Welcome all seeking refuge from low carb dogma!
“To kill an error is as good a service as, and sometimes even better than, the establishing of a new truth or fact” ~ Charles Darwin (it's evolutionary baybeee!)
I've never seen any evidence of it. Leptin and insulin converge on some of the same intracellular signaling pathways in the brain, so they should be additive or synergistic. The closest thing I've seen to support this idea is a cell culture study that showed chronic insulin treatment upregulated SOCS3, which is a negative regulator of leptin action. There's also a study showing that deletion of the insulin receptor in SF1 neurons in the VMH protects against obesity.NIRKO mice are fat, the opposite of what you'd expect if insulin was antagonizing leptin signaling in the brain overall. Insulin has never been shown to antagonize leptin in vivo to my knowledge.
Chris Masterjohn has a post to suggest otherwisehttp://blog.cholesterol-and-health.com/2010/11/is-insulin-resistance-really-making-us.htmlAnd insulin may increase leptin transporthttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2246012/?tool=pubmed
http://www.slideshare.net/ancestralhealth/ahs-slidesrobert-lustigSlide #39 Lustig cites a paper showing that leptin and insulin have opposite effects on (some) POMC neurons. The POMC is of crucial importance in regulating appetite and energy balance; there are some forms of severe obesity which are caused exclusively by a single mutation of a functional melanocortin receptor. Leptin depolarizes all POMC neurons. On the other hand insulin hyperpolarizes some POMC neurons. Both leptin and insulin however induce a fed state marked by an inhibited AGRP (function of POMC) but it seems evident that insulin is directly blocking this potent effect of leptin as if we functionally evolved for high insulin to temporarily block leptin. http://www.jneurosci.org/content/30/7/2472.shortAnother paper describing this.In slide #40 Lustig cites a paper which more directly shows that insulin directly inhibits leptin signalling; that is as long as insulin is elevated the functions of leptin are inhibited.The paper referenced can be found here:http://www.ncbi.nlm.nih.gov/pubmed/11596667And n=1: I was treated with leptin after massive weight loss. My basal leptin levels were severely low for a reproductive aged female (between 1-2). My insulin levels were not measured but must have been extremely low (leptin that low is consistent with profound body fat atrophy and almost no insulin acting on fat tissue as if one is either starving or if they have no fat cells at all to receive an insulin signal - only anoretic patients or lipodystrophy patients have leptin levels like this.The leptin produced powerful anorexia and increased metabolism and I kept losing weight much more than the other participants eating a normal diet; these other participants were never obese mind you. They had to reduce my dose to the lowest possible and I was threatened if I didn't stop losing weight I would be discontinued from therapy. I did not try to lose weight I was leptin hypersensitive apparently, probably due to the fact my diet is profoundly insulin suppressive.If I ate normal food (carbohydrate) I would become very hungry and lethargic as if I were not taking leptin at all, this was true even in the context of leptin therapy. On leptin, off leptin, my metabolism (appetite + energy) fails all the same. Leptin therapy only helps obesity in that it allows me to handle more glucose before hyperinsulinemia sets in.Furthermore my experience as an obese person was to respond to a ketogenic diet with incredibly anorexia and rapid weight loss. It was like flipping a switch in my body. If I was innately leptin resistant (so conventional wisdom / hypothesis of obesity would suggest) I cannot understand how my entire metabolism (appetite + energy) would change by avoiding foods that require significant insulin.I expect the usual suspects to come and sing the praises of glorious insulin the magical anti-obesity hormone so I will take a chance and try to interject my clinical research and personal experience and support the lustig hypothesis which is entirely correct from my vantage point.Furthermore the logic that fluctuations in glucose tolerance -> hyperinsulinemia -> functional inhibition of leptin signaling providing a selective advantage is entirely logical and fits in the overall framework of what we understand of the endocrinology and neurology of obesity. Many animals and humans become temporarily glucose intolerance and hyperinsulinemic and this is associated with (PRECEDING) weight gain as in puberty, pregnancy, seasonal change (dark season: +melatonin and -dopamine = glucose intolerance and weight gain) or a precipitous rise in stress hormones of other cause. The body preemptively triggers a thrifty metabolic state to respond to anticipatory nutrient depletion/stress (e.g. winter or sudden rise in stress hormone of psychogenic/physical origin) or increased nutrient demands (e.g. fetus/puberty/rapid growth).
If NIRKO mice are fat this only proves that pathological hypoinsulinemia promotes a thrifty metaoblic state which no one will argue (hypoinsulinemia = protein deficiency, caloric deficiency, you are STARVING to death. No one on a diet full of low carb calories is hypoinsulinemic!) NIRKO mouse does NOT provide any evidence what so ever that hyperinsulinemia prevents obesity because hypoinsulinemia is not hyperinsulinemia. Surprise: hormone and nervous system signals do not always have a linear positive cumulative effect. Sometimes the exact same molecule can have an opposite effect on physiology depending on its concentration. Evolution is KEWL LIKE THAT.For example low levels of progesterone (as is found during natural menstrual cycle) promote diuresis by antagonizing aldosterone receptor. High levels of progesterone do EXACTLY THE OPPOSITE and promote massive water retention by spiking cortisol levels (progesterone is a primary substrate for cortisol) and other mechanisms. The modern perinatal complication known as polyaminos (excessive amniotic fluid) is related to progesterone mediated / cortisol mediated glucose intolerance and a resulting extreme accumulation of amniotic fluid. This complication is associated with diabetes and also commonly occurs with macrosomia (macrosomia, or large body, which is the fetus expressing the effects of maternal diabetes i.e. hyperglycemia, which results in very high insulin levels acting on the fetus to induct IGF-1 and cause extreme body growth. It is polar opposite to the presentation of fetus with congenital insulin receptor deficiency known as donahue syndrome, as these infants cannot induct IGF-1 due to having an insulin receptor that is only 15% functional and so are born dwarfs in spite of tremendous hyperinsulinemia). Donahue syndrome infants are especially devoid of fat tissue development for this reason.Another example: Dopamine is known to be involved in wakefulness and one requires a minimum level of dopamine activity to be alert. The condition of "adhd" is treated with dopaminergic stimulants (which really often just glucose intolerance dopamine receptor downreguation and so one cannot focus or stay alert). However there is a critical threshhold of dopamine that promotes sleep and dreaming. Taking a stimulant (dopaminergic) will keep you alert and awake, but wouldn't you be surprised to find out that parkinson's patients cannot sleep AT ALL and cannot dream? You can't just say "well no insulin in the brain = obesity so that means hyperinsulinemia is the gateway to slimness". I would hope a doctor of obesity research would be more familiar with physiology and would know understand that one cannot automatically assume the same endocrine signal has a linear effect at high and low intensities.Our endocrine and nervous system was designed by evolution to capitalize or respond to environment. Hypoinsulinemia is a radically different condition than hyperinsulinemia so do not be surprised if our physiology treats them as such. Hypoinsulinemia suggets starvation and hyperinsulinemia suggests seasonal nutritional excess.
CarbSane I think this paper should help you out a bit. Its full free text.If NIRKO mice are fat it could be because Agrp insulin receptor knock-out means you fail to suppress hepatic glucose production on that yummy chow.
Thanks for weighing in here Stephan. I'd add that non-obese hyperinsulinemic LIRKO also seem to counter this latest version TWICHOO ... LWIFLTOO (grin). I have other interests at the moment so I thought I'd put this out there rather than sorting through the literature myself.
Thanks Steven! That was a great post by Chris.The fact that insulin resistance is not found in all obese people does not mean it plays no causal role, because obesity does not necessarily have the same cause in every person. Put that paper in the Library for another day too.
Thanks for those cites Wooo. It was actually a statement by Lustig in a talk I was viewing yesterday that prompted this question. He specifically says that "the work that we've done shows insulin blocks leptin at the brain". Nobody, to my knowledge, denies there's a relationship between insulin and leptin action, but neither of those papers indicate that insulin binds leptin receptors blocking leptin and/or that somehow insulin blocks leptin transport into the brain (hypothalamus). The first paper discusses different actions on different neurons for leptin and insulin. The second paper specifically talks about "post receptor" action. I note that in that second paper, they are talking about a *hypothesis* of how IR and profound hyperinsulinemia cause leptin resistance. I thought there was no such thing as LR. Nothing deceptive about my question. No need for the shadow blogging. Civil comments such as this are always welcome on my blog.
Very interesting paper! Another role for the benefits of adipocyte insulin action via fatty acids. Thanks! P.S. Was the closing snark really necessary?
"High levels of progesterone do EXACTLY THE OPPOSITE and promote massive water retention by spiking cortisol levels (progesterone is a primary substrate for cortisol) and other mechanisms."From Progesterone - Biosynthesis:- "Progesterone in turn (see lower half of figure to the right) is the precursor of the mineralocorticoid aldosterone, and after conversion to 17-hydroxyprogesterone (another natural progestogen) of cortisol and androstenedione. Androstenedione can be converted to testosterone, estrone and estradiol."Progesterone is a substrate for several hormones other than cortisol. Cortisol production is controlled by ACTH level. I'm not convinced that cortisol level rises in proportion with progesterone level. I think that ACTH level decreases when progesterone level increases, stopping cortisol level from rising excessively.During pregnancy, progesterone level increases a *lot*. Does cortisol level increase a *lot*? I think not. It does increase somewhat. There's also cortisol-binding globulin, which regulates free cortisol level.
@NigelI stated that low levels of progesterone in the early luteal phase of the menstrual cycle promote sodium wasting and diuresis by antagonizing the aldosterone receptor.High levels during pregnancy promote massive fluid retention.cortisol dose increase significantly during pregnancy, this is an endocrinological fact. You are correct that the endocrine system adjusts whenever cortisol levels increased but the need for cortisol is adjusted upward in pregnancy. However it still remains simple physiological fact most progesterone turns into cortisol.Megastrol acetate is a synthetic progestin used to treat cachexia as part of cancer especially (it is antineoplastic due to the fact progesterone is largely dumped into cortisol synthesis - cancer patients are placed on dexamethasone to inhibit cell replication rates). Megastrol acetate or "megace" is molecularly identical to progesterone and can cause adrenal suppression due to the fact it basically is metabolized as cortisol.
Is this of any use:
Hah! Of course, I forgot to provide the link!http://www.ncbi.nlm.nih.gov/pubmed/21422382
That's an interesting paper euler. I'm going to have to blog on this separately. Putting it in the library to get back to someday!
Just saw this:http://www.ncbi.nlm.nih.gov/pubmed/11566073
Moderation is currently on. Thanks in advance for your patience.