One question I've posed is does leptin have an antagonist hormone? Most hormones have complements that act to oppose their action. For example, insulin versus glucagon/growth hormone. As an aside, please recall that growth hormone is primarily a catabolic hormone that turns on the body's fat metabolism, a state we call fasted. Generally an antagonist allows the endocrine system to respond more rapidly than simply waiting for the pertinent hormone's concentration in the blood to clear. Does leptin need an antagonist? Or does it operate over such a long time-span that it normally wouldn't need one? Is the lack of an (apparent) antagonist perhaps one of the reasons leptin metabolism can go screwy?
As an alternative to looking into why leptin makes people fat, I thought it might be interesting to examine how a lack of leptin makes people skinny, or anorexic. Anorexia just
One of the markers that characterizes anorexia nervosa is low circulating leptin levels.
Now, leptin likes to interface with the hypothalamus, which is the part of your brain that essentially acts as an interface between the digital-fast (neural) and analogue-slow (endocrine) control systems of the human body. Lot's of things like to interface with the hypothalamus though, so please do not take this role of leptin as dogma. Together, the hypothalamus and pituitary are the master endocrine organ system, regulating the serum concentration of most of the hormones in your body. Essentially it integrates many different signals, and based on those signals decides what quantity of eight primary hormones to release (i.e. oxytocin, argigine vassopressin, adrenocorticotropic hormone, growth-hormone, thyrotropin (TSH), prolactin, luteinizing hormone, and follicle-stimulating hormone). The hypothalamus plays a crucial role in regulating immune function, metabolism, sex function, and mood/anxiety amongst many others.
The hypothalamus (and the pituitary by extension) tends to release hormones in pulses. When I say the hypothalamus exists on the border between digital and analogue that is nearly literally true. The hypothalamus samples the blood-stream for various feedback mechanisms (i.e. hormones) and when it adds together enough signals that indicate the system needs more growth hormone, it generates a pulse. This is done by the combination of neural and endocrine tissues. Leptin is one of the signals that contributes to whether or not pulses are released from the hypothalamus. If everyone's leptin receptor cells are identical, which is not likely, then low leptin levels will probably down-regulate some of the hypothalamic-pituitary hormones and up-regulate some others, while high leptin levels will do the opposite.
One very common side-effect of AN is the loss of the menstrual cycle (which has the scientific name amenorrhea) The menstrual cycle is initiated by a luteinizing hormone pulse, which implies that very low leptin levels have effects beyond simply regulating fat levels. This is not a surprising result; we would expect the body to shut down non-essential functions when it is starving. This result is correlated to circulating leptin levels (Blüher, 2007). Blüher has some interesting comments on the matter of leptin release:
Leptin secretion can be stimulated by insulin, glucocorticoids (RM: cortisol), and cytokines (RM: immune system catnip) (i.e. tumor necrosis factor [alpha]), whereas catecholamines (RM: "adrenaline"), free fatty acids, cold exposure and thyroid hormones inhibit leptin release [18,19]. Estrogens induce leptin production whereas androgens (RM: male sex hormones) suppress it, providing an explanation for the sexual dimorphism in serum leptin levels . Although anthropometric and clinical features (gender, fat mass/fat distribution, hormones and cytokines) may influence the secretion pattern of leptin, the crucial factor in regulating serum leptin levels seems to be caloric intake and the amount of energy stored in adipocytes .Another side-effect of AN is increased activity (aka hyperactivity), which is a homeostatic method to increase caloric expenditure. This is called activity-based anorexia (ABA) and is one of the primary animal models of anorexia. A review by Hillebrand et al. (2008) shows that leptin itself appears to be signaling the hypothalamus to encourage the brain to engage in this sort of behaviour, and that leptin-replacement therapy suppressed this activity. It's been hypothesized that hyperactivity would promote foraging behaviour in the paleolithic-era and in wild animals. Leptin also has a role in the homeostatic mechanisms behind thermogenesis via the basal metabolism of the thyroid hormones and brown adipose tissue (Rogers, 2009).
This result begs the question, are obese individuals sedentary because they have high circulating leptin levels? Was Gary Taubes, of Good Calories, Bad Calories fame, right in the lack of a relationship between exercise and obesity, even if he didn't know why? If so, hyper/hypoactivity as it relates to leptin would appear to be a case of positive feedback, where the signal tends to reinforce itself over time. It's only because gathering food requires so little energy investment today (get off couch, walk to pantry, grab chips) that this positive feedback cycle blows up so spectacularly. Historically putting on some fat might discourage activity via leptin, giving the organism a rest period.
Now on another front, anorexia nervosa patients who recover from the condition and regain body weight often regain too much and become overweight. This occurred even when caloric-intake and leptin levels were monitored during the body weight gain period to prevent excessive weight gain (Lob, 2003). So once again we see the dominance of the endocrine system and homeostasis over counting calories.
What might cause this higher than normal set-point of body mass index (BMI)? This question does not seem to have a firm answer quite yet so I'm going to speculate. The hypothalamus is a union of neural and endocrine tissue. Neurons, in particular, are quite plastic in that the amount of stimulus you have to apply to get them to fire changes depending on their exposure history. This is how memory is thought to work, for example. My hypothesis is that the neural component of the hypothalamus habituates to long-term leptin exposure.
There are clearly some threshold levels where leptin indicates an organism is in semi-starvation mode and generates compensatory behaviour (Müller, 2009). I can postulate that there may also be hibernation morphology at the top-end of the leptin spectrum. If the organism stays in semi-starvation mode for long enough, perhaps the sensitivity to leptin in the hypothalamus is reduced by the plasticity of the neural component. In this case, a crash weight-gain diet would not give the hypothalamus's neurons sufficient time to change their sensitivity to leptin, and adapt a new set point.
Maybe this is the reason why fast weight-loss programs typically fail miserably. The leptin set points for semi-starvation modes are at at abnormal levels, and pushing leptin through them induces behaviour that likely results in a rebound. The solution then is to be patient and go slow with weight loss or gain. If my hypothesis is correct, losing weight too fast may actually permanently distort leptin regulation.
I was technically morbidly obese in my late teens. In 2008, in 8 months I lost 100lbs. But I as far as I'm aware, fat cell count stays the same after a certain age.
So there's a good chance they're secreting excess leptin. And by your speculation, the fast weight loss may have made things worse.
Weight loss has been hard. The high fat magic didn't work for me. But I can cut calories back by a thousand more of less. So I can steadily lose weight.
Anorexia doesn't mean skinny.
It means not hungry.
This is very contradictory to leptin research though. Injecting rats with leptin makes them anorexic and lose all their weight. Rising leptin levels are associated with decreased hunger, which is the feedback mechanism that creates the set point phenomenon. Likewise, low leptin levels lower body temperature (metabolism) and increase hunger in a normal individual on the other end of that feedback loop.
It's more likely that anorexia stems from endorphin/dopamine addiction which extreme hunger stimulates. When an anorexic eats, they get withdrawal symptoms from these biochemicals which perpetuates the behavior. Yes, it is most definitely physiological, but I don't think it involves leptin on the appetite front.
More on leptin:
I hear you. There could be many things going on and at the moment we just don't understand enough about leptin. It was only discovered in 1994! So for the moment we have to settle for well-conceived (or ill-informed, depending on your point of view) speculation.
Leptin replacement therapy is an obvious treatment that I'm sure will become more common in a few years, in the same way that T4 supplementation is a valid way to treat hypothyroiditis.
For example, the cells that are receptive to leptin in the hypothalamus are very specific. Perhaps these cells are being destroyed (say by the adapted immune system via autoimmunity), or something in the diet is acting as an enzymatic inhibitor to the leptin receptor, etc. This would be analogous to the destruction of very particular dopamine secreting cells in Parkinson's disease.
Sorry if this causes you some angst but I figure people need information and discussion of the facts as we know them today can only help elucidate the true nature of the problem in the future.
You are correct, sir. I will make a correction.
Yes historically dopamine has been seen to have a role in anorexia nervosa, but it does not appear to affect hunger directly. For example, in the 4. Discussion section of Verhagen et al. (2009a), the authors state that, "We are not aware of reports on dopamine release when normal chow is presented to food-deprived animals. However, while general activity levels are strongly reduced after treatment with cis-flupenthixol, food-restricted rats still exhibit food-anticipatory activity (Fig. 5). If cis-flupenthixol effectively antagonized dopamine receptors in the rats in the present study, then this argues against involvement of dopamine in anticipatory activity in this model. This is in agreement with a study by Mistlberger and Mumby. They found that treatment with a selective dopamine D2 receptor antagonist, haloperidol, reduced activity levels but food anticipation maintained (Mistlberger and Mumby, 1992 R.E. Mistlberger and D.G. Mumby, The limbic system and food-anticipatory circadian rhythms in the rat: ablation and dopamine blocking studies, Behav. Brain Res. 47 (1992), pp. 159–168. Abstract | View Record in Scopus | Cited By in Scopus (37)Mistlberger and Mumby, 1992). We extended this finding by showing that also a mixed D1/D2 dopamine antagonist has a similar effect." This to me strongly suggests dopamine does not effect hunger.
Also see Verhagen et al. (2009b), which suggests leptin and not dopamine is responsible for hyperactivity. On the topic of thermogenesis, see Lechan (2004) and Lechan (2006) which discuss the role of leptin in the release of TRH and hence the hypothalamic-pituitary-thyroid-liver axis.
I am unclear on why you feel that rats injected with leptin becoming skinny is contradictory. If leptin concentration reflects fat cell fullness, and high leptin levels suppresses appetite, then rats injected with leptin should eat less ab lib.
'As an alternative to looking into why leptin makes people fat, I thought it might be interesting to examine how a lack of leptin makes people skinny, or anorexic. '
Leptin doesn't make people fat. The obese have high circulating levels of leptin; and develop leptin resistance as a consequence of this prolonged elevation. Their brains do not sense leptin and decrease hunger correspondingly, as would have been the case with normal leptin sensitivity.
Skinny people/anorectics have low leptin as a result of having depleted their fat deposits which produce leptin. Low leptin is the consequence of low fat mass, not the other way around.
i am a recovering anorexic, and as such have been doing a hellofalot of research on anorexia and the leptin-hormone-pituitary-hypothalamus connection. i have the recent endocrinology & metabolism book and am slowly getting through it.
anyways, my main question is with exercise increasing leptin sensitivity vs carbohydrate feeding and leptin recovery.
it seems through my reading and research that the 'carb refeeding' should restor leptin and thus regulate or up regulate hormones and hopefully mend the connection between my brain and body?
i normally eat a high fat, low carb, mod protein paleo diet so the whole 'carb refeeding' is sending me for a loop and i am trying to piece together research.
i know injected leptin will cure my ammenhorrea but for thousands of $$ a week for it i am looking to carb sources, preferably paleo to help. my only starting point is i know fructose is not used for leptin release but used in the liver.
I am interested in this topic because I have ceased menstration since becomIng paleo. I also and a convert from a vegetarian of 10 years to a meat eater now since becoming paleo. I think I have this hypothalamic amenorrhea. Does anyone know any medical doctor or someone who can help me with this??
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