Friday, May 20, 2011

Using Leptin to Treat Obesity

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

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12 Responses to “Using Leptin to Treat Obesity”

  1. Jim says:

    “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.”

    Yup, you read my mind Dr. Sharma!!

  2. Catnip says:

    I had a Duodenal Switch (DS) done to lose weight and would gladly do daily injections to help me keep the weight off. even if the most effective and aggressive weight loss surgery it can be a daily struggle.

    Sign me up, when do I pick up my prescription?

    CNC

  3. DebraSY says:

    Ditto to Jim.

    And here’s the thing: even if I were to consider WLS (which I wouldn’t, since I view it as ONLY a last resort for people of super high BMIs and other health compromises that cannot be addressed any other way) I would have to go through the miserable process of regaining all my lost weight to qualify. Ack!

    How ridiculous that there is NO help for the weight-reduced!!! We are viewed as “cured.”

    I read wistfully the musings from people (often here in the comments of this site) who are still in the loss phase or the brief honeymoon that follows loss, and they are so convinced that they have found the natural, healthy “lifestyle” that they will live the rest of their lives, and all I can think is, “Honey, you’ve got no idea what you’re up against when the endocrine changes, and when your joints start to fail you because of years of carrying extra weight, and when people roll their eyes at you for not being grateful for your good fortune and obvious wisdom in conquering this problem.” And trust me, it doesn’t matter how many years you keep it off, if you regain, people will “tsk tsk” you for not understanding that it requires a “lifestyle” change, not just a diet. I have a friend who regained after maintaining a 70-pound loss for 15 years. Her life changed, her daughters entered their teens and she got a new job, and maintenance just couldn’t go along for the ride. I sometimes feel like
    the character “Charly” from the movie of that same name and the book Flowers for Algernon by Daniel Keyes. Medical science takes Charlie from Developmentally Delayed to Genius, but he learns it’s only temporary. In one scene he watches a DD man, just trying to do his menial job in a restaurant, become the victim of unconscionable verbal abuse. When I’ve watched Biggest Loser, and have seen the trainers forcing fat people to exercise till they vomit, I’ve wept.

    Dr. Sharma: got any suggestions for the lay community? What can we do to advance a research agenda that supports maintenance after loss? I have written letters to the NWCR requesting they consider doing more empirical research, or at least releasing our contact info to empirical researchers. In their responses, I hear (between the lines) this condescending, “There, there, Sweetie. We know what we’re doing.” Would they listen to you, perhaps?

  4. Atchka! says:

    I thought leptin injections were tried for weight loss, but were discontinued because the injection sights were so uncomfortable afterward. That’s why the trials never went anywhere, because the actual leptin treatments were so unpleasant. Have they resolved this issue?

    Peace,
    Shannon

  5. Lucy A. says:

    Until these resent articales on leptin I had never heard of the stuff, however, with the complications of any major surgury being what they are combined with the potential for regain after surgery I would be willing to give these injections a try. If the injection site does become too painful I could have the option of surgery. Like you said the lipton does not help loss of weight but aids greatly in preventing it from returning, trade two cholesterol pills for a needle why not?

  6. Jim says:

    To DebraSY:

    I simply refuse to watch any of those “reality shows” – especially “The Biggest Loser,” because absolutely ALL of them are complete crap!

  7. DeeLeigh says:

    If fat people cared how unpleasant weight loss treatments were, then nobody would agree to weight loss surgery – and nobody would be on “Biggest Loser.” I hate to say it, but most fat people think that we deserve to be punished. We’re a bit masochistic. I’m sure that a lot of people would go in for daily leptin injections. At least they’re reversible (just by stopping) and will not, as far as we know, permanently damage your body like WLS does.

    Personally, I’ll wait and watch. I’d never agree to a treatment that I’m not convinced is safe, and the only way to prove to me that something is safe is through very long-term studies. I’m talking decades, not years. Being fat has very little impact on my life and I don’t expect it to reduce my lifespan much, if at all. On the other hand, WLS regularly kills people or ruins their lives, and government approved weight loss drugs (I’m talking about Redux) have a poor track record as well.

    For those who aren’t familiar with Redux, it and it’s off-label predecessor fen-phen caused irreversible heart valve damage in at least 1/4 of the people who used them. They were removed from the market after people started dying. You can still find stories about it from the early 00s if you Google it, for example, this one, from the Seattle Time and this one, from Time Magazine, for example.

  8. RobA says:

    Interesting article Doc. I have a question re: Leptin:

    I understand that leptin injections into obese people don’t help much, the thinking being that the person is obese in the first place because there is a problem with their leptin receptors. Which makes sense. If their braind cant read their leptin levels naturally, it wouldnt be able to read the injected leptin either.

    My question is this: what if leptin were injected in people who DONT have an issue with leptin receptors but are on the low end of bf% (say 9-10%) and whose leptin levels have dropped because of that? For example, the bodybuilder who needs to be at 6% bf, but is stalled at 10% due to lowered leptin levels?

    In this scenario, it SHOULD help the individual bust through the fat loss plateau, would it not? As the person has fully functioning leptin receptors.

    This is just hypothetical btw. I understand its dumb and dangerous to inject something that clinical trials havent proven is safe….just trying to understand how leptin works.

  9. Arya M. Sharma, MD says:

    RobA: There is no reason why anyone would want to be at a BF% of under 10%. Leptin has been shown to help with maintaining weight loss – it is not effctive for promoting weight loss.

  10. RobA says:

    lots of fitness and bodybuilding athletes would like too. “Contest shape” is usually 6-7% bf. Im at 11% and trying to get lower.

    Thanks for the response.

  11. biafra mei says:

    I need to the leptin where can i order

  12. Sebie says:

    I need it too, maybe we could do another trial, I am ready.

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