Wednesday, 11 July 2012

Ketosis and adiponectin - there is a link!

Some discussion on the recent post by tom naughton on the interview with Dr Phinney. I questioned some of Dr Phinney's points on that forum about the importance of serum ketone levels.

Dr Phinney argues that it takes weeks to "keto-adapt" and that the serum ketone levels are very sensitive to not only carbs but also protein in the diet. I think most people knew this, that protein affects serum ketone levels not just carbs. Dr Phinney argues that a low-carb diet must also be a very high fat diet, something which I certainly agree with. But I wasnt to sure on the affects of differing serum ketone levels could have.

Anyway, shortly after I stumbled on this paper which is a big piece of the puzzle. Basically what this says is that beta-hydroxybutyrate stimulates adiponectin secretion through the GPR109A receptor. ( ignore the stuff about niacin ).

Check out the wikipedia page to get a glimpse of how beneficial adiponectin is to health.

So now the picture is very clear, high fat diet along with low carb and low(ish) protein not only results in high glp-1 secretion but also high adiponectin secretion due to high levels of serum ketones. Both glp-1 and adiponectin are very important for curing metabolic syndrome.

Transgenic mice with increased adiponectin show impaired adipocyte differentiation and increased energy expenditure associated with protein uncoupling.

Ah ha! Adiponectin suppresses adipocyte differentiation, what this means is that high levels of adiponectin directly inhibits fat tissue growth! bingo! And it makes sense, high serum ketones is a marker of starvation, and fat tissue growth is the last thing you want when your starving!

4 comments:

  1. Adiponectin is one of those hormones that has been very misunderstood, like leptin. For obesity it is actually bad, as adiponectin can promote a sort of starvation metabolism state where fat growth is encouraged compared to a lower adiponectin condition.

    It helps blood sugar control by encouraging fat cell growth. Adiponectin actually encourages adipocyte differentiation in most studies:

    http://www.ncbi.nlm.nih.gov/pubmed/15834118

    http://repositorium.sdum.uminho.pt/bitstream/1822/7832/1/Avides_PEP%5B2%5D.pdf

    ^^^ Most research is like this. The latter study is all about growing new fat tissue with bacteria derived adiponectin. Nicht gut.


    The most important regulator of adiponectin is fat cell size. If starving (small fat cells) make adiponectin, it makes good logical sense to assume adiponectin would promote fat growth, don't you think? As usual, obesity research FAILS. It fails in understanding everything.

    WHen adiponectin is high, leptin is low, and vice versa. They are complementary hormones. Adiponectin makes you a fattie, leptin makes you not a fattie. They are like insulin and glucagon in a sense.

    Adiponectin is great for diabetes because things that make you fatter are things that promote insulin sensitivity (read as: as long as you are growing fatter you avoid severe diabetes). If a hormone is telling your fat tissue to steal all the lipid, your insulin sensitivity will improve (first because there is less fat in the blood to oxidize and promote IR, secondly because growing fat tissue can also use glucose for this, which will be turned into triglycerides and stored in the fat tissue under direction of adiponectin).


    A common mistake is to assume that more insulin sensitive = thin. This isn't true.
    Most things that help diabetes actually cause fatassery. See insulin therapy, or most diabetic drugs (some diabetic drugs work just like adiponectin; the class of diabetes drugs know as TZDs work by growing new fat cells, and they do this partially by increasing adiponectin activity).
    Insulin resistance is more commonly associated with fat gain resistance, in the true definition of the term. Drugs that promote weight loss often promote insulin resistance and poor glucose oxidation, like stimulants such as caffeine

    http://diabetes.diabetesjournals.org/content/56/3/583.full

    This study shows that adiponectin signalling is modulated differently by various receptors. Loss of receptor 1 promotes obesity and low metabolic rate, whereas loss of receptor 2 is a superior protection from weight gain and superior oxidation of fat.

    I suspect that adiponectin increased by weight loss probably alters receptor signalling so that metabolism is retarded and fat gain is superior.

    In general, however, when it comes to fat tissue physiology, adiponectin most specifically promotes new fat cell growth and this is how it helps diabetes/glucose control. This is similar and redundant with the TZD class of OHAs.

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  2. I know that heavy niacin dosing produces severe glucose intolerance, I thought this was due to increased serum FFA but perhaps it could also be because of the adiponectin?

    The dimorphism between the adiponectin receptors is confusing to say the least, AdipoR1 is ubiquitously expressed and exhibits high affinity to the ligand, whereas AdipoR2 exhibits intermediate affinity. ( from pmed id 22450341 )

    Is this another negative feedback mechanism? At low concentrations AdipoR1 would be hit more than AdipoR2 and thus promote leaness, but at higher concentrations of adiponectin I would expect the ratio of R1 hit to R2 hit to be lower such that R2 is hit more, thus slowing metabolism. This feedback mechanism keeps the system stable, such that ever increasing adiponectin doesnt send your metabolism into overdrive.

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    Replies
    1. Hi Kindke,
      Most likely the niacin induced glucose intolerance may cause increased FFA as a symptom of glucose intolerance. I haven't reasearched niacin much to comment more than this, but higher FFA is a sign (and a cause) of it. Adiponectin would be predicted to decrease glucose intolerance, by promoting adipogenesis and fat gain.

      The affinity for receptors makes perfect sense, then. As one gains weight, adiponectin is suppressed, which means receptor 2 will be minimally stimulated. Simultaneously, leptin is overexpressed, and this promotes fat tissue oxidation and maximal metabolic waste.
      As one starves, the fat tissue shrinks, adiponectin is overexpressed and receptor 1 is maximally occupied with more signalling at receptor 2, to slow metabolism. Leptin synthesis decreases as well and metabolism is arrested to a hault.

      Either way, adiponectin has been quite misunderstood by obesity research; it's usually described as "good" and "more the better" when most objective evidence shows adiponectin to be a sort of starvation chemical that helps promote fat growth when it is overexpressed, which is why shrinking fat cells increase the adiponectin.

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  3. You make so many great points here that I read your article a couple of times. Your views are in accordance with my own for the most part. This is great content for your readers. how to achieve ketosis

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