Figure 5.1 Leptin Receptor Signal Cascade.
From this diagram you can see that there are three feed forward signal propagation pathways. Specifically the PhosphatidyIinositol 3 Kinase (PI3K) pathway (7), the Janus Kinase (JAK2)/Signal Transducers and Activators of Transcription (STAT3) pathway (6), and finally the Mitogen-Activated Protein Kinase (MAPK) pathway (8).
The first thing you should notice is that activation of the Suppressor Of Cytokine Signaling (SOCS3) pathway (shown in red) forms a negative feedback path in the JAK2 signaling cascade. This is of the outmost importance as it, along with another enzyme called Protein Tryosine Phospatase 1 Beta (PTP1B), is the prime culprit causing leptin resistance in the obese.
Another thing that might be apparent if you are familiar with insulin signaling is that both the PI3K and the JAK2 pathways are part of insulin’s cascade. As I alluded to in the last installment, there is significant cross talk in the leptin and insulin signal cascades. Therefore insulin resistance leads to leptin resistance, and vice versa. This is of the utmost importance for the obese. Keep this in the back of your mind for the time being, as it will be important when we discuss leptin’s effects on the obese.
The next subject we should discuss is that final box at the right hand side of the figure that says “Gene Transcription & Ion Channel Modulation.” Leptin can have fast acting or slow acting effects on cells; it can act slowly by causing gene transcription, which leads to various proteins being made, or it can act very quickly by modulating ion channels, thus altering the firing rate of various neurons. Because of this it’s always important to keep the temporal effects of leptin signaling in mind. It might also be useful to conceptualize its actions from the perspective of the big picture, as well as the small picture.
In other words transcription handles the bigger things like hunger, sex hormones, thyroid status, etc., whereas the ion channel modulation is more geared toward the regulation of the smaller picture (insulin control, lipolysis, etc.). Please be aware that this is not technically correct. There is much cross over between regulation of the small and big picture. However, conceptualizing leptin’s effects in this manner may help keep things organized in your mind for the time being until you start to see the interplay between all of the systems.
So at this point in time if your head isn’t spinning you’re a whole lot smarter than I am. It took me forever to piece this stuff together. But if you don’t get it just yet don’t worry about it.
With that out of the way we can finally begin our discussion of leptin’s effects on the hypothalamus. However before we can do so we have to introduce some new players in our friendly game. Specifically, its time to move beyond discussing leptin by itself and start discussing it in relation to brain glucose levels and insulin.
I am Jack’s Overworked Hypothalamus
It’s all about brain, baby! More specifically, it’s all about control of the brain’s glucose supply. What we are about to learn is that pretty much everything the brain does it does for two reasons. The first motivation is to keep the brain glucose levels in an optimum range. Secondly, provided the first need is met, the brain does just about everything it can to keep your sex organs functional. This makes perfect evolutionary sense. Biological imperative number one is survival and number two is propagation–everything else is secondary. What is really fascinating is when you extend this line of reasoning you really start to see that the body did not evolve equally; it’s not balanced. Basically every system favors the brain over the body. Essentially everything in your body functions to keep your brain’s glucose levels where they need to be (9).
Remember those glucose sensitive (ATP-K) neurons we discussed just a minute ago? Well this is important and it may not have struck you just yet, so I will spell it out. Because those special neurons change their firing rate in relation to glucose levels, the result is that glucose is not just a fuel source, it is a hormone! Surprise… yes that delicious pasta, that lovely chocolate bar—they are not just fuel for your body, they signal and modulate all sorts of stuff in your brain.
So with in mind let’s examine the manner in which insulin, leptin, and glucose interact with the hypothalamus to control the brain’s glucose supply, and in an indirect way end up controlling everything else.
We will start our discussion of the brain’s glucose control with the Ventro Medial Hypothalamus (VMH) and the Para Ventricular Nucleus (PVN). From this point forward, when we discuss things in the brain, you can safely assume that leptin and insulin exhibit almost identical behavior. This is interesting in and of itself, as in the rest of the body leptin and insulin have opposing actions on most tissue. Essentially, you have this object called the VMH sitting in the back of your brain, and it is responsive to both glucose and leptin. The VMH is littered with Kir6.2 neurons (4). It is primarily responsible for the very immediate effects brought about by hypoglycemia (lower brain glucose levels); the VMH is also responsible for the release of EPI and N-EPI primarily to the liver, as well as adipose tissue (10).
Figure 5.2: VNH/PVN Control System.
Leptin acts to lower the firing rate of the neurons in the VMH where as glucose does the opposite, as shown in figure 5.2 above. This makes perfect sense. When your brain’s glucose levels are low, the normal excitation that glucose exerts on the neurons is removed and leptin becomes the dominant signal. Thus the firing rate will lower, which leads to EPI and N-EPI release. This causes glucose and fatty acids to be released into the bloodstream by the liver and adipose tissue, respectively. A decreased firing rate will also cause a release of EPI near the pancreas, bringing down insulin levels. The lowering of insulin serves to keep muscle and fat from stealing the glucose the brain desperately needs. It’s important to note at this point that brain glucose uptake is not mediated by insulin as it is in muscle and fat. Brain glucose transport is controlled by GLUT1; it is not mediated by insulin like GLUT4 is in muscle and fat tissue. Thus, when the VMH lowers insulin, it is purposefully directing glucose to the brain and simultaneously away from muscle or fat tissue.
At this point you should be able to connect the first set of dots and see how this relates to dieting. When you first start a diet your brain thinks you are hypoglycemic because of your reduced caloric intake. As a consequence, glucose signaling at the VMH lowers, and the leptin signal wins out in their oppositional battle. This decreases the firing rate of the neurons, causing EPI and N-EPI to be released. This is great, as you’re in prime dieting mode now, burning up fat and getting lean. The problem is that as time goes by, leptin levels also start to lower as a result of reduced calorie intake. When this happens, leptin is no longer available to decrease the firing rate of the neurons in the VMH. Because of this, the release of EPI and N-EPI slows down and your dieting progress plateaus. Fascinating don’t you think? You finally have a scientific explanation for why standard calorie restricted dieting doesn’t work.
Most of the effects of the VMH are actually carried out by another part of the brain called the Para Ventricular Nucleus (PVN) (11). Many of the nerves that are being modulated by leptin and glucose are hardwired to the PVN and help it to carry out its duties, which it executes primarily by lowering GABA tone (12), though dopamine, serotonin and histamine are also involved. In other words, reduced firing means less GABA is delivered to the PVN. You may have been slightly confused by the above paragraph, specifically the notion that REDUCED firing leads to more EPI and N-EPI release. This is where the PVN comes in to play. The PVN drives many different systems, though all of them are related to low brain glucose. The PVN normally wants to run full throttle, pumping out all types of things to flood your blood stream with glucose. It’s the constant firing of the VMH neurons that keep it from doing this. Basically the VMH acts as a brake, making sure the PVN does not run wild. This makes sense, as GABA is a relaxing neurotransmitter, and thus acts to lower the firing rate of the neurons in the PVN.
The PVN is not just responsible for telling the SNS to release EPI and N-EPI. It also sends the adrenal medulla into action as well. The adrenal medulla is the gland that manufactures EPI (a.k.a. adrenaline) as well as cortisol. Cortisol is quite lipolytic, yet excessive cortisol release is as we know a chief source of diet-induced muscle loss. The PVN is likewise responsible for signaling the pituitary to lower TRH, GnRH, and LH, which decreases thyroid hormone production and test levels. The PVN also causes the pituitary to release growth hormone, so now you also know what is responsible for its fasting-induced increase.
The PVN is additionally responsible for causing the pituitary to release a peptide called vascular endothelial growth factor (VEGF). Now you should be asking, “What in god’s name is my brain doing releasing a growth factor while it thinks it’s starving?” Well, this is a very special growth factor. VEGF up regulates GLUT1 content in the blood to brain barrier. At the same time it’s slowing metabolism and releasing every hormone in the toolbox that’s lipolytic and glycolytic, it’s upregulating its own nutrient-transport proteins. The brain is at this point doing everything in its considerable power to funnel every last bit of nutrition toward securing its proper functioning. The brain is essentially harvesting the body to ensure its own survival.
Next up on our journey through the brain is another similarly intertwined pair: the Lateral Hypothalamus (LH) and the Arcuate Nucleus (ARC). The LH is a little more interesting than the VMH. It contains mostly Kir6.1 neurons, but it also has some Kir6.2 neurons as well. Recall from above that kir6.2 neurons like those in the VMH increase their firing rate in the presence of glucose. The Kir6.1 neurons are the opposite; they increase their firing rate at very low glucose levels but become almost completely inactive at higher levels. So this means that the LH basically behaves in a manner opposite of the VMH; the LH will decrease its firing rate in the presence of glucose. However, because there are some (around 5%) Kir6.2 neurons, the glucose-induced suppression of firing never completely goes away in the LH (13). Also of interest is that the LH does not have leptin or insulin receptors, unlike the VMH.
So what does the LH do? Well, I am glad you asked. The LH is that evil area of the brain that creates orexigenic peptides (14); namely, Neuro-Peptide Y (NPY) and Agouti-Related Peptide (AgRP). Now take a second and ponder that. The pesky 5% of Kir6.2 neurons exist for a reason. That reason is to make you hungry even when you have plenty of glucose. If that’s not proof of the thrifty phenotype I don’t know what is. Your brain is basically telling you to keep eating even when it senses that you’re full. Now that’s messed up!
As I am sure you are well aware, leptin does modulate hunger. So how does it affect the LH? Well this time it has to take an indirect route, as there are no leptin receptors in the LH. Leptin’s effect on the LH is instead modulated through the melanocortin system. When leptin enters the brain it binds to the OB-Rb receptor on yet another set of neurons called the pro-opiomelanocortin (PMOC) neurons, located in the Arcuate Nucleus (ARC)(15). By binding to the PMOC neurons in the ARC, leptin activates the JAK2 pathway as shown in figure 5.1 (16). This causes PMOC protein to be produced. Just to be clear there are PMOC neurons and PMOC protein—they are not the same thing. PMOC neurons make PMOC protein.
There is a special peptide called alpha-Melanocortin Stimulating Hormone (alpha-MSH). Alpha-MSH is a chuck that is broken off of the PMOC protein, at which point alpha-MSH wanders over to the LH, where it binds to the M4 receptor and lowers neuron firing rate. This in turn lowers those nasty orexigenic peptides as shown in figure 5.3 below (17). It’s worth mentioning at least in passing that there are some other substances that modulate the LH apart from leptin and glucose; namely, orexins and glutamate (16). However, their importance pales in comparison to that of leptin or glucose. Also worth noting is that, in the ARC, leptin also causes the release of Cocaine and Amphetamine-Related Transcript (CART) which is another anorexic neuropeptide. However it appears that alpha-MSH is the main regulator here.
Figure 5.3: LH Control System.
So let’s connect the next set of dots. When we diet our brain glucose lowers, thus the inhibition on the LH is partially lifted. As a result you start to get a bit hungrier then normal. As time passes your leptin levels begin to plummet. This results in a lowering of alpha-MSH, which serves to almost completely remove the brakes on the LH, causing massive upregulation of NPY and AgRP. Of course it only stands to reason that this is the prime cause of the sinister and dreaded “Cocoa Puff madness” that afflicts so many of our brethren.
Clearly leptin and glucose are your friends. More importantly, leptin is simply screaming to be positively manipulated. After all, the initial decrease in glucose signaling that accompanies caloric restriction isn’t particularly deleterious, and in some ways even aids us by releasing lipolytic hormones. With some intelligent supplementation we should be able to handle the few downsides like excess cortisol, decreased testosterone and suppressed thyroid hormone. The real problems only take hold when our leptin levels plummet. Being both hypoglycemic as result of calorie restriction and having low leptin levels basically causes all hell to break lose.
Well that’s all for this installment. In the next issue we will pick up where we left off and see where the system breaks down. We will specifically look at those who are not already lean, as their problems are distinctly different than those a dieting bodybuilder might experience. As always, should you have any questions I am available in the Avant Labs online forum to answer them. So until next time this is your humble author Spook signing off.
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