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The Key To Obesity Management Lies In The Science Of Energy Homeostasis

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]

Clearly,

“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.

@DrSharma
Edmonton, AB

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Zona Incerta Stimulation Provokes Instant Binge Eating in Mice

The neuronal control of appetite and food intake is among the most complex and fascinating systems.

Now, in a paper published in Science, Xiaobing Zhang and Anthony van den Pol from Yale University, New Haven, report the identification of a novel role of the zona incerta in inducing profound binge eating behaviour in mice.

The zona incerta, is a little know part of the central nervous system within the subthalamus with extensive projections all the way from the cerebral cortex into the spinal cord. It is thought to play an important role in limbic-motor integration as well as synchronizing brain rhythms.

The researchers showed that optogenetic stimulation of zona incerta GABA neurons or their axonal projections to paraventricular thalamus excitatory neurons rsults in an immediate (in 2 to 3 seconds) binge-like eating behaviour – the animals ate up to 35% of their total energy requirements in just 10 mins.

Furthermore, while intermittent stimulation of these neurons led to body weight gain, ablation reduced weight.

The authors suggest that the identification of this novel orexigenic system may lead to better treatments not just for binge-eating disorder.

@DrSharma
Edmonton, AB

 

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POMC Mutation Obesity Responds To Melanocortin-4 Receptor Agonist

sharma-obesity-hypothalamusMelanocyte-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

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Does Glycemic Response to Food Really Affect Appetite?

GI-Foods-7-HealthA 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.

@DrSharma
Edmonton, AB

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Arguments For Calling Obesity A Disease #8: Can Reduce Stigma

sharma-obesity-hypothalamusNext, 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.

@DrSharma
Edmonton, AB

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