Sunday, August 25, 2024

Protons (76) Those D12492 fed mice (Speakman and Tucker again)

For people who are thinking about re-listening to Tucker's discussion with Prof Speakman, at


you could do worse than to check the section from time point of 24 minutes through to 26m 20. Speakman is describing exactly the phenomenon in the graph below, beautifully illustrated from the Schwartz laboratory. I may just have mentioned this many times in multiple blog posts:






















He also describes, in brief, the concept of Reward as applied to these data.

To me, the Reward hypothesis has approximately zero explanatory power for the phenomenon in the graph and Speakman eloquently describes this deficit. He and Tucker discuss how an addictive drug drives progressively increasing consumption, but an high fat diet clearly has a decreasing drive to eat until near normal consumption resumes by about a week.

But always with residual obesity and slow, on-going weight gain.

Let's consider a better explanation for the behaviour of the mice in the Schwartz lab.

Linoleic acid in the D12492 is around 18% of total calories, according to a table I downloaded from Research Diets in 2011. This is well above the insulin sensitising dose noted for humans in the last post.

The whole argument from the Protons hypothesis is that linoleic acid has the ability to facilitate insulin signalling to a) increase post-prandial fat storage b) inhibit fasting fatty acid oxidation. That is a recipe for an acute loss of calories in to adipocytes and an hypocaloric crisis.

Which is easily corrected by eating some more. As in the above mice.

Now, before we look at the next paper, some ground rules need to be set out.

Metformin.

This is the most mis-represented drug ever investigated and almost all of the conclusions published about it are incorrect.

Metformin is an inhibitor of insulin signalling which therefore results in a decreased phosphorylation of AKT. Every time. See here here
here and many more places. It *appears* to improve insulin sensitivity, lowering the plasma level of insulin and glucose, but this is because it inhibits hepatic gluconeogenesis via inhibiting mtG3Pdh. That drops hepatic glucose output and that is what lowers the insulin level.

And don't forget SHORT syndrome, discussed here.

Having established that, let's put some ideas in to perspective. Linoleic acid is a pathological insulin sensitiser. Metformin is an insulin desensitiser.

The converse drugs to metformin are the glitazones. In vivo these *increase* the phosphorylation of AKT. What else would you expect? They really are insulin sensitisers. Their standard side effect is a worsening of obesity. Of course.

We are now in a position to explain the "hyperphagia" of mice fed high fat, high linoleic acid diets such as the D12492 used in the Schwartz lab.





We need to look at this paper:

Metformin Reduces Body Weight Gain and Improves Glucose Intolerance in High-Fat Diet-Fed C57BL/6J Mice

The mice were offered something very similar to D12451 (45% fat rather than the 60% fat of D12492)  but we don't know from which company it was purchased or even if the lard included was from Japan or America. No gas chromatography was used this time so a best guess might be around 10-15% of total calories as LA.

In the first hour of access each mouse eats roughly 5.5g of it, ie 28kcal, that's roughly a third of the 70kcal/d that the Schwartz mice would eat in a full 24h period while on a chow diet:


















But the really interesting finding is what happens when you either reduce insulin signalling with metformin or increase it with pioglitazone.

Blunting insulin signalling (metformin 300mg/kg p/o) before access to the food decreases the one-hour food consumption by 80%.

That's 80 per cent.

5.5kcal in an hour to 1.0kcal in an hour.

The food is still yummy, it will still light up the endogenous opioid, endocannabinoid and serotonin systems (dopamine too I guess) of the hypothalamus but the hyperphagia essentially disappears. The hyperphagia is made worse by pioglitazone, of course.

It's simply about pathological insulin sensitivity being corrected by an insulin signalling inhibitor.

It is an energy supply problem.

So metformin is a partial rescue drug for LA toxicity. It's not perfect but it illustrates basic physiological principles. Obviously the correct solution to obesity is the reduction of linoleic acid in the diet to around or just below 2% of calories. Ruminant fat. Not metformin. Not a GLP-1 agonist.

Oh, almost forgot. Near normalisation of calorie intake: I've said it before, hyperphagia ameliorates over a week because distended adipocytes increase their basal lipolysis and will raise FFAs high enough to a) induce enough insulin *resistance* to reduce LA's lipid storage effect and b) overcome the blockade of CPT1 from malonyl-CoA. Adequate calories then become available *provided* adipocytes stay distended. Under-eating simply shrinks the adipocytes, reduces basal lipolysis mediated FFA release and re-establishes pathological insulin sensitivity. Because there is now a need to maintain adipocyte size, food intake must trickle along at levels just high enough to maintain adequate obesity for adequate caloric availability from increased basal lipolysis to resist insulin.

Peter

19 comments:

  1. Thanks for the clarifications about what metformin really does!

    On revisiting the subject, I found this quote in my files: "Many other factors also influence testosterone levels and fertility. Two of the more interesting examples are metformin, a very commonly used medication for diabetes that has the curious side effect of reducing testosterone (which can be debilitating for older men who are already deficient in testosterone), and the widely used sugar replacement stevia, which has been repeatedly studied for its testosterone reducing and contraceptive properties."

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    1. Yes, trading drug side effects for some amelioration of of LA toxicity. Never a solution!

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  2. Peter, here they use Metformin as AMPD inhibitor, so they suppressed xanthine oxidase induced ROS.
    "In vivo, we show that sucrose fed rats also develop fatty liver that is blocked by metformin in association with both a reduction in AMPD activity and an increase in AMPK activity"

    Counteracting Roles of AMP Deaminase and AMP Kinase in the Development of Fatty Liver
    doi:10.1371/journal.pone.0048801

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    1. Running out of time, got two days climbing and hiking in Sheffield. But until they include linoleic acid and insulin signalling in their idea the details they investigate will provide no insight. Fatty liver is excess fat storage. That's linoleic acid. Otherwise fructose -> FGF21 and BAT activation. It's a weight *loss* drug, until you add LA. Then all the minutiae go wrong and we get paper after paper after paper, missing the elephant in the room...

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    2. Oh yes, LOX/HETE as switch between good fructose and bad fructose. Little different mechanism, same effect.

      Novel role of xanthine oxidase-dependent H2O2 production in 12/15-lipoxygenase-mediated de novo lipogenesis, triglyceride biosynthesis and weight gain
      https://doi.org/10.1016/j.redox.2021.102163

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  3. Nice work, really interesting post!

    I saw this recently:

    "Emerging evidence suggests that metformin-associated weight loss is due to modulation of hypothalamic appetite regulatory centers, alteration in the gut microbiome, and reversal of consequences of aging." *

    It doesn't seem to be very effective in humans, not compared to CB1 inhibition or GLP-1 agonism, however.

    "In these obese patients with PCOS, metformin maintained the weight loss and enhanced the metabolic and biochemical parameters achieved by treatment with rimonabant, compared to 6 months of metformin treatment alone." **

    There's clearly an interaction, however...

    * "Metformin: Mechanisms in Human Obesity and Weight Loss"
    https://doi.org/10.1007/s13679-019-00335-3

    ** "Metformin maintains the weight loss and metabolic benefits following rimonabant treatment in obese women with polycystic ovary syndrome (PCOS)
    https://doi.org/10.1111/j.1365-2265.2008.03345.x

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    1. Tucker, I don't view metformin as a weight loss drug. More of a partial normaliser of the metabolic defect induced by LA/insulin. This post came out of searching for metformin as normalising the depresses bmr of the post obese. You pcos paper might do that. Will ckeck when we get home!

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  4. Also, will metformin have a longevity benefit in the absence of chronic LA consumption? I guess a profound "no".

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  5. great post!

    so metformin and pioglitazones are on opposite sides of the 'insulin coin', is one more powerful than the other? i'd venture to guess pioglitazones are more powerful, since they can make people quite fat it seems, but that metformin is nowhere near as good as for fat-loss

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  6. Protons perspective and the role of unsaturated fats in obesity doesn't exist still for Taubes who is still peddling carbs.
    See this paper published last month in Nature Metabolism (along with Spearman, Hall and Astrup, who are peddling Energy Balance model)
    https://www.nature.com/articles/s42255-024-01106-8

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  7. Gyan, I email back and forth with Taubes and he's been made aware of the Proton's perspective. He's open to the linoleic acid story in general and admitted he may have been excessively carb focused in his research for GCBC. He's asking for evidence, as are we! Wouldn't it be nice if there at least a couple trials who explicitly tested the hypothesis? Currently we're stuck with trials that can only provide tangential/indirect answers to the question. Maybe we should take a page out of Dave Feldman's book and create a groundswell of popular support to obtain the funds that can test the Proton's hypothesis?

    I'm (currently) of the view that the Protons hypothesis can explain why carbs (i.e. amount x degree of refinement) and linoleic acid (from approximately ~4% up to ~15% of total kcals?) are obesogenic

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  8. Hi Raphi,

    I have emailed your gmail address

    Best

    Peter

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  9. Asking for evidence, is he?
    He has been careful NOT to plot trends in vegetable oil consumption.
    And he is so convinced by the evidence that he has co-authored papers that recommend unsaturated fats for cardiovascular health.
    To scapegoat refined grains and sugar is utterly unobjectionable to the mainstream.
    That's why Taubes is now co-authoring with Hall.

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  10. Hi Gyan, please see my tweet where I ask Gary if he has conceded that "PUFAs seem better than SFAs for CVD risk", as this claim was put forth by resident nutrition Twitter psycopath Kevin Bass https://x.com/raphaels7/status/1584918534366314497.

    Gary replied clarifying that this is incorrect, saying "No, I haven't conceded that. The BMJ asked me to co-author an article with Walter Willett among others, we argued (fought) over content, and I agreed to compromise (as did he) with the phrase 'evidence exists' because it does" https://x.com/garytaubes/status/1584965734295568386

    If we do the guilt-by-association thing then we also need to criticize Dave Feldman for partnering with Cromwell et al. in their LMHR studies; I was 20m from the stage where Cromwell was sitting when he said (paraphrasing), "Look, I'm an apoB/statin guy". After the talk I walked up to him, shook Cromwell's hand and thanked him for taking Dave and his ideas seriously and partnering with him in good faith.

    I'm not saying I'd be able to do what Dave did, but I sure as hell wish more people would be able to

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    1. "Evidence exists" is a classic misleading phrase. Evidence exists that the Earth is flat. Evidence exists that homeopathy works. Etc.

      Willett is much better than Taubes at this game, which is why he's at the top of the ivory tower and Gary is tilting at windmills.

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  11. This comment has been removed by the author.

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  12. This attitude was excusable 20 years back, perhaps even 10 years ago, but in 2024 to co-author a paper on obesity without even a mention of unsaturated fats, not even a mention that vegetable oil have increased in tandem with obesity is simply not excusable.
    He is wedded to carbohydrate-insulin model and to studies that discredit low-carb.
    He saying he hasn't paid any attention to unsaturated fats is merely a polite way of saying that he isn't going to care about any other theory of obesity.

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    1. "...is merely a polite way of saying that he isn't going to care about any other theory of obesity."

      Oh trust me, he's much less polite.

      But one has to feel for the guy. Such an outcome keeps me up at night...

      "Hi, my name is Gary, and I've been barking up the wrong tree for 30 years..."

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  13. Peter, my thoughts are that this early peak is fat type independent as they can use any long-chain fats, zero short and medium chain. If control diet has cca 85% ? of carbs+proteins and D12492 has 20% + 20% so 40%. This gives 85/40=2.1 times food intake, this is in good accordance with the chart above. My post on this topic below.
    Jaromir
    https://mct4health.blogspot.com/2024/09/who-will-tell-us-that-we-have-eaten.html

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