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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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The Edmonton Obesity Staging System Predicts Early Complications After Bariatric Surgery

sharma-obesity-bariatric-surgery21Regular readers will be well aware of the Edmonton Obesity Staging System (EOSS), which classifies individuals living with obesity according to the presence and severity of medical, mental and functional complications on a 5-point ordinal scale.

We have previously shown that EOSS provides a better assessment of mortality risk than BMI, waist circumference, or the presence of metabolic syndrome.

Now, a paper by Sonja Chiappetta and colleagues from Offenbach, Germany, published in SOARD, shows that EOSS strongly predicts early surgical complications and mortality in patients undergoing bariatric surgery.

The authors analysed data from 534 patients, collected prospectively, for patients undergoing laparoscopic sleeve gastrectomy (LSG), laparoscopic Roux-en-Y gastric bypass (LRYGB), or laparoscopic omega-loop gastric bypass (LOLGB).

As typical for a bariatric surgery population, the mean BMI was around 50 kg/m2.

While the total postoperative complication rate for the entire patient sample was 9%, the complications rates were 0% for patients with EOSS Stage 0 (5% of patients), 1.6% for Stage 1 ( (12%), 8% for Stage 2 (71%), 22% for Stage 3 (13%) and 100% for Stage 4 (0.2%).

There was no significant difference in BMI levels across EOSS stages and not consistent association of EOSS stage with age.

From these findings the authors conclude that,

“Patients with EOSS≥3 have a higher risk of postoperative complications. Our data confirm that the EOSS is useful as a scoring system for the selection of obese patients before surgery and suggest that it may also be useful for presurgical stratification and risk assessment in clinical practice. Patients should be recommended for obesity surgery when their EOSS stage is 2 to prevent impairments associated with metabolic disease and to reduce the risk of postoperative complications.”

@DrSharma
Edmonton, AB

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Bariatric Surgery Improves Mitochondrial Efficiency

sharma-obesity-mitochondriaOne of the more frustrating aspects of weight loss, is that it is often associated with decreased metabolic rate and increased ‘fuel efficiency’.

Thus, following weight loss, not only does the body need fewer calories, doing the same amount of physical work uses fewer calories than before (the joke is that, if you ran 5K a day to lose weight, you have to run 10K a day to keep it off).

Now, a study by Maria Fernström and colleagues, published in Obesity Surgery, shows increased mitochondrial efficiency following bariatric surgery.

The researchers performed skeletal muscle biopsies in 11 women before and at 6 months after gastric bypass surgery.

Measurements in isolated mitochondria showed a marked increase in coupled respiration (state 3) and overall mitochondrial capacity (P/O ratio) with a non-significant increase in uncoupled (state 4) respiration.

Thus, at 6 months following gastric bypass surgery, both the mitochondrial capacity for coupled, i.e., ATP-generating, respiration increased as well as the P/O ratio improved.

As the authors note, not only would this increased “fuel efficiency” in part explain the decreased basal metabolism often associated with weight loss but also the propensity for weight regain that often follows weight-loss interventions.

Obviously, due to lack of a control group, this study does not demonstrate that these changes are in any way specific to weight-loss following bariatric surgery.

Also, given that the nadir of weight loss is generally not achieved until about 18 months following surgery, the changes observed in this study may not represent the maximum increase in mitochondrial efficiency to be achieved with further weight loss.

@DrSharma
Edmonton, AB

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My Miniseries on Obesity As a Disease

NN Benefits White Paper CoverOver the past weeks, I have presented a miniseries on the pros and cons of calling obesity a chronic disease.

Clearly, I am convinced that the arguments in favour, carry far greater chances of effectively preventing and controlling obesity (defined as abnormal or excess body fat that impairs health) than continuing to describe obesity merely as a matter of ‘lifestyle’ or simply a ‘risk factor’ for other diseases.

That said, I would like to acknowledge that the term ‘disease’ is a societal construct (there is, to my knowledge no binding legal or widely accepted scientific definition of what exactly warrants the term ‘disease’).

As all societal constructs are subject to change, our definitions of disease are subject to change. Conditions that may once have been deemed a ‘normal’ feature of aging (e.g. type 2 diabetes or dementia) have long risen to the status of ‘diseases’.  This recognition has had profound impact on everything from human rights legislations to health insurance to the emphasis given to these conditions in medical education and practice.

People living with obesity deserve no less.

Thus, I come down heavily on the ‘utilitarian’ principle of calling obesity a disease.

When, calling obesity a ‘disease’ best serves the interests of those affected by the condition, then, by all means, call obesity a ‘disease’ – it is as simple as that.

First consequences of the American Medical Association declaring obesity a chronic disease are already evident (see here and here).

We can only hope for the same impact of the Canadian Medical Association declaring obesity a disease – the sooner, the better for all Canadians living with obesity.

@DrSharma
Edmonton, AB

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Arguments For Calling Obesity A Disease #9: Medical Education

sharma-obesity-medical-students1Next in my miniseries on the pros and cons of calling obesity a ‘disease’, I turn to the issue of medical education.

From the first day in medical school, I learnt about diseases – their signs and symptoms, their definitions and classifications, their biochemistry and physiology, their prognosis and treatments.

Any medical graduate will happily recite the role and function of ADH, ATP, ANP, TSH, ACTH, AST, ALT, MCV and a host of other combinations of alphabet soup related to even the most obscure physiology and function – everything, except the alphabet soup related to ingestive behaviour, energy regulation, and caloric expenditure.

Most medical students and doctors will never have heard of POMC, α-MSH, PYY, AgRP, CART, MC4R, or any of the well studied and long-known key molecules involved in appetite regulation. Many will have at best a vague understanding of RMR, TEE, TEF, or NEAT.

The point is, that even today, we are graduating medical doctors, who have at best a layman’s understanding of the complex biology of appetite and energy regulation, let alone a solid grasp of the clinical management of obesity.

Imagine a medical doctor, who has never heard of β-cells or insulin or glucagon or GLUT4-transporters trying to manage a patient with diabetes.

Or a medical doctor, who has never heard of renin or aldosterone or angiotensinogen or angiotensin 2 trying to manage your blood pressure.

How about a medical doctor, who has never heard of T3 or T4 or TSH managing your thyroid disease?

Elevating obesity to a ‘disease’ means that medical schools will no longer have an excuse to not teach students about the complex sociopsychobiology of obesity, its complications, prognosis, and treatments.

As I mentioned in a previous post, suddenly, managing obesity has become their job.

No longer will it be acceptable for doctors to simply tell their patients to control their weight, with no stake in if and how they actually did it.

Thus, if there is just one thing that calling obesity a ‘disease’ can change, it is expecting all health professionals to have as much understanding of obesity as they are currently expected to have of diabetes, heart disease, lung disease, and any other common disease they are likely to encounter in their medical practice.

Apparently, simply treating obesity as a ‘lifestyle’ problem or ‘risk factor’ was not enough – hopefully, recognising obesity as a  ‘disease’ in its own right, will change the attention given to this issue in medical training across all disciplines.

@DrSharma
Edmonton, AB

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