A good place to start our discussion is with the Sympathetic Nervous System (SNS). So, we’ll be discussing here Leptin and Sympathetic Nervous System (SNS). The SNS is just a fancy name for a bunch of nerve fibres that run throughout your body. It just so happens that these nerve fibres deliver potent chemicals called catecholamines to the various tissues of your body. Specifically, I am referring to epinephrine (EPI) and nor-epinephrine (N-EPI). These are those wonderful chemicals of which I am sure you are all aware. They are affectionately referred to as beta-adrenoceptor agonists; they are the chemicals that make Ephedra work its magic.
Well as it turns out leptin exerts much of its effects on body composition via the SNS. When for instance rats have their SNS artificially deactivated leptin fails to do its job (1). No fat burning, no lipolysis, nothing. So that’s clue number one that most of the leptin’s effects are somehow related to the nervous system and the brain, and not so much by the direct tissue effects that we explored in the last instalment. Not that those effects are not important it’s just that the brain, well…. It’s always more important, as we will soon see.
What Will You Read Here?
Leptin and Sympathetic Nervous System
What is really interesting is that the good doctors were kind enough to examine exactly where the SNS was activated by leptin (2)(3). As previously stated leptin activates the SNS and causes it to release EPI, and N-EPI. However, unlike the carpet-bombing approach of Ephedra, leptin’s actions are more like a surgical strike. Ephedra causes the indiscriminate release of EPI and N-EPI from nerves all over the body. Not so with leptin.
Leptin is somehow smart enough to up-regulate EPI and N-EPI in precisely the right tissues. It causes EPI and N-EPI to be released at points near fat tissue, muscle tissue, and the liver. Yet leptin avoids causing release of these chemicals near the heart and blood brain barrier; it avoids causing EPI and N-EPI release in areas that are known to be responsible for most of the potentially negative side effects associated with Ephedra. So with leptin one receives the best of both worlds: increased lipolysis, with little to no side effects. Now however we must ask the all-important question: “How in the hell does leptin do that?” Which leads us perfectly to our next topic…
An Axon and a Dendrite Walk In To a Bar…
Enter the whimsical world of the hypothalamus, that magical little computer inside your brain that seems to control just about everything. Hold on to your seats folks because things are about to get complicated. But don’t fret, as I will take it slow and move you through it step by step. There are even pretty pictures, this time around.
Before we can jump in to our discussion of the hypothalamus it would be beneficial to digress for a moment and talk about adenosine-tri-phosphate sensitive potassium channels (ATP-K channels), as I figure most of you are not aware of their effects. However if you are already familiar with these little fellows then feel free to skip ahead.
How A Nerve Cell Works?
The way that a nerve cell works is that it builds up a voltage across its cellular membrane by separating potassium on one side and sodium on the other. This basically creates a tiny battery as each has a slightly different electrical charge. When the nerve cell fires it opens up its potassium gates; this is just like connecting a circuit to a battery. When this happens an electrical current flows down the length of the nerve till the battery is discharged. Then the cell can start the process all over again. The body controls the firing of nerves by controlling those potassium gates—they act just like a switch in an electrical circuit.
Recently it has been discovered that there are special kinds of nerves that have unique potassium gates. These nerves are members of the potassium (K+) inwardly rectifying channel subfamily (KIR6.0). Two very unusual members of this family of nerves are KIR6.1 and KIR6.2. These two types of nerves are often called glucose responsive or glucose sensitive neurons (4); they contain a unique type of potassium gate called an ATP sensitive potassium channel (ATP-K channel). What is interesting about these nerves is that they will close (hyperpolarize) or open (depolarize) their gates. Meaning they will fire less or fire more, respectively. This opening and closing of the gates is controlled directly by the ATP levels, and more importantly brain glucose levels.
I hope you are aware that I am not droning on about this boring material because I think it’s fun (ok maybe a little). There is a reason. You see the hypothalamus is literally brimming with these ATP-K neurons. Also of interest is that many of these neurons express the long form leptin receptor (OB-Rb)(5). However they also seem to express some of the short forms as well. Thus far we have only discussed the long form receptor in any detail, however the short forms will soon become important so just keep them in the back of your mind for now.
I think it’s necessary that before we move on we take a closer look at leptin’s signaling cascade. Below in figure 5.1 you will find a pictorial representation of leptin’s signaling cascade initiated through the long form (OB-Rb) receptor.
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.
Concluding Leptin and Sympathetic Nervous System
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.
Refernces for Leptin and Sympathetic Nervous System
(1) Dobbins RL, Szczepaniak LS, Zhang W, McGarry JD. Chemical sympathectomy alters regulation of body weight during prolonged ICV leptin infusion. Am J Physiol Endocrinol Metab. 2003 Apr;284(4):E778-87. doi: 10.1152/ajpendo.00128.2002. Epub 2002 Dec 27. PMID: 12626326.
(2) Gerendai I, Halász B. Central nervous system structures connected with the endocrine glands. findings obtained with the viral transneuronal tracing technique. Exp Clin Endocrinol Diabetes. 2000;108(6):389-95. doi: 10.1055/s-2000-8134. PMID: 11026751.
(3) Jansen AS, Hoffman JL, Loewy AD. CNS sites involved in sympathetic and parasympathetic control of the pancreas: a viral tracing study. Brain Res. 1997 Aug 22;766(1-2):29-38. doi: 10.1016/s0006-8993(97)00532-5. PMID: 9359584.
(4) Miki T, Nagashima K, Seino S. The structure and function of the ATP-sensitive K+ channel in insulin-secreting pancreatic beta-cells. J Mol Endocrinol. 1999 Apr;22(2):113-23. doi: 10.1677/jme.0.0220113. PMID: 10194514.
(5) Spanswick D, Smith MA, Groppi VE, Logan SD, Ashford ML. Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels. Nature. 1997 Dec 4;390(6659):521-5. doi: 10.1038/37379. PMID: 9394003.
(6) Tartaglia LA. The leptin receptor. J Biol Chem. 1997 Mar 7;272(10):6093-6. doi: 10.1074/jbc.272.10.6093. PMID: 9102398.
(7) Rahmouni K, Haynes WG, Morgan DA, Mark AL. Intracellular mechanisms involved in leptin regulation of sympathetic outflow. Hypertension. 2003 Mar;41(3 Pt 2):763-7. doi: 10.1161/01.HYP.0000048342.54392.40. Epub 2002 Dec 16. PMID: 12623993.
(8) Shibuya I, Utsunomiya K, Toyohira Y, Ueno S, Tsutsui M, Cheah TB, Ueta Y, Izumi F, Yanagihara N. Regulation of catecholamine synthesis by leptin. Ann N Y Acad Sci. 2002 Oct;971:522-7. doi: 10.1111/j.1749-6632.2002.tb04517.x. PMID: 12438173.