Obesity is not permanent

Take a group of obese people (> 250 lbs) and put them on a massive calorie restricted diet.  They lose weight and metabolic rate plummets.  Weight loss fail?  In most cases, yes.  But a recent study showed that the decrepit post-weight loss metabolic rate gradually improves in parallel with an increase in dietary fat ingestion to such a degree that even after two long years: totally food intake was almost back to normal, energy expenditure improved, and all this happened despite continual weight loss.  In other words, obesity is not permanent. 

creme brulee

Decreased energy density and changes in food selection following Roux-en-Y gastric bypass (Laurenius et al., 2013)

Statistically speaking, no diet on Earth comes close to RYGB in terms of weight loss success.  Long term.  Seemingly permanent.  It’s the closest thing to a cure we’ve got.

Laurenius

Body weight is down by 30%, and energy expenditure is rising faster than a speeding bullet.  because food intake is increasing while body weight is dropping – they’re probably more active too ** weight loss than more exercise –

But there’s a more mystical aspect to RYGB that warrants attention.  (it could be the increasing fat intake, but for now let’s just say it’s RYGB per se).  According to this pearl, weight loss of only 10% via diet alone causes energy expenditure crash by 394-500 kcal/d, and physiological replacement of leptin via subcutaneous injection can increase this by 234-454 kcal/d (Rosenbaum, Murphy, Heymsfield, Matthews, and Leibel, 2002).

Rosenbaum

Leptin dose was 0.08-0.14 mg/kg fat mass & adjusted as necessary until plasma leptin levels reached pre-weight loss levels.  Baseline: 23 ng/mL; weight loss: 16.8 ng/mL; weight loss + leptin: 24.8 ng/mL.

But maybe energy expenditure crashed because of the diet?  It was quite possibly absolutely the worst diet anyone could intellectually conceive: 40% corn oil, 45% glucose, and 15% casein (Leibel, Rosenbaum, and Hirsch, 1995).  Leibel

OK, now my money is on diet.  If you lose weight via corn oil & glucose, then leptin levels plummet while leptin sensitivity becomes exquisite.  And so leptin injections work.  In the Laurenius RYGB study, we don’t really know what they were eating, but it wasn’t worse than 40% corn oil, 45% glucose, and 15% casein.  obviously.


Which brings us here:

Randomized double-blind placebo-controlled study of leptin administration after gastric bypass (Korner et al., 2013)

4.5 years after RYGB surgery in patients who dropped 30.8% of their body weight and were clinically hypoleptinemic – ie, they’re leptin levels were 21.6 ng/mL, whereas a similar BW-matched cohort weighing 94.9 kg was at 33.5 ng/mL.  Leptin injected at 0.05 mg/kg BW BID = super duper physiological leptinemia of 234 – 281 ng/mL.  It was a crossover study, so here are the data for those who got placebo first (left) and leptin first (right):Korner 1

but it didn’t work all that well :/Korner 2

What went wrong?

Lesson 1: they bollixed the crossover.   There was NO WASHOUT PERIOD.  But this would’ve worked in favor of leptin.  Skip ahead if you are fluent in Prelude to a crossover and part deux.  In those assigned to placebo first, nothing would’ve happened in the placebo phase, then they would’ve lost weight in the leptin phase.  Leptin +1.  In those assigned to leptin first, they would’ve lost weight in the leptin phase, they regained it in the placebo phase.  Leptin +2, placebo -1.

This actually appears to have happened – see the small rise in body weight in the placebo group?  That’s the sign of a bollixed crossover.


Lesson 2: leptin resistance.  It took a few weeks for leptin levels to accumulate to such high levels.  It’s possible that by week 8 (150 ng/mL) leptin was working, so weeks 8-12 they lost weight.  But 150 ng/mL is too high.  Leptin resistance started kicking in and by week 12, when leptin levels were pushing 250 ng/mL the result was full blown leptin resistance.  Leptin stopped working.  The data support this possibility.

Alternatively, maybe they were just eating better than 40% corn oil, 45% glucose, and 15% casein, and weren’t starving.  And maybe the RYGB cured them, so leptin injections worked as well in them as it does in regular people.  Ie, not at all, unless violent doses of leptin are injected (0.3 mg/kg, which is 6 times higher than the dose which increased plasma leptin levels 10-fold in Korner’s post-RYGB patients). (although this would appear to negate the leptin resistance theory [shhh!]).

From Heymsfield 1999:Heymsfield

Diet alone = paltry weight loss, rarely successful probably because of dire need for leptin injections.

RYGB = cured.  Leptin injections don’t work because they don’t have to.

 Lesson 3: 40% corn oil, 45% glucose, and 15% casein = epic FAIL

calories proper

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  • http://www.facebook.com/people/Doc-Jayh/100001759793744 Doc Jayh

    Interesting! I’ve known that a chance to cut is a chance to cure, but I do wish more people would not need a surgeon to have permanent weight loss unless that surgeon was just a enthusiastic cheerleader!

    • http://www.caloriesproper.com/ William Lagakos

      Di Doc Jayh, lol.
      Thanks for the comment and I agree, it’d be unfortunate if the only cure was a surgical one. But hey, a cure is a cure :/
      -Bill

  • http://twitter.com/TheNutriMan Pat Davitt

    Great post. If the Corn oil and glucose diet was an epic fail, has their been a study using a “better” diet and looked at the same outcomes as Laurenius? Aside from the potential QOL improvement do to massive reduction in “excess weight”, were most of the health markers significantly improved in that study? Kelley and Goodpaster have done some great work showing gastric bypass improves many health markers, but not necessarily mitochondria or fat oxidation. Ultimately, what do you think was the main cause of success in Laurenius’s paper? or in RYGB, in general?

    • http://www.caloriesproper.com/ William Lagakos

      Hey bud,
      Thanks for the questions – I’ll try to tackle them one at a time.
      -That was from 2 different studies: Leibel used hypocaloric corn oil & glucose to induce weight loss; Laurenius used RYGB. But on another note, I can’t think of a good diet intervention study in post-GB patients.
      -Laurenius didn’t report anything else, but I’m gonna say Yes, massive weight loss combined with ever-improving EE bode well for metabolic health imo.
      -RYGB cures hyperplastic fat tissue FTW! Diet likely contributed to their improving health, but I don’t think they would’ve seen such great benefits sans RYGB. Some good diet intervention studies on post-GB patients are highly warranted. Also, there is a small subgroup who aren’t cured by RYGB – I’d like to know more about them.

      all best,
      Bill

  • Jonathan Serfaty

    Hey! What’s wrong with casein??? :)

    • http://www.caloriesproper.com/ William Lagakos

      Hi Jonathan, nothing! Well, it might bother some folks with GI issues, but the main culprits were corn oil & glucose. Casein was collateral damage.
      best,
      Bill

      • Jonathan Serfaty

        Heh. Sorry, sarcasm was lost in translation…. obviously casein was the only beneficial part of that absurd diet.

  • Jane Plain (Woo)

    Hi Bill
    I cant believe I never read this before, lol.

    Just want to comment on the 3 month leptin peak. This is observed in all leptin studies and it is the result of non-neutralizing antibodies binding the leptin making it physiologically inactive. The high leptin is not a sign of leptin resistance at the receptor level; it is a product of the body detecting subtle differences in the drug vs native leptin, and responding to it as a foreign protein. The body then produces binding antibodies that make the drug less effective, and when leptin levels are measured they are a billionty + 10.
    It usually happens by month 3 if it is going to happen.

    Again, this isn’t true leptin resistance at the receptor level, it’s just the body locking up the leptin and making it not available for use… and ironically on a blood test it looks like your leptin level is extremely high.

    In the study I participated in, most of the women began making non-neutralizing antibodies in this fashion. I know I certainly did, my leptin levels went from like 20 (high physiologic) to like 80 by the end. However, in terms of clinical effectiveness, there was little to no change, because I am leptin supersensitive, the slight decrease effectiveness secondary to antibodies was not enough to make the drug stop working.

    The antibodies persist even after the drug ceases to be injected; after the study my basal leptin was 9, even though in the pre-drug condition it was between 1-2 (very hypoleptinemic). I dont know if they persist forever, I assume the body stops making them after awhile. I think the antibodies are actually helpful in the post-drug condition because they help “prolong” the half life of your own leptin, artificially raising it.

  • Jane Plain (Woo)

    The reason leptin injections do not exhibit much effect in obesity is because in obesity leptin signalling is already more or less working properly; the obese exhibit endocrine signs of hyperleptinemia like chronically suppressed ghrelin and exaggerated IGF1 and excessive gonadotropins/LH. Gross leptin signalling is already *maximal* in obesity, conventional obesity. It is a misconception that leptin produces weight loss. Leptin has no effect on reducing body weight, the physiologic function of leptin is to merely terminate energy conservation feedback loops of the body. Everything leptin does, is crank the thermostat up to 100%.

    Being leptin deficient is like living in a house in the middle of winter where the owners are stingy and refuse to turn on the heat, making you wear sweaters inside at all times.

    Being leptin replete is like going to a house where the thermostat is always maxed out and people are actually pretty warm even when its zero degrees outside.

    In both cases, gas reserves might be exactly the same, but in the latter condition, people are *wasting* the energy and in the former condition, they are hoarding it producing discomfort/misery .

    Thermostats, like leptin signalling, is finite; you can only turn up the heat so high, no further energy waste is observed. Even if I stand at my thermostat and keep trying to crank it up higher, it will only go to 80. Having a leptin of 200 doesn’t help, if your leptin receptors are already saturated at a leptin level of 20.

    Leptin will only produce maximal energy waste, maximal IGF1 signalling, maximal T3 levels, maximal production of gonadotropins (sometimes, ironically, to fertility disorder from overproduction…). It can not cure obesity, though, because obesity is a different animal.

    Obesity is mostly related to energy using disorder, not otherwise leptin related; mitochondrial insufficiency/deficiency, fuel oxidation defects, adipocyte hyperplasia/differentiation under trivial provocations, SNS deficits at the adiopcyte level or gross physiology, and a million other things other than “leptin”. Leptin just stops energy conservation as much as it can.

    Leptin terminates energy conservation. Obesity, OTOH, is a disease most closely related to insulin excess particularly in postprandial period, exacerbating energy use disorder, adipocyte hyperplasia, insufficient fasting use of body fat/continual reliance on glucose inappropriately , insufficient use of glucose at meals with insulin hypersecretion… all problems of pathological obesity eventually boil down to insulin. The insulin hypothesis is more or less correct in that regard but not complete.

    Perhaps I should write blog entry regarding this :) Leptin rules energy waste vs conservation, it does little to nothing to help obesity… but it makes 100% of the difference in treating post-obese condition however.

    • http://www.caloriesproper.com/ William Lagakos

      LOL ha! yes, for a moment there I thought I was reading The Scribble Pad! Thanks for the comments – they’re loaded with fodder for future blog posts.

      Leptin resistance = leptin antibodies high; receptor works fine but no ligand around. Leptin sensitivity = exquisite receptor signaling; antibodies are irrelevant.

      Role for pramlintide? Seems to work well with metreleptin in obese patients, but pharma doesn’t really seem to
      be pushing it so maybe not.

      • Jane Plain (Woo)

        I’ve learned that research into hormone analogues is doomed from outset as they are not financially marketable. This is because the drug vehicle is often injection, and also because they cannot really be patented like a novel designer drug molecule can.

        The thing is, it’s not that these treatments don’t work for weight – they certainly do help – it’s that they don’t work from a $$$ point of view. They are hard to sell and not profitable.

        Hormone research is used to understand the things hormones do so they can invent novel patentable molecules targeting 1 or 2 of the effects. Doomed to failure.

        Not familiar with the therapy of amylin + leptin for obesity; I suspect this therapy will not gain foothold due to potential SE. I also think bolstering amylin in obesity (who still have strong beta cell function) is probably not good idea long term, better to address the situation with a theraputic high fat/low carb diet which slows gastric motility and insulin hypersecretion in the first place. Leptin replacement would then be administered as needed for weight loss stalls and signs of metaboilc crap out post starvation/weight loss.

        • Jane Plain (Woo)

          Second problem of obesity research is presupposing the obese can not/ will not adhere to a diet. All therapies are designed assuming the patient will never quit eating at mcdonalds or drinking soda. In reality, the use of poor quality food excessively is both a sign and a cause of improvement.

        • http://www.caloriesproper.com/ William Lagakos

          I work with a couple of these companies – it’s all about the GPCRs, always seeking orally active small molecule ligands for the GPCR du jour.

          • Gk Kartsonis

            Hi…very interesting post. Do you have any practical suggestions in terms of medical therapies for post weight loss individuals?

            Thanks.

          • http://www.caloriesproper.com/ William Lagakos

            The “post” period is the hard part – and unfortunately there aren’t a whole low of options. Perhaps you could discuss metreleptin with your GP. I tend to be biased toward nutrition interventions (ie, LCHF), but a high protein diet (25%) fared pretty well in this study: PMID 15303109.