Saturday, August 4, 2012

Lorcaserin: the Latest FDA-approved Obesity Drug

The FDA recently approved a new drug called lorcaserin (brand name Belviq) for the treatment of obesity.  Lorcaserin causes an average of 13 lbs (5.8 kg) of weight loss over a year, compared to 5 lbs (2.2 kg) for placebo (1), which is less than the other recently approved drug Qsymia (formerly Qnexa; topiramate/phentermine).

Learning about obesity drugs is always a good opportunity to gain insight into the mechanisms that underlie the development and reversal of obesity.  If you've been following this blog for a while, you already have a pretty good guess what organ this new drug acts on.  Make your guess and read on!


Lorcaserin acts in the brain, like most other obesity drugs.  In fact, I would say this drug is one of the most straightforward of all of them.  It stimulates a specific neurotransmitter receptor, the serotonin 2C receptor, which is expressed in several brain regions.  In particular, this receptor is expressed in the hypothalamus, in a key population of cells called POMC neurons.  The hypothalamus is the central regulator of body fatness, and POMC neurons suppress food intake and lower fat mass when activated (2).  POMC neurons express serotonin 2C receptors, and activating them with serotonin, lorcaserin, or other drugs suppresses food intake and causes fat loss.   Research in mice has shown that POMC neuron signaling is required for the effects of similar drugs, suggesting that they act through this pathway (3, 4).

POMC neurons are an important part of the system that regulates body fatness in humans, but there are a number of other neuron populations that are also important (including the recently characterized NOS1 neurons, which seem to be very important; 5).  Under normal circumstances, POMC neurons respond to circulating leptin, ghrelin, fatty acids, and other indicators of body energy status, using these signals to balance food intake, energy expenditure and fat storage.  Lorcaserin bypasses this and stimulates POMC neurons directly, lowering food intake and the body fat "setpoint".  It is truly amazing that stimulating a few hundred tiny neurons in the hypothalamus can have a significant effect on food intake and body fatness.  These neurons all together could fit on the head of a pin.

35 comments:

R A Z Z said...

I have always liked the academic tone of you blog, Stephan. I am glad more people are realzing that morbid obesity is a genuine disease state, with fat tissue being a verified endocrine organ, and not some passive storage despot. I am happy that more people realize that obesity is not the passive accumulation of calories, but rather, an elevated fat mass setpoint level which is voraciously defended as if your very life depended on it.

I hope through your blog, as well as mine, that less (uneducated) people will blame victims of morbid obesity and realize that plenty of them are trying and that we are NOT completely in control of our weight. Biology has the strongest say.

I'm glad progress is being made with this new drug coming out.

In order to treat people such as Manuel Uribe and others like ( people who weight 600 to 1000 pounds etc.) effectively we NEED drugs.

A nutritious diet , exercise and general movement , while important for health reasons, are very ineffective as solutions for the treatment of true morbid obesity, as experiments show repeatedly.

The body's intrinsic control mechanisms win out over the very long term, making voluntary factors have extremely limited potency to affect body weight much. The general public NEEDS to respect the limits of voluntary factors in treating obesity.

There probably will be a day where the super morbidly obese may be normalized.But, for that to happen, there remains literally OCEANS of unknowns about this phenomenon to be discovered. We MUST understand besity far better than we do.

Dr. Friedman is conducting ongoing research currently in neurobiology and genetics. The public would be surprised to learn that eating is an extremely complex behavior with many factors being involved in deciding to whether to initiate feeding.

It's nice to see that people like yourself are asking the RIGHT QUESTIONS( e.g. understanding neurobiology better)

All the while the NON- science Internet "guru" salesmen websites are all asking, "What cheese is the moon made of?" and completely swindling their readers.

Take care,
Raz

Karg said...

Seems like a lot of potential risk for a few extra pounds a year. Pretty sure this would be far better served with dietary intervention that lowered addictive food and reduced carbs together.

Do we know the long term effects of this? Nope, they can always recall once a few hundred people keel over right? =/

Yes, there is need for a real medical approach from pharmacy but this really seems a lot of risk for little gain, no?

gunther gatherer said...

This is great info, Stephan, although I agree with Karg that drugs are not the answer.

How do POMC neurons work together with SIRT1? Apparently there is a relationship, noted here:

http://www.news-medical.net/news/20100707/POMC-neurons-suppress-appetite-induce-weight-loss-Research.aspxhttp://www.news-medical.net/news/20100707/POMC-neurons-suppress-appetite-induce-weight-loss-Research.aspx

I'm asking because SIRT1 is downregulated in those with insulin resistance.

BTW, reservatrol and antioxidants have been claimed to activitate SIRT1 (and so POMC neurons, which could have a downstream effect on weight loss). Do you think antioxidants could be a good way to "heal" the hypothalamus?

gunther gatherer said...

My paste above went pear-shaped. Here's the proper link:

http://www.news-medical.net/news/20100707/POMC-neurons-suppress-appetite-induce-weight-loss-Research.aspx

R A Z Z said...

In people with a regular "over fat" condition I would do everything possible to avoid drugs. All drugs are going to have side effects. And all humans are going to have to be guinea pigs initially.

However, with genuine diseases, (cancer, coronary artery disease, ALS, Parkinson's etc.) natural things do not do that much.

It's cool and fashionable among the uneducated Internet "gurus" to bash the pharmacuetical industry. There is some truth to this.

But, without them , people who have serious diseases would be screwed. These drugs save lives. They are not perfect either. We NEED them though. And we need to improve drugs.

There are many people who picked alternative natural cancer tretment and died. Gerson Therapy, for example, is complete FRAUD.

People such as Michael Hebranko nd Manuel Uribe have fat cell disregulation gone completely haywire. These men will never get down to a good size and stay there with any known natural methods. People like these men are going to need drugs to correct their disease state.

If a coronary artery disease patient or a Parkinson's Disease patient did not take the proper medications they would die or die sooner at least. The natural treatments have their major limitations.

Take Alzheimer's for instance. Evben with medication, many do not do well. A natural treatment would be even less effective.

Drugs are very, very useful. We NEED them. Any responsible medical doctor would admit as much.

The people always railng on drugs are largely uneducated Internet crackpot gurus. A real, qualified doctor from one of the top major hospitals in the United States would laugh these Internet crank charlatans out of their offices.


I am speculating that one day we will have drugs which directly target fat cell regulation ( something unprecedented) And if they are shown to be very effective, the commercial weight loss industry and their fraud will be out of business completely.

I find it DISGUSTING what the uneducated, lowest common denomonator type loser , Jillian Michaels, does to morbidly obese people. It is complete nonsense. I wish Dr. Jeffery Friedman would call her out publicly.

Drugs given to HEALTHY people who do not need them is what I am against. That is what is wrong. But, we NEED them in society and they are life saving fabulous.I am SO glad we do not live in the Palelolithic era anymore.

R A Z Z said...

*Typing mistakes due to no contact lenses in again.

*denominator and other words.

Willy C said...

@Razz,
Your posts are ridiculous.
Michael Uribe lost 400 lbs through a dietary intervention.
"A nutritious diet , exercise and general movement , while important for health reasons, are very ineffective as solutions for the treatment of true morbid obesity, as experiments show repeatedly."
This is completely untrue.
A nutrition diet, in the case of someone above their ideal weight (defined by their preferred competition, health goals, etc.), will by neccesity involve less than maintenance level calories. This will result in weight loss. If it doesn't, you further reduce food intake to account for any discrepances in metabolic rate, measuring food, etc. REALLY SIMPLE!
You will lose weight.
THere is NO way around this.
The problem isn't designing a weight-loss approach that WILL BE effective.
The problem lies in a weight-loss approach that people WILL ACTUALLY FOLLOW.
That's where different diets come in.

At the end:
-You have to be eating less calories than you need to lose weight.
-This is generally unpleasant.
-This is difficult for people to adhere to.
That's it.


+_+_+
Your point about 'natural' is not consistent.
Do you mean that you'd prefer a pharmocalogic approach to weight loss as opposed to a dietary or activity level one?
How is a dietary aproach any less or more natural than a pharmacoligcal one?
Focus on risks, gain, adherence, not 'natural' or not.
Sure, its easier, because people arelazy and prefer taking a pill to suffering for a few months over not eating as much as they used to, but if you can get the same benefits (really, much more, because most weightloss pills aren't THAT effective compared to a probably adhered to diet) without any side-effects by eating less and/or moving more, what's wrong with that?
The problem comes down into people not following the diet.
That is where the neurobio comes in by explicating the mechanisms behind overeating and why its hard to undereat for some people (it affects metabloic rate, but you can always bypass that by simply adjusting food down to account for metabloic slowdowns).
Still, if you want to lose weight, eating less should ALWAYS be the first option, unless you've got a hormonal problem.

Derek Weiss said...

Best thing about this new med is the possibility of birth defects. So all you need to get a prescription is a negative pregnancy test. Brilliant.

The obese male parter, who has been infertile from a bunch of fat accumulation around his pampiniform plexus, causing a rise in testicular temps, and a drop in sperm motility. As well as a bunch of estrogen floating around from aromatase upregulation, suddenly loses a bunch of weight and can finally see his penis.

No that he can see it, he's excited. In addition, his weight loss has improved his testosterone, and he's horny as hell with his first valid erection in years.

He knocks up his partner, who is also taking this wonder drug. Whammo! She prego. Here come the birth defects.

Sue said...
This comment has been removed by the author.
R A Z Z said...

You're WRONG Willy C YOu have not looked in top this.

My posts are BACKED by the RESEARCH from Dr. Jeffrey Friedman, Dr. Rudolph Leibel Dr,. Micahel Rosenbaum

ALL of theior research SHOWS:
When it comes to your body weight, the body HAS A MIND OF ITS OWN.

YOU, Willy C ,have OBVIOUSLY NOT read and UNDERSTOOD "Modern Science vs the Stigma of Obesity"= a scientific paper with all of the major research by Dr. Jeffrey Friedman

Obesity is DISEASE STATE. Manuerl Urbe CANNOT be helped currently. He ONLY got down to about 450. He is STUCK there and PROBABLY will REGAIN.


I am CORRECT that the scientific research HAS SHWON that diet and exercise are NOT effective for the LONG TERM tretament of severe obesity- the kind Maunuel has.

YOu read Internet gurus too much.Stick toe WORLD RENOWNED SCIENTISTS

R A Z Z said...

"Eating less is a FAILURE. The BODY ACTIVELY RESISTS this.

If you drop your beliefs and LOOK at Dr. Leibel's research you will see this:

Caloric restriction ( dieting) is a FAILURE- A COMPLETE FAILRE- to solve obesity in studies.This is WELL KNOWN.

Lastly , there is a MASSIVE reduction in energy expenditure- far surpassign what would be expected from the weight loss. Dr. Leibel points this out.


You did not watch the videos I linked to obviosuly.


http://www.youtube.com/watch?v=2i_cmltmQ6A

Concentrate on Dr Lebel and Dr Rosenbaum. Ignore the other doctors parroting the party line.

People REGAIN even when they MAINTAIN their workouts and diets as Dr. Linda Bacon has pointed out.

The body RESPONDS to weight loss attempts as if you LIFE depneded on it- says Dr Leibel.

Over the LONG TERM the BODY'S intrinsic control mechanisms win out.


Diets are NOT a solution for the lon gterm tretament of a 600 pounder.

Diets THEMSELVES ar the WRONG METHODOLOGY. It has NOTHING N - O- T-H--I-N-G TO DO WITH "COMPLIANCE"


It is DIETING THAT FAILS. You have swindled by the Internet shysters if you think otherwise.

R A Z Z said...

Voluntary factor do NOT affect body weight much over the VERY LON GTERM

This is Dr. Jeffrey M. Friedman- the real deal. he is one of the very to obesity experts on the planet. he clearly states this here:



Voluntary factors are extremely limited.

http://www.youtube.com/watch?v=


research this Willy C m

My posts are NOT ridiculous AT ALL. In fact, it is information YOU could LEARN from.


http://www.youtube.com/watch?v=8fkDmGDDmBM


For fuether discussion email me privately, Willy.

Do your Internet gurus whos ell fat loss books provide you with such HIGH QUALITY scientific information? No, they don't. And they charge you a PREMIUM PRICE for JUNK.

Ilja054 said...

Спасибо! Интересный пост! Кое-что для себя новое узнал! :)

Don! said...

Regardless of whether you lose the weight using only lifestyle interventions or if drugs were used, the problem is going to be maintenance. It's not as simple as "suffering for a few months." It may take years for setpoint to adjust downward, if at all.

As for simply reducing caloric intake even further to account for the metabolic slowdown, that can work short-term, but again, long-term is the real issue. Maintaining below setpoint is possible, but you'll most likely be hungry all the time, cold, exhausted, and vulnerable to every bug that's going around. BTDT.

That's not to say that I think drugs are the answer, and certainly not this particular drug. There is no simple answer.

jimpurdy1943@yahoo.com said...

Is there some way that I can put RAZZ on ignore? His incessant name-calling and drug-pushing is way beyond silly.

montediaz said...

RAZZ,

Why are you still fat?

Regards,

Monte.

Eric said...

Stephen,

Love the blog, hate RAZZ. His incessant posting does a disservice to your work.

LeonRover said...

Eric, FYI

Dictionary say:

RAZZia (n.) A plundering and destructive incursion; a foray; a raid.

'Nuff said.

Slainte

ali sheikh said...

A nutrition diet, in the case of someone above their ideal weight (defined by their preferred competition, health goals, etc.), will by neccesity involve less than maintenance level calories.

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Jane said...

@LeonRover
I forgot to thank you for your comment on the previous thread about Razz. It was very helpful. I have been wondering for some time why Stephan doesn't boot him out. Any ideas? I can't imagine it's because Razz flatters him. It must be because he tried kicking someone out and it backfired on him.

LeonRover said...

Jane,

"Sorry, the blog at razwellsblog.blogspot.com has been removed. This address is not available for new blogs."

Res ipsa loquitur.

Coprolalia reaps its own desserts.

Slainte

Donald Sparks said...

I will agree that being obese can be brought on by a number of things but most of the obesity in North America is caused by being lazy and unwilling to change mental habits. One problem I find in North America is the fact that when there is a problem we can't initially solve, we label it a disease and begin prescribing medication for it.
This is one issue that has helped the constant rise in health care costs. Instead of taking what we already know to help slim down we go in and see a doctor and have medications prescribed to fight obesity.
Obesity begins with our lifestyle we live. When we live a lifestyle of fast food, twinkies, potato chips, ice cream and unhealthy food in our daily routine and do no exercise or something physical we build fat. It is the bodies natural operation isn't it. There is more money spent running back and forth to the doctor, year after year to fight a battle we need to be fighting with ourselves over the bad unhealthy habits we can change by ourselves.

My mother suffers from a hyperthyroid and she controls her weight through exercise like walking, treadmill and using a very healthy program she got myself and my wife involved with. We know from facts that a little junk food is as healthy as not eating any. The body needs a little to help shock itself to keep fighting against fat build up.
If we keep labeling everything as a disease all were are creating is more of a burden on the health care system and telling folks that their issue is medically related all the time and that is false. Proper nutrition, exercise and the will to succeed is one of the most phyically and mental motions to get rid of extra pounds.
If you truly have a medical issue that needs addressed then take it up with the doctor or a nutritionist but we need to stop spreading the word disease because in my opinion it is a cop out and a coined up problem created by medical companies to increase profits.

If we don't hit success do we create a brand new disease called success less syndrome. We know as a society there are issues that cause and create problems but the first place we go is the doctor, when we know the true answer lies inside each and everyone of us. It's called eating healthy, exercise and stop the excuses. Success isn't created for doing nothing , it is created by taking action and not making excuses for your short comings.

Battractive said...

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Jane said...

@LeonRover
Wow! How very interesting.

Jane said...

@Donald Sparks
'.. most of the obesity in North America is caused by being lazy and unwilling to change mental habits. ..'

I don't think this is correct. I think most obesity is actually caused by addiction to junk food. This means uncontrollable cravings, not laziness.

'.. We know from facts that a little junk food is as healthy as not eating any. The body needs a little to help shock itself to keep fighting against fat build up. ..'

I have never heard this argument, and to me it sounds like the justification of an addict.

In my experience, uncontrollable food cravings come from eating 'empty calories'. Your body craves the missing vitamins and minerals.

The only cure is to stop eating empty calories, completely, for ever. Eating a little won't do, it just maintains your addiction.

Paul N said...

Jane, I am with you here. The junk foods are not only nutrient deficient, they have been carefully made to be hyper palatable.

So food tastes, good, but no nutrients - it fools the body's system such that the message for more nutrients is manifested as "eat more good tasting food", but we have become conditioned that junk food tastes good.

Our desire for umami (fermented) foods can be met by vinegar foods, such as ketchup. Our taste sense is satisfied, but it has been fooled. And then when we taste real fermented foods, we don;t like them as they are "too strong".

AS with almost any improvement project, it needs some willpower to go up against this, and a satisfying alternative.

That is why I think the LC/VLC diets work - by tasting good, it takes less willpower to stay on them.

And they deliver a lot of fat soluble nutrients that have been missing - something a drug simply can't do.

George Henderson said...

Stephan, look at this link
http://tvnz.co.nz/close-up/video
The second item is about your dairy fat study.
We can see your name on it. "World Famous in New Zealand" as we say here.
Great work.

Jane said...

@Paul N
Yes, exactly.

Lone Star said...

One thing I know after 45 years struggling with weight and early onset depression (atypical) is that there is more to the obesity issue than "eat less - move more" and that we have not even begun to understand the neurological and metabolic aspects of dealing with this condition. I do believe medical therapies (drugs) may be very helpful due to my own experience.

I have lost the same 40 pounds three times in my life (age 26, 30, and 54) and gained it back fairly rapidly when I quit the diet except for once (age 30) when I maintained a weight loss of 40 pounds effortlessly for about 5 years without avoiding the starchy foods and desserts I had always craved. For the first and only time in my life I ate what I wanted, when I wanted and didn‘t gain an ounce. My body behaved like a naturally thin person -- it was a miracle!

The weight loss at age 30 happened as a result of a serious depression which, for the first time in my life, caused me to quit eating rather than my usual overeating and oversleeping in response to depression. After several ineffective antidepressant drug trials I hit on Nardil which literally turned my life around. I felt “normal” for the first time in my life. I continued to take Nardil/phenelzine (30mg) for the next 5 years during which time I effortlessly maintained a weight of 130 lbs.

At 61 years of age, I now realize what an anomaly this 5 years of my life represented. What explained my ability to maintain my weight loss at age 30 and not the other two times? The “palatability” of the food I was eating did not change nor did the foods ability to promote insulin secretion differ before and after each weight loss experience, yet for 5 years I was immune to weight gain!

My theory is that it was due to the antidepressant drug. Various studies on phenelzine have indicated that it can alter fat metabolism and circadian cycles, activate HPA activity (which is now thought to be hypoactive in atypical depression), moderate appetite and somehow affect leptin. Nardil is generally known for causing weight gain but that certainly didn’t happen to me. I believe it must have powerful and as yet largely undetermined effects on the body’s weight/metabolic/stress system. I wonder if the drug works most effectively to prevent regain (as in my case) but not help to lose weight to begin with? I obviously don’t have any answers but I believe there is perhaps something there for obesity researchers to consider.

We do know that 95% of overweight people regain the weight they have worked very hard to lose and after all we are learning about human metabolism this can not be put down to laziness. I was not a more (or less) noble or disciplined person at age 30 than I was at age 26 or 54.

On the contrary, my self-discipline and weight loss efforts at other times of my life were much more exemplary. In my twenties I lost weight on the weight watchers program and in my mid-fifties I dieted for 9 months on a very low carbohydrate (<20 grams/day) and low calorie (<900/day) diet with daily exercise (walking 2-3 miles a day). I quit losing weight on this diet even though I reduced calories to 700 and increased my exercise (intermittant jogging - terrible for my knees). I was not a happy camper and not an easy person to live with either! I gave up this diet after realizing that every single calorie over about 800/day made me gain and gain big! I kept telling myself it was impossible but it was happening! The effort to maintain this weight loss was making me (and my family) miserable. Something other than lack of will power and laziness is going on here!

George Henderson said...

Here's my theory of the obesity epidemic;
or rather, the difference between rice eaters etc and western carb eaters.
Why vitamin fortification might make a difference after all:
http://hopefulgeranium.blogspot.co.nz/2012/08/the-role-of-vitamin-fortification-in.html

No way do I think this is a whole answer, but it may be a missing piece of the puzzle that helps explain some anomalies.

Jason Hreha said...

What do you think about this study?

Egg Yolk Consumption Almost as Bad as Smoking When It Comes to Atherosclerosis, Study Suggests

Nyx said...

This is interesting, but it made me wonder whether high-carb meals do lead to higher serotonin levels, and would that not produce the same effect? I have previously gotten confused about whether high-carb meals really have that effect or not. But if they do, would that not have the same effect as this medication?

George Henderson said...

@ Jane,

"'.. We know from facts that a little junk food is as healthy as not eating any. The body needs a little to help shock itself to keep fighting against fat build up. ..'

I have never heard this argument, and to me it sounds like the justification of an addict."

To me too, Jane, but I have heard it before: in a Neil Strauss interview with Christina Aguilera, she says "junk food's OK if you just eat a little at a time".
It really worked for her.

RLL said...

Science-based Medicine blog has a good discussion of the egg issue.

res 'Fast Foods', first it is a meaningless label. A hamburger, large fries and large shake drink for lunch? Sure, pick ONE. Then look at what you are eating the rest of the day.

lenny marci said...

Weight loss managementis only one way to keep your weight normal. Overweight or underweight is not good for health.It's about improving your life in dozens of significant ways.