Dr. Sharma's Obesity Notes

Over the next little while, I will be taking a few days off and so I will be reposting some of my favourite past posts. The following article was first posted on Feb 2, 2008:

With the “sensational” results of obesity surgery being publicized in the media, it is not surprising that expansion of bariatric surgery is receiving increasing support. In every province, health plans are carefully looking at expanding access for their populations.

In light of these development it may be time for a word of caution.

Obesity surgery is not just about surgery. In fact, even the most enterprising bariatric surgeons will readily agree that the actual surgery is just a small (but important) technical piece in the overall treatment plan.

No doubt, good surgical outcomes require well-trained experienced surgical teams but we know that much of the long-term outcome depends on what happens before and after surgery.

Done in the wrong patients with no or little long-term follow up, what could be a life saving operation can become a disaster – and weight regain is perhaps the least that can go wrong. Much more severe and potentially devastating are the nutritional deficiencies and the psychological and social consequences that are not seldom after surgery.

For surgery to produce good long-term results it is absolutely essential that as access to surgery expands, so does the pre-surgical selection and education process as well as the access to life-long post-surgical monitoring.

Expansion of surgical programs does not just need more surgeons and OR time – it needs dietitians, psychologists, physicians, occupational therapists, social workers and other health professionals who are trained and qualified to prepare and follow-up surgical patients.

In the end it will be family doctors who have to look after the 1000s of patients who will be asking for and undergoing surgery. Given the numbers of eligible patients and the geographic distances in Canada, this task of preparing and following patients for life cannot be performed by a handful of Centres of Excellence. This is particularly true for the adjustable gastric band, which while offering a simpler and safer surgical procedure, does require regular and ongoing adjustments to be fully effective.

If we hope to see the spectacular results from the published studies on bariatric surgery replicated in daily practice, we must start bringing primary care providers up to speed on counseling, preparing and following their patients.

Ignoring this task will leave 1000s of Canadians stranded post-surgery with nowhere to go when things go wrong.

Obesity surgery is NOT just about surgery.

AMS

Regular readers are well aware that losing weight is never a ‘cure’ for obesity – in fact, we know that any weight loss (by whatever means – perhaps with the exception of surgery) leads to hormonal changes that will facilitate weight regain. This is why conventional (diet and exercise) weight-loss strategies sooner or later tend to result in relapse or weight regain.

Just how pervasive and multi-faceted these long-term hormonal responses to weight loss are, is demonstrated by Priya Sumithran and colleagues from the University of Melbourne, in a paper published in the New England Journal of Medicine.

In order to examine whether or not changes in the circulating levels of several hormones involved in the homeostatic regulation of body weight persist over time, the researchers studied 50 overweight or obese individuals, who participated in a 10-week very-low-calorie-diet weight-loss program.

The 36 subjects, who completed the intervention lost about 14% of initial weight and were still well below initial weight (about 8%) 62 weeks after the start of the study.

This weight loss was associated with significant reductions in levels of leptin, peptide YY, cholecystokinin, insulin, and amylin, whereas levels of ghrelin, gastric inhibitory polypeptide, and pancreatic polypeptide increased – most of these changes were still clearly evident at 62 weeks.

In addition, subjective levels of hunger increased and remained significantly elevated at 62 weeks.

Thus, the authors note that:

“One year after initial weight reduction, levels of the circulating mediators of appetite that encourage weight regain after diet-induced weight loss do not revert to the levels recorded before weight loss.”

Given these profound and persistent hormonal changes that affect hunger, appetite, and metabolism, it should come as no surprise that maintaining weight loss is so difficult. It certainly seems like the homeostatic system is happy to wait for the weight to come back – even if this takes several months or even years.

As I have noted before, the challenge in obesity treatment is never how to lose weight – it is all about how to keep it off. This is why, I am never too enthusiastic about new diets or medications that promise to help lose weight – unless these diets or medications also counteract or effectively block the counter-regulatory responses seen in this study, chances are that they will be ineffective in the long term.

Or, as the authors put it:

“..successful management of obesity will require the development of safe, effective, long-term treatments to counteract these compensatory mechanisms and reduce appetite. Given the number of alterations in appetite-regulating mechanisms that have been described so far, a combination of medications will probably be required.”

We do not really need new treatments for weight loss – we do, however, need treatments for weight-loss maintenance or for keeping patients in ‘remission’.

Unfortunately, the regulators still do not appear to have a pathway for approving drugs that will help with the latter.

AMS
Edmonton, Alberta

Hat tip to Bill Colmers for pointing me to this article.

Sumithran P, Prendergast LA, Delbridge E, Purcell K, Shulkes A, Kriketos A, & Proietto J (2011). Long-term persistence of hormonal adaptations to weight loss. The New England journal of medicine, 365 (17), 1597-604 PMID: 22029981

Over the past two days, I have been discussing the role of leptin in the physiology of human energy regulation.

I discussed the fact that much of the hypometabolic and orexegenic response to weight loss can be attributed to a fall in leptin levels below a leptin ‘threshold’.

I also discussed findings that replacing leptin can attenuate the hypometabolic and orexogenic response to weight loss, thereby potentially making it easier to keep weight off.

So how good is the evidence from leptin treatment studies and why has leptin not found its way into clinical use for obesity management?

First of all, this is not because leptin is not available or ineffective in humans.

Leptin is highly effective in promoting weight loss in rare individuals with congenital leptin deficiency and can dramatically correct diabetes and other metabolic problems in individuals, who lack leptin due to lipodystrophy.

But, as discussed in yesterday’s post, simply injecting leptin (even at higher doses) in obese individuals does not necessarily result in appreciable weight loss – so leptin alone cannot be a ‘weight-loss’ treatment.

Rather, if at all, it would have a role in the prevention of weight regain.

This idea was nicely demonstrated by Leibel and colleagues in a now classic paper published in the Journal of Clinical Investigation in 2005.

In this study, 10 inpatient subjects (5 males, 5 females [3 never-obese, 7 obese]) were examined under 3 sets of experimental conditions:

(a) maintaining usual weight by ingesting a liquid formula diet;
(b) maintaining a 10% reduced weight by ingesting a liquid formula diet; and
(c) receiving twice-daily subcutaneous doses of leptin sufficient to restore 8 am circulating leptin concentrations to pre-weight-loss levels and remaining on the same liquid formula diet required to maintain a 10% reduced weight.

During leptin administration, energy expenditure, skeletal muscle work efficiency, sympathetic nervous system tone, and circulating concentrations of thyroxine and triiodothyronine returned to pre-weight-loss levels.

In a subsequent study from Leibel’s lab also published in the Journal of Clinical Investigation in 2008, leptin was shown to reverse the increased neuronal activity in brain areas known to be involved in the regulatory, emotional, and cognitive control of food intake.

Thus, together, these studies strongly suggest that the weight-reduced state may be regarded as a condition of relative leptin insufficiency and that prevention of weight regain might be achievable by reversing this leptin-insufficient state, in this case by replacing leptin.

This idea was taken a step further by Amylin and Takeda, who partnered in a clinical development program on a combination of pramlinitide, an analogue of the hormone amylin, released by the pancreatic beta cell and involved in glucose homeostasis and satiety, and metreleptin, a recombinant leptin analogue.

After promising results in early studies (with about 13% weight loss), this program recently ran into problems due to the appearance of antibodies to metreleptin in a couple of trial participants. It is not clear when or if this development program will continue.

This, in short, is the current status of leptin as a treatment for obesity and one will have to see how this development program moves forward.

Nevertheless, it also seems prudent to determine whether there could in fact be a regulatory pathway to license a drug for weight-loss maintenance.

I, for one, have no doubts that many individuals who have lost serious amounts of weight would probably be quite open to the idea of having to resort to daily injections to keep the weight off and would perhaps even prefer injections to having bariatric surgery.

AMS
Edmonton, Alberta

Disclosure: I have received consulting honoraria from Amylin/Takeda the makers of pramlintide/metreleptin

Rosenbaum M, Goldsmith R, Bloomfield D, Magnano A, Weimer L, Heymsfield S, Gallagher D, Mayer L, Murphy E, & Leibel RL (2005). Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. The Journal of clinical investigation, 115 (12), 3579-86 PMID: 16322796

Rosenbaum M, Sy M, Pavlovich K, Leibel RL, & Hirsch J (2008). Leptin reverses weight loss-induced changes in regional neural activity responses to visual food stimuli. The Journal of clinical investigation, 118 (7), 2583-91 PMID: 18568078

Yesterday, I posted about the presentation of Columbia University’s Rudy Leibel on how losing weight results in a hypometabolic and orexogenic response mediated largely by a fall in plasma leptin levels that, as a rule, accompany any attempt at reducing fat stores.

This post elicited a number of responses that I will try to address in this follow-up post.

Several readers wanted to know whether there is a way to readjust your ‘leptin sensitivity’ so that the brain no longer wants to restore body weight to pre-weight loss levels.

The short answer is ‘no’. Although there are several proposed strategies (special diets, refeeding days, exercise strategies, etc.) floating around in the popular literature, there is very little scientific evidence that this can actually be done. The sad fact is that anyone, who has ever lost weight, has to continue with efforts to keep it off – this includes people who have had bariatric surgery, who if they ever decide to reverse their surgery – will rapidly gain their weight back (even after years of keeping it off). This, by the way, is why bariatric surgery has to be seen as a definitive and permanent solution and why temporary devices like gastric balloons, which have to be eventually removed, are not a permanent treatment for obesity.

Another reader wanted to know, that if this was true, why some people are successful in maintaining long-term weight loss.

The answer to this is that these individuals somehow manage to continue their efforts (whatever those may be) in the long-term. The best studied group of individuals who have succeeded in the long-term are perhaps those represented by the National Weight Control Registry, who, using various strategies manage to reduce their caloric intake to about 1400 KCal (the same amount that is effectively eaten by successful post-bariatric surgery patients) combined with considerable amounts of exercise (upto 400 KCal worth every day). Such ongoing efforts are clearly beyond what most people can do without completely changing their lives. So, what the NWC participants actually demonstrate, is not so much that sustaining weight loss is possible but rather that this requires an almost ‘superhuman’ effort (some would say ‘obsession’) – indeed the NWC registrants represent a rare minority of people attempting to lose weight by diet and exercise alone (the NWC registry has a few thousand registrants compared to the tens of millions who try losing weight every year).

Finally, some readers wondered about ‘leptin resistance’, a term often used to describe the fact that obese people apparently need higher circulating levels of leptin (hyperleptinaemia) to suppress their appetite and burn more calories than lean people.

In his talk, Leibel made clear that ‘resistance’ may not be the best way to describe this phenomenon.

Rather, he preferred to refer to an elevated leptin ‘threshold’, implying that there is an upward shift in the levels of leptin required to suppress the orexogenic and hypometabolic response elicited by caloric restriction.

Leibel prefers the term threshold, because even in people with a high threshold (i.e. obesity), once you have administered enough leptin to restore baseline levels and suppress the orexogenic response that follows weight loss, there is no further decrease in appetite, even at higher leptin doses. This is why simply injecting additional leptin into a person who is at their usual weight (i.e. prior to weight loss) has little to no effect on appetite, which incidentally, is exactly why leptin does not produce weight loss and would not meet thergulatory criteria for as a weight-loss drug (the rare exception being in individuals who are born with a genetic lack of leptin).

Perhaps the difference between ‘resistance’ and ‘threshold’ can best be understood by comparing leptin to insulin. In people who are resistant to insulin (e.g. patients with type 2 diabetes), you can ‘overcome’ this resistance by simply injecting increasing amounts of insulin. Even in the most insulin-resistant individual, you can eventually lower blood glucose levels by injecting more insulin – if you inject too much, these individuals will experience hypoglycemia, i.e. experience the physiological impact of too much insulin.

In contrast, the hypometabolic and orexogenic state following weight loss will respond to leptin injections only up to a dose that is just high enough to restore pre-weight-loss levels (the threshold level) – adding additional leptin will not increase metabolism or suppress appetite further.

Thus, while people with insulin resistance will respond to increasing doses of insulin to the point of hypoglycemic shock, people with an elevated leptin threshold will achieve a maximum metabolic and anorexogenic response (albeit at higher levels than people with a lower threshold) beyond which leptin has no further effect.

This may seem like a ‘semantic’ distinction but from a treatment perspective (and the science behind it), this difference is substantial and explains why high doses of insulin can always be used to treat diabetes even in the most insulin-resistant individual whereas leptin only works upto the point where it restores levels to the respective (pre-weight loss) threshold.

Obviously, the key question is why some people have a higher leptin threshold or rather why this threshold (that can also be thought of as the famous ‘set point’) only seems to move in one direction (namely to higher levels) and then becomes permanent (unless it is moved to even higher levels by weight gain).

As Leibel explained, the reason that this leptin threshold appears permanent, may be due to the fact that it becomes ‘hardwired’ into the brain – a process that is essentially irreversible (perhaps with the exception of patients with cancer cachexia). It is therefore perhaps not surprising that it actually takes neurosurgery (in animal experiments) to ‘reverse’ this threshold – an approach that is clearly not feasible in humans.

Several readers also asked whether leptin is available and whether it works in humans to help keep weight off – more on this topic tomorrow.

In the meantime, here is a link to a previous post on Leibels ‘Threshold Theory‘.

AMS
Edmonton, Alberta

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