impulsive eater? Do you have a hard time meal planning or keeping a food journal? Do you find it hard to remember if you had breakfast or not (never mind what you actually ate)? Do you start every new diet or exercise program with super enthusiasm, only to lose interest a few days later? Does your day lack a routine (for no good reason)? These are just some of the ways in which Attention Deficit Hypertactivity or just Attention Deficit Disorder (ADHD/ADD) can sabotage your efforts to control your weight. Now, an article by Philip Asherson and colleagues from Kings College London, UK, published in The Lancet Psychiatry discuss important conceptual issues regarding the diagnosis and management of ADHD/ADD in adults. Although ADHD/ADD is largely thought to be a problem in kids and youth, it remains a considerable and often undiagnosed issue in adults. Thus, as the authors point out, “…treatment of adult ADHD in Europe and many other regions of the world is not yet common practice, and diagnostic services are often unavailable or restricted to a few specialist centres.” This is all the more surprising (and disappointing) given that adult patients respond similarly to current drug and psychosocial interventions, with the same benefits seen in children and adolescents. With regard to diagnosis it is important to note that, “Symptoms of ADHD cluster together into two key dimensions of inattention and hyperactivity-impulsivity, are reliably measured, and are strong predictors of functional impairments, but they reflect continuous traits rather than a categorical disorder.” “Of particular relevance to adult ADHD is the relative persistence of inattention and improvements in hyperactive-impulsive symptoms during development, so that many patients who had the combined type presentation of ADHD as children present with predominantly inattentive symptoms as adults.” “In clinical practice, the continuous nature of ADHD should not present diagnostic difficulties in moderate-to-severe cases, but might cause difficulties in mild cases with more subtle forms of impairment. Careful attention is needed to assess the effect of ADHD symptoms on impairment and quality of life, including an understanding of the broader range of problems linked to ADHD (eg, executive function [self-regulation] impairments, sleep problems, irritability, and internal restlessness), in addition to functional impairments such as traffic accidents and occupational underachievement. Therefore, some individuals, who seem to function well, might nevertheless suffer from a substantial mental health problem related to ADHD.” Key criteria according to… Read More »
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