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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.

Edmonton, AB



Balancing Benefits And Harms From Redefining Obesity

The final and eight item on the disease definition modification checklist developed by the Guidelines International Network (G-I-N) Preventing Overdiagnosis Working Group published in JAMA Internal Medicine,  deals with issue of determining the benefit/harm ratio of the proposed new definition.

With terms to redefining obesity as the presence of abnormal or excess body fat that impairs health, I have discussed the potential benefits and harms in previous posts.

The question is, whether or not the overall balance comes down on the benefit or harm side of the equation.

Here, the authors of the checklist have the following to offer,

“Modifying a disease definition should be guided by a balanced assessment of the anticipated benefits and harms, using the best evidence available. The definition should reflect the values and preferences of patients and the wider community and include the impact on resource usage….In general, we recommend that panels consider both an individual and societal approach to assessing the overall benefits and harms of changing disease definitions. We recommend introducing a new disease definition where there is an expected positive balance of harms and benefit for individuals, and in aggregate at the societal level.”

In addition, the authors note,

“Different definitions may be required for research purposes, for example more stringent standardization, than for clinical purposes where more stringent definitions may deny access to care for patients who would benefit.”

Thus, as we have seen, changing disease definitions is not just a matter of opinion but rather, the pros and cons must be considered both at an individual and societal (resource) level.

That said, disease definitions are in constant flux as new knowledge and treatments emerge – obesity, should be no exception.

Indeed, guidelines would be amiss in not reconsidering the validity of current definitions and exploring potential changes as part of the guidelines process. The published checklist can certainly serve as a guide for this process.

Edmonton, AB


Are There Any Harms Of Redefining Obesity?

The seventh item on the disease definition modification checklist developed by the Guidelines International Network (G-I-N) Preventing Overdiagnosis Working Group published in JAMA Internal Medicine,  deals with issue of potential harms to patients.

Given the obvious benefits of redefining obesity as the presence of abnormal or excess body fat that impairs health outlined in the previous post, it is nevertheless prudent to explore the possibility of unintentional harms.

Obviously, expanding the term obesity to include millions of people, who currently fall under the BMI threshold but may well have health impairments attributable to their body fat, may not sit well with these folks. In fact, they may find themselves shocked to learn that they would now be considered to have obesity (more a reflection of the stigma attached to this term, than its non-judgemental medical meaning).

Thus, the authors of checklist remind us that,

“The potential harms from diagnosis include the physical harms of diagnosis and treatment; psychological effects, such as anxiety; social effects, such as stigma and discrimination; and financial consequences, such as effects on employment….Potential harms also include the misapplication and misinterpretation of the disease definition when taken from a confined research application to more widespread clinical use.”

A, perhaps more concerning issue, is the impact that redefining obesity may have on limited resources for obesity management in the healthcare system.

“Changes in resource usage can result in harm by reducing access to care for some patients and by diversion and distraction of clinical care. This can happen at both the societal level, with resources taken from areas more important to health, and at the individual level, by distracting individuals from activities more important to their well-being. Modifications of disease definitions can have considerable impacts on costs, including the costs of testing, and the resources needed for treatment and follow-up for those diagnosed using the new criteria. There may also be resources needed for training and implementation regarding the change, and to minimise misdiagnosis. Costs are particularly important in low- and middle-income countries where inappropriate disease definitions can result in considerable diversion of limited health care resources.”

These concerns are far from trivial. Not only are current resources for managing obesity in our healthcare systems limited (to non-existant), but one of the main reasons that employers and payers balk at providing access to obesity treatments, is the sheer number of individuals that already qualify for such treatments. Significantly expanding the pool of eligible patients, is therefore. unlikely to be met with much enthusiasm from these stakeholders.

Not only would one need to demonstrate that providing obesity treatments to people currently below the BMI threshold can significantly reduce their risks, one would also need to demonstrate that such efforts turn out to be cost-effective in the long-term.

Given our limited treatments, there does not appear any practical way of providing these treatments to everyone who meets the current BMI definition of obesity, let alone the millions of additional people, who would be considered to have obesity, if the disease definition was expanded to include anyone whose health may be impaired by the presence of abnormal or excess body fat.

Thus, as much as redefining obesity may make biological sense based on our understanding of the complex pathophysiology and substantial health impacts of this chronic disease, the societal harms (particularly on resources) of such a move must be carefully considered.

Edmonton, AB


How Will Patients Benefit From Redefining Obesity?

The sixth item on the disease definition modification checklist developed by the Guidelines International Network (G-I-N) Preventing Overdiagnosis Working Group published in JAMA Internal Medicine,  deals with issue of incremental benefits to patients.

With the current BMI-based definition, this measure is generally used to decide whether or not a given patient receives obesity treatments.

But, as readers are aware, not everyone with a BMI over a certain threshold would have the same degree of health issues (if any) and therefore not everyone currently classified as having obesity would necessarily benefit from treatment.

On the other hand, there are a substantial number of individuals who currently fall below the BMI threshold, but have significant health problems attributable to the presence of abnormal or excess body fat. These individuals, would currently not have access to obesity treatments.

Thus, as the authors of the checklist point out,

“Wherever changes in disease definitions will alter which patients receive treatment, it isessential to assess treatment benefits and harms, focusing on the balance of benefits and harms for those diagnosed by the new definition and not diagnosed by the previous definition. Changes to disease definitions can provide benefits to patients, mostly by providing access to treatments  with beneficial effects.”

However, the authors also warn that,

“…evidence from previous treatment trials in patients with later or more severe disease cannot be extrapolated to patients with milder or less severe disease…”

This means that evidence for treatment benefits will require clinical trials to include participants covered by the new definition.

Guideline committees should also consider the possibility that broadening the diagnosis may provide validation of symptoms and access to social and other benefits in individuals not previously qualifying for such benefits.

Berlin, D


Precision and Accuracy of Defining Obesity

The fifth item on the  disease definition modification checklist developed by the Guidelines International Network (G-I-N) Preventing Overdiagnosis Working Group published in JAMA Internal Medicine,  deals with issue of precision, accuracy, and reproducibility.

Obviously, any definition of obesity that requires clinical assessment and clinical judgement will not have the precision, accuracy, or reproducibility of simply measuring height and weight.

Thus, if we define obesity as the presence of abnormal or excess body fat that impairs health, we will necessarily have to deal with the issue of assessing health, which is not something that you can simply measure by stepping on a scale.

Rather, because abnormal or excess fat can affect virtually every organ system as well as psycho-social well-being, we are going to be faced with a rather complex system of diagnosing who has obesity and who hasn’t.

In fact, as the authors of the checklist point out,

“…an appropriate gold standard will rarely be available and therefore, traditional measures of diagnostic test accuracy, such as sensitivity and specificity, will generally not be appropriate.”

Both repeatability (agreement in identical conditions) as well as reproducibility (agreement across comparable conditions) may result from biological variability, analytical variability, and clinical judgement.

The only way to test the reproducibility and precision will be to evaluate the use of the new definition in clinical practice and ultimately determining whether or not clinicians can reasonably agree on who has the condition and who doesn’t.

While this may seem daunting to non-clinicians, let us remember that in clinical practice many diagnoses are dependent on clinical evaluations and clinical judgement, whereby experienced clinicians or specialists may perform better than the novice or the non-specialist (a good example is psychiatry, but there are countless other examples).

Moreover, there will always be grey areas in “borderline” cases, where examiners may disagree on the exact result and only time will tell, who is right.

Welcome to the messy world of clinical practice.

Just because BMI is simpler, more precisely measured, and more reproducible, does not make it a better measure of diagnosing whether or not someone actually has a disease.

After all it only makes sense that it will take a complex definition to diagnose a complex disease.

Edmonton, AB


Obesity Prognosis

Continuing in my discussion of the disease definition modification checklist developed by the Guidelines International Network (G-I-N) Preventing Overdiagnosis Working Group published in JAMA Internal Medicine,  I turn to the fourth item, which deals with issue of prognostic ability of changing the obesity definition?

Indeed, as pointed out by the authors of the checklist,

“The most important feature of a disease definition is its ability to accurately predict clinically meaningful outcomes.”

This, of course is, where BMI fails hands down.

As we have demonstrated using several large data sets, the ability of BMI to predict mortality is rather limited with almost no relationship between outcomes and BMIs, at least over a rather wide range of BMI levels.

Contrast this to the power of predicting outcomes when using a definition that actually looks at the presence of health impairments, such as the Edmonton Obesity Staging System

When applying this system, which takes into account the impact of excess weight on mental, physical, and functional health, the prognostic power ranges from virtually no risk (Stage 0) to halving your chances of being alive in 20 years (Stage 3).

Thus, a definition of obesity that actually considers impairments in health have a far greater prognostic power than simply knowing someone’s BMI.

If nothing else, this alone should be a reason to abandon BMI for a more meaningful definition of obesity, that actually considers health and not just size.

Edmonton, AB