Yesterday, I co-chaired and spoke at a session on obesity management at the 25th Annual Scientific Meeting of the American Society of Hypertension in New York.

Later in the afternoon, Jeff Friedman, who played a prominent role in the discovery of leptin, thereby hearkening in the modern era of adipocyte and appetite physiology, presented an update on the potential role of this system in the therapeutic management of obesity and diabetes.

While leptin has therapeutic efficacy in rare cases of genetic leptin deficiency, its use in non-genetic “garden-variety” obesity has proven disappointing. Indeed, there appears to be more evidence that leptin plays an important role in defending against weight loss, than to support its roled in the prevention of weight gain.

Thus, the dramatic decline in sympathetic activity, fall in metabolic rate and increased hunger that follows weight loss is likely due to the decrease in the leptin signal that unleashes the biological drive to rapidly regain weight and defend against further weight loss.

Indeed in most obese individuals, leptin levels increase in proportion to weight gain, while at the same time these individuals display leptin resistance, rendering these increased levels of leptin as biologically ineffective (a notion akin to the hyperinsulinemia associated with insulin resistance in patients with type 2 diabetes mellitus).

This state of affairs limits the use of leptin for the treatment of obesity, as the high doses of leptin that would be required to overcome the leptin resistance are poorly tolerated.

But recent research points to another possible use of leptin (or leptin analogues) in weight management, namely as a way to prevent weight regain after weight loss.

The basic idea here is to substitute leptin after weight loss in an attempt to trick the body into thinking that it still has as much body fat as it had before. Studies that have combined the peptide pramlinitide (which induces weight loss) with metreleptin (a long-acting analogue of leptin) are showing promise in terms of long-term weight loss maintenance (albeit at the cost of injections).

Friedman also discussed new data showing that leptin may have potent antidiabetogenic effects independent of any effects on weight loss or food intake. Some of this action may be mediated by leptin’s ability to increase plasma levels of Insulin-like Growth Factor Binding Protein 2 (IGFBP2), which has profound inhibitory effects on hepatic glucose output.

Several studies to further exploring the interaction between leptin and IGFBP2 and the antidiabetic effect of this protein are currently underway in Freidman’s lab to better understand these novel findings.

AMS
New York, New York

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Hedbacker K, Birsoy K, Wysocki RW, Asilmaz E, Ahima RS, Farooqi IS, & Friedman JM (2010). Antidiabetic effects of IGFBP2, a leptin-regulated gene. Cell metabolism, 11 (1), 11-22 PMID: 20074524

When an overweight or obese person presents with a sign or symptom of a disease in clinical practice, the clinician needs to always consider the following questions:

1) Is the presenting condition causally related to excess weight?

2) Is the presenting condition merely aggravated by excess weight?

3) Is the presenting condition unrelated to excess weight?

If the presenting condition is largely caused by excess weight (e.g. sleep apnea, type 2 diabetes, hypertension, gastroesophageal reflux disease, etc.) then there is a good chance that weight loss will reverse or “cure” this condition.

If, on the other hand, the condition is not caused by obesity but is merely aggravated by excess weight (e.g. COPD, congestive heart failure, urinary incontinence, etc.), then, although weight loss may not fully reverse this condition, it could very well reduce symptoms and make the condition more manageable.

In contrast, if the condition is unrelated to excess weight (e.g. a flu infection, migraine headaches, infectious hepatitis, etc.), then losing weight is unlikely to have any effect on this condition at all.
Accordingly, in the first case, if excess weight is indeed the causal factor, then not addressing obesity can only be considered “palliative care” (as in primarily managing an overweight Type 2 diabetic patient with hypoglycemic drugs or merely placing an overweight patient with obstructive sleep apnea on CPAP). In other words, symptomatic treatment without also targeting excess weight is unlikely to fully resolve the problem. These patients would have a primary indication for weight management – anything else is a “band-aid” solution.

When dealing with conditions not causally related to obesity, but where excess weight is a significant aggravating factor, the primary focus should of course be on treating the underlying condition. Only if this is not possible, will weight loss be an option to at least ameliorate the condition – this would be a secondary indication for weight management.

Obviously, for conditions presenting in overweight and obese patients that are unrelated to excess weight, weight loss is unlikely to have any impact on the problem. Thus, the focus should be on treating the underlying problem, which when solved, will still leave enough time to address the excess weight issue – if clinically indicated. These patients would have a tertiary indication for weight management.

Indeed, it is in cases 2 and 3 where mistakes are most often made; automatically assuming that all problems in overweight or obese patients must be a consequence of their excess weight can lead to delay of proper diagnostic procedures and treatments.

Thus, for example, assuming that the back pain in an obese patient is likely weight related can delay the diagnosis of osteoporotic fractures, spinal disc syndromes or even identification of metastasis. Similarly, simply assuming that exertional dyspnea in an obese patient is a consequence of excess weight may result in missing underlying interstitial, infectious or embolic disease.

It is therefore crucial that before jumping to the conclusion that excess weight is the primary problem for all symptoms and problems in overweight and obese patients, clinicians should maintain due diligence in terms of history, physical examination and diagnostic testing before simply recommending weight loss. This is not to say that these patients may not also benefit from weight management, but it certainly should not be the first priority before addressing the presenting complaint or condition.

Indeed, nothing frustrates overweight and obese patients more, than when every symptom or complaint is automatically blamed on their excess weight leading to the useless advise to simply “eat less and move more”.

AMS
Berlin, Germany

While I am taking a brief break from clinics and other obligations (including daily blog posts), I will be reposting past articles, which I still believe to be relevant but may have escaped the attention of the 100s of new readers who have signed up in the past months.

The following was first posted on 08/25/08

I have previously blogged on the profound effect of second generation antipsychotics (SGA) on weight gain. A new article by Melissa Blouin and co-workers from Laval University (Quebec City, Canada), published in this month’s issue of OBESITY, now examines the effect of these compounds on appetite, hunger, satiety, restraint and food preferences in SGA-treated patients (n=20) compared to controls (n=18).

Following a standardised breakfast, SGA patients had more hunger, higher cognitive dietary restraint, disinhibition and susceptibility to hunger than controls. In contrast to the controls, disinhibition in SGA-patients was largely triggered by internal cues. Although SGA-patients displayed higher strategic restraint behaviour, they also reported lower satiation after the buffet meal. No differences were found in food preferences.

This study has a number of interesting angles. Not only were the SGA-treated patients more susceptible to hunger, they were also more likely to consciously restrain their food intake, perhaps as a strategy to control their weight. This of course explains in part the fact that they were less likely to feel full or satiated after a meal than the controls.

It is well known that cognitive restraint (i.e. voluntarily trying to limit food intake) produces a tendency to overeat or even binge when restrictions are lifted (e.g. social disinhibition). The ultimate result, paradoxically, is weight gain or re-gain. This counter-regulatory phenomenon has been well described by Janet Polivy (University of Toronto) and essentially shows that food deprivation amongst dieters (achieved with cognitive dietary restriction) produces a tendency to overeat, explaining why long-term dieting does not work for restrained eaters. In other words - trying to simply eat less as a treatment for obesity is doomed to failure!

On a humanitarian note, the SGA-patients appear to be caught in an unfortunate vicious cycle: The antipsychotics alter eating behaviour to increase body weight - patients try to avoid further weight gain by cognitively restraining their food intake - as a result they feel less satiated and end up eating even more.

Complicated!

Of course, from this study, we don’t really know if the patients’ abnormal behaviour is due to their medications or simply due to their underlying disease. A third group of subjects consisting of psychotic patients treated with older antipsychotic medications may have answered this question.

Nevertheless, the study does demonstrate that we need to be very cautious in simply blaming someone with obesity for their condition. As this study reminds us - trying to not gain weight by simply eating less, is often a prescription for weight gain.

AMS
Edmonton, Alberta

While I am taking a brief break from clinics and other obligations (including daily blog posts), I will be reposting past articles, which I still believe to be relevant but may have escaped the attention of the 100s of new readers who have signed up in the past months.

The following was first posted on 30/03/08 (the Edmonton Obesity Staging System suggested in this original post, is now published in the International Journal of Obesity. Also note the foresight expressed in this post in light of Margaret Wente’s thought-provoking comment published in yesterday’s Globe and Mail - as this “classic” blog post demonstrates, we were well over a year ahead of Margaret in our thinking about what constitutes obesity and who needs treatment - good to see the mainstream media catch up!).

Current definitions of obesity based on BMI and waist circumference (WC), while widely accepted, are hardly helpful in counseling individual patients. Readers of my blog are probably quite familiar with my views on this.

As most clinicians will readily agree, when dealing with indiviual patients, both measures lack sensitivity and specificity with regard to identifying the presence or risk of obesity-related risk factors, comorbidities, psychopathology, global functioning or quality of life.

In fact recent epidemiological studies emphasize that good health including low morbidity and mortality is possible over a wide range of BMI. Thus, basing the decision on who to treat and who to leave well alone solely on measures of weight or size is neither sensible nor does justice to the complexity of the relationship between excess body fat and its impact on health and well-being. The well-established obesity-chronic disease paradox makes decisions on who to treat and who not to treat even more uncertain.

Telling healthy large people who have no apparent comorbidities, functional limitations or reduced well-being to lose weight may be counterproductive in that it can introduce and reinforce dissatisfaction with body image, foster frustrations and despair (given the poor long-term success of weight loss attempts) and lead to unhealthy behaviours focusing on weight loss (e.g. excessive exercise or dieting) rather than on healthy lifestyles (which are possible at almost any weight).

Thus, for practical purposes, it is important to move beyond defining who needs obesity treatment simply based on BMI and/or WC to a more clinically meaningful system.

Indeed, what we direly need is a classification of obesity that is clinically relevant in that it helps identify patients who have or are at high-risk of obesity-related complications and are most likely to benefit from treatment.

In this context, it may be worthwhile to look at the systems of classification and staging used for other disease states.

Oncologists have long used the TNM system to classify the extent of cancer spread. This system has established itself for the classification and staging of the vast majority of cancers not only because it is clinically meaningful in that it reflects extent of disease, indicates prognosis and allows evaluation of treatment response but also facilitates surveillance and research.

Psychiatrists and other mental health workers now routinely report on their patients using the five axes set out in the DSM-IV, each of which refers to a different domain of information that help the clinician plan treatment and predict outcome. The five axes are:

Axis I Clinical Disorders (all mental disorders except Personality Disorders and Mental Retardation)

Axis II Personality Disorders and Mental Retardation

Axis III General Medical Conditions (must be connected to a Mental Disorder)

Axis IV Psychosocial and Environmental Problems (for example limited social support network)

Axis V Global Assessment of Functioning (Psychological, social and job-related functions are evaluated on a continuum between mental health and extreme mental disorder)

While these systems are by no means simple or easy for the layman to understand, they are clinically useful and provide a standardized framework within which it is possible to describe the extent and impact of disease in a way that all clinicians, researchers and payors will understand.

Contrast these systems to the rather simplistic obesity classification, where knowing that a given person has Class II obesity (BMI 35-39.9) tells you virtually nothing about that person’s health or well being. Furthermore, it provides no meaningful guide in determining outcomes: e.g. someone who weighs 120 Kg with a BMI of 39 (Class 2 obesity) despite losing 10 Kg (8% weight loss) still has Class II obesity (BMI 36). This classification neither tells us what (if any) comorbities were actually present or whether (or not) these actually got better.

Now I am no expert on disease classification and realise the large amount of work and consensus meetings that go into developing these classification systems. But I am a clinician, who regularly sees patients and would be happy to see even the simplest form of staging that provides a meaningful framework.

The simplest classification I can think of would be to use a staging system similar to the following:

Stage 0: no apparent obesity-related risk factors (blood pressure, lipids, glucose, etc.), physical symptoms, psychopathology, functional limitations, or impairment of well-being

Stage 1: presence of obesity-related sub-clinical risk factors (elevated blood pressure, impaired fasting glucose, fatty liver, etc.), mild physical symptoms (dyspnea on moderate exertion, occasional aches and pains, etc.), mild psychopathology, mild functional limitations or mild impairment of well-being

Stage 2: presence of established obesity-related chronic disease like hypertension, type 2 diabetes, sleep apnea, osteoarthritis, reflux disease, polycystic ovary syndrome, depression, anxiety disorder, moderate limitations in activities of daily living and/or well being.

Stage 3: established end-organ damage like myocardial infarction, diabetic complications, severe osteoarthritis, significant psychopathology, significant functional limitations and impairment of well-being

Stage 4: severe (end-stage?) disabilities from obesity-related chronic disease, severe disabling psychopathology, severe functional limitations and severe impairment of well-being

Thus for e.g. a 24 year-old physically active female with a BMI of 32 with no measurable risk factors, functional limitations or self-esteem issues would have Class I, Stage 0 Obesity - benefits of treatment will be marginal or non-existent.

A 32 year-old male with BMI of 36 with hypertension and sleep apnea would have Class III, Stage 2 Obesity - definite indication for obesity treatment.

A 45 year-old female with BMI of 54 who is in a wheel chair because of severe gonarthritis with severe hypoventilaltion would have Class III, Stage 4 Obesity - will require aggressive obesity treatment unless deemed palliative.

But this may not be the only conceivable system. In fact, given the significant importance of psychopathology, personality traits, physical disease, psychosocial and enviromental factors as well as global functioning, I wonder if an approach similar to the axes in DSM-IV may be best. Of course, one could easily envision combinations of both systems, e.g. applying staging to Axis III disorders.

Obviously any such system would need careful definitions and perhaps a complex manual of diagnostics and classifications similar to DSM-IV - but at least we would have a way to assess, describe, treat, monitor and research obesity in a way that goes beyond the relatively meaningless anthropometry-based classification, which is nothing short of useless in clinical practice.

I can see why health authorities, professional organisations and even clinicians may be reluctant to devise a more complex classification of obesity - all I can say is that the present classification does not provide a meaningful framework in which to make clinical decisions or evaluate outcomes. There is certainly a need for a more complex system to guide practice (and research).

More often than not in clinical medicine - simple is simply wrong!

AMS
Edmonton, Alberta

As a nephrologist, I come from a field in which many key decisions are based on the outcome of a biopsy specimen. There are indeed many areas of medicine in which tissue biopsies are routinely used to establish a diagnosis or to guide treatment. Could the same hold true for obesity?

We have long known that obesity is by no means a homogeneous condition and that the clinical manifestation of obesity related comorbidities covers a wide and unpredictable spectrum of disorders. It is thus only likely that different forms of obesity are heterogeneous at the tissue level and in their response to treatment.

A first indication of just how adipose tissue biopsies may be used in clinical practice now comes from a study published in this month’s issue of the International Journal of Obesity. In this paper, Wang and colleagues from the Pennington Biomedical Research Center, Baton Rouge, LA, USA, use microarray gene expression technology to group 72 otherwise healthy obese men and women into two distinct clusters (denoted red and green). Interestingly, the red cluster contained no men, had “red” patients had less visceral fat and smaller fat cells. More importantly, it appeared that the patients in the green cluster appeared to respond with slightly greater weight loss to adrenergic treatment with ephedra and caffeine (not exactly my choice of antiobesity drugs) in an 8 week intervention.

Although the authors may be a tad overenthusiastic in terms of proclaiming that this paper now “brings us into an era of personalized treatment in the obesity clinic”, there is certainly some hope that fat biopsies may someday prove to provide a clinically useful predictor for response to specific treatments.

Obviously much needs to happen before anyone would seriously consider routine fat biopsies in clinical practice. For one, we would need prospective studies on sensitivity and specificity to detect clinically significant differences in response. Obviously, cost-effectiveness analyses would also need to establish the cost/benefit ratio for what is still a very expensive technology.

For now, nonetheless, the study confirms what I have maintained all along - obesity is a heterogeneous disorder and there is no reason to assume that any one treatment will work for all.

AMS
Edmonton, Alberta