Thursday, July 7, 2011

Does Neuronal Scarring Determine the Body Weight Set Point?

As regular readers are well aware, one of the major dilemmas in obesity management is the fact that virtually any attempt at weight loss is counteracted by complex mechanisms that aim to restore the body back to initial weight.

So far, no one has discovered a way to reverse or ‘reset’ this mechanism so that, once weight is lost, the body ‘relaxes’ and ‘accepts’ that new, lower body weight again.

This is why, no matter what program, diet, exercise, medication or surgery you chose for weight loss, when you stop the program, diet, exercise, medication, or reverse the surgery, your weight comes back – there are almost no exceptions to this rule.

So how does weight gain lead to this apparently ‘permanent’ resetting of the body-weight ‘set point’?

A recent paper by Tamas Horvath (Yale) together with colleagues from the US, Europe and Australia, published in the Proceedings of the US National Academy of Science, suggests that ‘micro-scarring’ of neurons that regulate hunger and satiety in the hypothalamus (the key homeostatic centre of eating behaviour) may play an important role in this process.

The researchers first studied the microscopic organisation of synapses (nerve-nerve contacts) in the anorexigenic (hunger-suppressing) proopiomelanocortin (POMC)-expressing nerve cells of the arcuate nucleus in lean rats that were vulnerable or resistant to diet-induced obesity.

There was a clear quantitative and qualitative difference in the synaptic organisaton of POMC cells between these animals, with a significantly greater number of inhibitory inputs in the POMC neurons in weight-gain susceptible rats compared with resistant rats.

Then, when given similar high-fat diets, the POMC cells of weight-gain resistant rats formed more connections whereas the susceptible animals actually lost synapses.

Importantly, this loss of synapses was associated with a process called ‘reactive astrogliosis’ or ‘glial-scarring’ whereby, in an ‘inflammatory’ response, astrocytes ensheath the POMC neurons, thereby making them ‘permanently’ inaccessible to new synapses (hence the use of the term ‘scarring’).

In addition, this formation of glial ‘scar’ tissue, also made the POMC cells less accessible to blood vessels (i.e. increased the blood-brain barrier).

As all ‘scarring’ processes in the body, these micro-scars are in essence, irreversible, or in other words, permanent.

Thus, these findings clearly show how increased caloric intake in ‘obesity-prone’ rats (and humans?) can lead to permanent changes in the cell-architecture of the arcuate nucleus thereby essentially ‘locking in’ the new ‘set point’.

Obviously, no diet, exercise, medication or surgery will undo the ‘scarring’ in these key centres of the brain (in the same way that no diet, exercise, medication or surgery will undo a scar in your skin or anywhere else in your body) – which is perhaps why none of these interventions will ever lead to ‘permanent’ weight loss unless they are continued in the long-term.

Although this may sound very disappointing and discouraging, these findings may eventually lead to new treatment strategies that can help prevent the ‘resetting’ by reducing or preventing the ‘inflammation’ that promotes the formation of astrogliosis with weight gain.

Perhaps, as in rats, those ‘rare’ people who appear to be (genetically?) weight-gain resistant or have less problem losing weight and keeping it off, can do so simply because they have more synapses in their POMC neurons to start with, easily grow more synapses when exposed to excess calories, or simply do not develop the ‘micro-scarring’ in their brains with weight gain.

Of course, scar or no scar, none of this means that treatments don’t work – of course they do, as long as the treatments continue.

So, the runners, who lost weight running, will have to keep running, the dieters, who lost weight dieting, will have to keep dieting, the patients who had bariatric surgery, can expect weight regain if they ever reverse the surgery – when the ‘treatment’ stops, the weight comes back!

As I have said before, the first measure of success in obesity management is stopping the gain – less weight gain – less scarring?

Successful obesity management is prevention!

AMS
Edmonton, Alberta

Horvath TL, Sarman B, García-Cáceres C, Enriori PJ, Sotonyi P, Shanabrough M, Borok E, Argente J, Chowen JA, Perez-Tilve D, Pfluger PT, Brönneke HS, Levin BE, Diano S, Cowley MA, & Tschöp MH (2010). Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity. Proceedings of the National Academy of Sciences of the United States of America, 107 (33), 14875-80 PMID: 20679202

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9 Responses to “Does Neuronal Scarring Determine the Body Weight Set Point?”

  1. Paulette says:

    This makes a lot of sense. It helps explain why behavior change must be permanent and I would rather understand the physiological reasons behind weight gain, following lapse of weight loss practice. Kind of explains why after losing ~ 60 pounds some years ago, I have regained 30 pounds, but have stabilized here for about 4 years. I have incorporated enough eating behaviors to maintain here. These changed behaviors have become permanent.

  2. Anonymous says:

    Concerning “… the dieters who lost weight dieting, will have to keep dieting; when the ‘treatment’ stops, the weight comes back …”

    After the weight loss, do studies identify the difference between –

    GROUP 1. The people who “stop dieting” – meaning they go back to the way they were eating in the first place, before the treatment.

    They would gain weight because they resumed doing what caused the problem in the first place. No treatment for any condition would prevent relapse if the person repeats what caused the problem in the first place.

    A doctor who puts a cast on a broken arm so the arm heals doesn’t expect that arm to then be able to withstand all future injury without ever breaking again.

    Why would the newly thinner person resume bad eating ? Denial, wishful thinking, a feeling that after going through treatment they should be able to eat whatever they want, the feeling that not overeating or not having food “treats” is deprivation (that’s a cultural thing), overestimating the amount of food there is in a”normal” diet … etc etc etc …

    I know, I’ve been there, Group 1 has included me.

    GROUP 2. The people who stop a weight loss diet, but then eat a controlled diet to maintain the new weight.

    Does eating a controlled diet mean a person is “in continuing treatment”? Or is eating a controlled diet just doing what most ordinary weight people do all the time to maintain a healthy weight?

    If after weight loss a person eats a maintenance diet that is basically the same as a person who never had a weight gain/loss, following that maintenance diet doesn’t mean they’re “in continuing treatment”, it just means they’re doing what most people have to do. (Including envying the few people who can eat anything and not gain weight.)

  3. Anonymous 9:13 cont'd says:

    If after weight loss a person has to follow a diet that is very different from from the controlled diet most people have to follow anyway to maintain a healthy weight, then that person would be “in continued treatment”.

    What would that exceptional diet be, and what are the conditions that would require it?

    It would be a great help to identify who needs to follow an ordinary controlled weight maintenance diet like most people, and who would need to follow an exceptional “treatment” diet to maintain weight loss.

  4. DebraSY says:

    To Anonymous: Do a site search on the words “Rudy Leibel.” Dr. Sharma wrote three posts in a row on why maintaining lost weight is so difficult, and he relied heavily on the work of Dr. Leibel. Very enlightening.

  5. Lucy A. says:

    The weight lose maintenance is one thing that is like control of any other chronic condition-be it blood sugar, blood pressure, cholessterol, and depresion. Just because there is treatment there still a need to be continue maintenance some will not need as much maintenance as others. If I need to continue to journalize my food intake and count calories to lose weight then continuing to do so to maintain the lose is like taking my anti depresents. I do not want my health to be adversely affected by my eccess weight. Maybe I will have to keep taking the two cholesterol medications but, I hope not. Whatever, the case I am going to keep the weight off even if I do not qualify for baratric sugery. This insight is always greatly appreciated, thanks.

  6. NV Giridharan says:

    Well..this is an excellent work and goes in accordance with what I have been thinking all along.In our animal facilities we have 4 strains of rats and in 1997 a mutant obese rat emerged out of one strain and now it has been well chracterised, and we are narrowing on the locus that is mutated to give it, the obese phenotype. The question we are now asking is ,how come one of the strain became vulnerable to obese mutation, while others didnot , though all of them were getting similar diets.We are now challenging all the 4 with high protein,fat and CHO diets and going to look for genetic and epigenic changes that may occur favouring either an increase in weight or resistance to put on weight.Our preliminary data before experiment showed that these strains vary with respect to fat percenatge as well in physcical activity.We will now look in to neuronal junction of hypothalamus concerned with nfood intake as done here, which will give a clear answer why the mutation occuresd in a particcular strain and not in others.
    I also maintain that when we say over weight , it referes to somatic changes and can be corrected by life style changes, and when it comes to obesity , it is gentical and the only way to correct it is by bariatric surgery and continued use of
    drugs and life stye changes .In the latter case , you may be able to control weight to certain extent , but not fully..Thanx Sharma , for putting this very important paper..

  7. Anonymous 9:13 cont'd says:

    To debresy; yes, i checked that rudy leibel post on leptin. Very interesting and applies to many people I’m sure.
    But I put myself in what I called Group 1: those who regain weight because they (we) resume eating badly, so regain weight. For years I’d lose weight, then go back to eating ice cream by the litre – I’d have regained weight even if there were no leptin or neural scarring or any other effects.

    Then I lost 63 lbs.over 2 years, then regained 30 lbs over 3 years. That’s a regain of less than a lb a month. I wasn’t binging anymore, but the regain was there. (Now I’ve lost 15 of those 30 lbs ) . But a regain of less than a lb a month is, for me, possible to avoid. I have to be diligent about weighing regularly and following a diet, and going back on my weight loss diet immediately if I gain more than 2 lbs.

    So these Days I’m in what I call Group 2: I have to eat a controlled diet, and be vigilant about losing a small regain, instead of ignoring it until it adds up to a big problem.

    Now the question is, am I in the same state as Dr S’s patients who require permanent treatment – treatment!! – not just ordinary care to watch my weight and eat right, like almost everybody has to. In other words, do I have to be on the same diet as a post-bariatric surgery patient to avoid weight regain? For me, the answer is no, I don’t have to eat like a post bariatric surgery patient. I do have to eat carefully and get some exercise – but that’s not at the level of “treatment”. Yes, it is a culture shift, and my mother thinks I’m anorexic because I don’t eat her desserts, but my friends eat salads and go for a walks and think that’s ordinary.

    Why do I think this distinction is important?
    Because if someone has the leptin/neural scarring/other effects then treatment IS required. This person would have to follow a program probably similar to a post bariatric surgery patient, probably including an extremely low calorie diet, medical monitoring, special nutrient supplements as found necessary, counselling, etc, as Dr Sharma outlined in excellent recent posts on bariatric surgery.

    It is fair that if a person has these neural scarring/leptin/other problems, then they should be entitled to full medical care and treatment just like a bariatric surgery patient.

    Right now, it seems like if you get bariatric surgery, you get everything from special tests to counselling – and if you’re not a SURGERY patient, you get nothing but diet advice. It’s as if once you’re a SURGERY patient, you get everything possible. If you’re not eligible for surgery you also are denied other aspects of treatment, even though you may be in as bad a condition as the surgery patient, or even worse condition, but for some reason cannot have surgery.

    In an ideal world, everybody would get every possible treatment. In the real world (I’m in Canada, public health care), resources for treatment are limited. Those who get bariatric surgery get a great deal of non-surgical medical help. Those who don’t get surgery also don’t get all the non-surgical medical help the surgery patient gets.

    If there are specific conditions that are identifiable in a particular individual as medical problems (leptin, neural scarring, other), that should be a valid reason for getting just as much medical help as having undergone bariatric surgery.

    On the other hand, as resources are limited (Canadian public health care), I would not put myself in that category. I have found that for me a cultural shift is enough to have a significant effect on my weight.
    I think as Canadians we have an obligation to make whatever individual changes we can to avoid obesity and to lose excess weight.

  8. DebraSY says:

    @Anon. Under your group 2 category, you asked the following question:

    “Does eating a controlled diet mean a person is “in continuing treatment”? Or is eating a controlled diet just doing what most ordinary weight people do all the time to maintain a healthy weight?”

    I don’t know the answer to the first part. (I’m in the US, not Canada.) The Leibel research answers part two of that question with a resounding “no.” Maintainers eat less and exercise harder than people who are at the same weight but have never been obese.

    A persistent cultural myths is that “maintenance” is easier than weight-loss dieting. Simply, it is not. For the fortunate people, it is can be about the same as weight-loss dieting, just with fewer “rewards” once the weight is gone (little encouragement and fewer compliments, because it’s assumed you are “cured”). For other people, maintenance is exponentially more difficult than weight loss: the endocrine changes are very challenging, and the aforementioned lack of rewards can make it a lonely pursuit.

    I approach maintenance as a part-time job and a scientific experiment. This is helpful for me.

  9. anon says:

    Microscarring calls for micromassage or microultrasound or some other kind of nano-de-scarring mechanism. Maybe biochemical. Someone will find an answer. It is the Banting and Bests of our time who will be able to find a way to stop the scarring or help melt it away. It used to be that men would have to pass kidney stones – very painfully – but now ultrasound just blasts those stones to nanopieces. Mind you, money got put into an area where pain was most keenly felt and no shame was attributed to the problem. But Banting and Best were very aware of the shaming of young diabetics who “sinfully” ate bread, and they still found a solution because they cared. So there is hope for those medical nanohealers to do it again in our time – it will happen. And they will do it for all who are “scarred” – not just those who make it onto the bariatric list.

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