Silent Leptin Resistance

Conventional leptin resistance has something do with obesity.  It is known.  Silent leptin resistance is … err … complicated. 

Divide and conquer

Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding (Shapiro, Scarpace, et al., 2008 AJP)

A remarkable 60% fructose diet fed to rats for 6 months had absolutely no effect on energy balance.  Nil. QED.
Fig 1

Food intake and body weight were unaffected because the levels of and sensitivity to endogenous leptin were identical in both groups.

Enter the Dragon

Enter the Dragon

“Silent Leptin Resistance” – The fructose-fed rats are, however, profoundly resistant to the satiating effects of Metreleptin (a pharmaceutical grade injectable leptin analog):

Fig 2

Lustig says Leptin Resistance is obesity.  These data say that Silent Leptin Resistance could predispose to obesity.  The figure above shows resistance to the satiating effect of Metreleptin in fructose-fed rats.  Thus, Silent Leptin Resistance can be accurately gauged by measuring food intake in response to Metreleptin.  Recall the levels of and sensitivity to endogenous leptin is identical in these two groups (compare the two open bars in this graph or E & F in the figure above).  Silent Leptin Resistance is unmasked only after pharmacological intervention.  But since the rats had normal body weight and food intake, what is the relevance of Silent Leptin Resistance?  These rats were markedly predisposed to obesity.

As I’ve blogged about previously (the great difficulties of weight loss), the correlations of leptin with 1) body weight, and 2) specific measurements of appetite like “hunger” and  “urge to eat” are not very strong.  Further, not only does leptin fail to accurately gauge appetite, neither leptin levels nor appetite correlate very well with weight re-gain in humans (Sumithran et al., 2011).  In this study, it appears as though this confusion is specific to endogenous leptin, as the effects of Metreleptin seem to accurately quantify some meaningful aspect of Silent Leptin Resistance and predict the propensity for weight gain (see below).

The most interesting data have already been presented, but the editorial money bag is the next figure.  Half the rats from each group were switched to moderate sugar high fat diets and the fructose pre-fed rats became significantly more obese than the low sugar fed controls.

Fig 3

Both groups switched to high fat ingested more calories initially, but those pre-fed high fructose diets gained significantly more weight than those pre-fed the low fructose diet.  Thus, while the physiology of endogenous leptin was proper in its inability to detect differences in the fructose-fed rats PRIOR to the diet switch, when the rats were for all intents and purposes equally leptin sensitive, it was only the response to Metreleptin that predicted the propensity for weight gain after exposure to an obesogenic diet.

Fructose did not dysregulate endogenous leptin sensitivity, and accordingly, food intake, body weight, and leptin levels were similar in fructose-fed and control rats prior to the diet switch.  But fructose loaded the gun, Metreleptin revealed a bullet in the chamber, and the obesogenic diet pulled the trigger.  What do you think is going on in those [rare] skinny people with Lean Metabolisms who eat HFCS-rich foods and chug soda all day long?

I don’t know the full implications of what would be revealed by further investigations into Silent Leptin Resistance, but I know that none of this bodes well for sugar.

calories proper

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  • Kade Storm A.K.A. Hedonist

    “What do you think is going on in those [rare] skinny people with Lean Metabolisms who eat HFCS-rich foods and chug soda all day long?”

    I think that our metabolic issues manifest in a different manner that is both subtle yet problematic in the long run. I foresee problems manifesting in a manner that most won’t have reason to take seriously–until it’s too late–because they haven’t gained weight or ballooned up while just looking and feeling a bit under the ideal margin and attributing such degradations to other irrelevant variables (such as ageing, stress, etc. — all good variables, but not dominantly relevant to this issue).

    • William Lagakos

      great point. The differences will be subtle, and they’re unlikely to notice the effect of consistently looking & feeling <100%, then <95%, then <90%, etc.

  • CynicalEng

    The 60% fructose was compared against 60% corn starch (for those not yet looking at the full paper) with fat and protein same.

    • William Lagakos

      Thanks for pointing that out.

  • Jake W

    60% fructose diets in rats have a lot in common with real-world consumption of fructose by humans. because we eat lots of pure fructose, and we’re great at de novo lipogenesis as a species. wait, scratch all that…

    • William Lagakos

      Yup. This is mainly a cost issue. Animals are expensive to maintain (daily cage fees, cost of food, etc.), so researchers try to get where they’re going as quickly as possible.

  • carbsane

    A 60% fructose diet is virtually impossible to consume naturally. Even the biggest sugar junkie doesn’t consume all of their calories as HFCS which would bring them to 55%. I had a discussion with Peter Attia on his blog regarding fructose-only interventions as well. While the balance can vary, an excess of fructose to glucose of more than 10% (if even that) is not relevant to any human diet.

    Peter wrote:

    ” I agree with your comment about the lack of utility about fructose-only interventions. While they may be mechanistically interesting, they don’t appear clinically relevant.”

    Irrelevant diet fed day in and day out to a mouse for 6 months …. And they say I blog on silly studies 😉

    Well, we do see that fructose doesn’t make them fat, but high fat diets do.

    • Nihil

      1.) Thank you for deciding which studies are relevant to humans and which aren’t.

      2.) If I read your backhanded not-so-subtle insinuation that Dr. Lagakos’ blogging about this study and/or this study are silly – I have to disagree strongly. I, for one, think this study is highly interesting and Dr. Lagakos’ blogging is both informative, entertaining and, above all, clear and understandable. Easy to follow. Important characteristics for a scientist and a writer.

      3.) Your last sentence needs no comment, everyone can judge it and the expertise of a person writing this sentence, or for that matter, that whole comment for themselves.

      • carbsane

        Guess you can’t process the 😉

        I enjoy Bill’s blog, whether or not I agree with what he writes. I do think this study is a stretch to base anything on, that’s all.

        As to point 3, then you didn’t need to comment.

        • Jane Plain (Woo)

          It’s not a thesis. It’s food for thought.

          • carbsane

            Who said it was? Food for thought … perhaps. Bill and I share a common experience in working with rodents. I’d say a 60% fructose diet in a mouse is pretty irrelevant and I presume he would too in his current line of work.

          • Jane Plain (Woo)

            Dr Bill Lagakos is a scientist.

            You are not of even a remotely comparable education/background, so I don’t know why you continue to blog/mislead people into believing you are educated at the phd level.

          • carbsane

            You have no idea what you are talking about Wooo.

    • Sam Knox

      You can’t seem to decide whether your advanced degree is in chemistry or metallurgy/materials science, but no matter.

      I’m sure your education and clinical experience are equivalent to Dr. Lagakos’s.

      I’m sorry, did I say “Dr. Lagakos”? I meant to say your good friend and colleague “Bill”.

      • Jane Plain (Woo)


        • carbsanity

          I’m only the most important obesity researcher since Ancel Keyes. Show some respect.

          • carbsane

            Ditto this one please Bill.

  • Nihil

    Thanks for writing about this study, Bill! I have read the abstract a while ago and puzzled over it, meaning to revisit it but lost track.. And your blog post helped me make sense of it and alerted me to points I would have otherwise missed. Keep up the good work!

    (And maybe do some PR work. I see that you have blogging for years, but I only found your blog some days ago, through comments on other blogs… I had to critize the Suppversity for the same thing back when it was nigh a small community suppcollege)

    • William Lagakos

      Thanks, Nihil!

  • donald rosart

    On the relevance of 60% fructose diets… Jimmy Moore reports consuming what? Twelve or more full-sugar sodas a day, before going low carb? And sometimes whole boxes of L’il Debbie cakes. What matters? Percentage of calories, or absolute dose?

    I could see certain populations–children, bodybuilder “hardgainers”–where a high calorie intake relative to body mass might make the question of the question of absolute fructose intake important.

    Remember the brief period when diabetics were sometimes encouraged to switch to fructose because of its lower glycemic index?

    It would be nice to see a study with some different amounts of fructose, to see at what point the effect shows up in rodents.

    • William Lagakos

      Hi Donald,
      The point about absolute dose is an interesting one as I suspect the effects of fructose will be differ depending on the metabolic & hormonal landscape. For example, I would expect a worse outcome in a hypercaloric scenario than if food was restricted by 10 or 20%.

  • Jane Plain (Woo)

    Very interesting.

    I wonder if it requires a certain duration abstinent of sugar to restore normal leptin sensitivity. Perhaps, mediated by dopamine downregulation/endorphin system related to sugar? There is evidence much of the appetite regulating effects of leptin are mediated by the dopaminergic system of the brain, which is notably blunted by overexposure to sugars (which produce drug-like exaggerated bolus of dopamine and endorphin producing insensitivity to both).

    Perhaps what is being observed isn’t really silent leptin resistance, but sugar addiction (which so happens also makes leptin impotent to reduce feeding behavior secondary to acquired dopamine insensitivity).

    On my blog I actually just posted a study demonstrating bromocriptine can compensate from many of the neuroendocrine aberrations of ob/ob mice even w/o leptin treatment. (related to NPY/CRH).

    It would be quite interesting to prolong the lives of the mice, abstinent of sugar for a longer period, and then repeat the leptin test. My money is that they would respond normally to the physiologic effect of high leptin with time allowed for neuroendocrine status to normalize post sugar diet.

    Exaggerated obesity from high fat diet would also be expected of dopamine / endorphin downregulation. Less normal satiation.

    • William Lagakos

      What got me was the pre-HFD stuff (6 months is pretty long for a rat study) – normal leptin levels, food intake, and body comp.

      The addiction angle is interesting. There is a lot of stuff out there on dopaminergics vs. sensitization & tolerance. Dopaminergics also regulate appetite… definitely seems like there could be a role for leptin in there.

      • Jane Plain (Woo)

        Yup; in ob/ob dopaminergics can work almost as leptin recplacement. Leptin exerts theraputic effect and *requires* a normal dopamine system.

        It is known overexposure to sugar results in dopamine/endoprhin insensitivity, so my bet is that the mice were impotent to respond to higher leptin/higher dopamine states secondary to a 60% sugar diet.

        What I would have liked to see is a few days/weeks of normal eating after exposure to the sugar pre-treatment, before exposure to the high fat + metreleptin. I think it is likely, then, there would be no difference, as the dopamine system would have had time to recover / dopamine receptors upregulate after abstinence of sugar.

        • William Lagakos

          Ha! –> to see exactly how “hard-wired” the fructose-induced leptin resistance really was. If they were cured by a week of normal eating, this would have implications for the addiction tie-in; rodents become sensitized to dopaminergics such that even after a period of abstinence, the response to drug treatment is still altered (LTP?).

  • Jane Plain (Woo)

    And a personal anecdote as an IRL fatty who was trailed with leptin:

    -On very low carb diet, even a low physiologic replacement dose produced massive energy and appetite inhibition. This is in accordance with the putative leptin supersenstivity effect of low TGs/ketone. The researchers were like WOO WE ARE GOING TO THROW YOU OUT STOP LOSING WEIGHT LOL. The lowest dose was very very effective. Meanwhile the never-obese participants were barely exhibiting a therapeutic effect (and their leptin issues were more related to nutrient deficiency or hypercortisolemia from overexercise…)

    -The few times I ate a more normal diet, I exhibited fatigue and great hunger and blood sugar instability as if I was not taking any leptin at all.

    I realized then (my) obesity had very little to do with leptin signalling directly, other than to say (my) obesity featured functional leptin signalling inhibition as part of fat gain state.

    • William Lagakos

      Sooo, “diet” is a confounding factor in (your) obesity? independently causing both fat gain and leptin resistance… but the fat gain & leptin resistance aren’t causally related.
      need more coffee to process this

      • Jane Plain (Woo)

        I tend to think it isn’t so much leptin “resistance” but functional inhibition of leptin signalling / decreased leptin sensitivity associated with fat gain states. This is unique to people vulnerable to obesity I imagine. As in, some of us have bodies which adaptively int he presence of food that can facilitate fat storage, will modify physiology to *enhance* fat storage by suppressed leptin signalling. It is likely archaic adaptive anti-starvation genetics.

        I don’t consider it a true resistance because within hours of consuming a diet suggestive of nutrient scarcity, low carb, the “opportunistic” fat storing seems to terminate and there is supersensitivity to leptin again.

        Logically if one heralds from environment where there were great fluxes in nutrient availability, it is more adaptive to feast / store lots of fat when possible. Hypothetical of course.

  • William Lagakos

    3 weeks of sucrose & lard-induced leptin resistance was reversed after only 4 days of chow feeding in this study:

  • carbsanity

    …And furthmore, J. Stanton owes me an apology, and Richard Nikoley, and Jimmy Moore, and Gary Taube$…

    • carbsane

      In case anyone has any notion otherwise … this is not me. Bill could you please delete the above?

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