Skeletal muscle serves an important role in metabolic regulation: it is the primary site for glucose disposal in the body. If skeletal muscle fails to dispose of blood glucose the body will spend less time each day in the hypoglycemic state, and will as a result have a lower metabolism. Let’s explore leptin and skeletal muscle in detail.
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Leptin and Skeletal Muscle
Skeletal muscle glucose control is strongly linked to fatty acid metabolism since fats and carbohydrates serve as the primary fuel source for muscle. Fuel selection operates in a seesaw or pendulum fashion. That is to say, if one oxidizes a large amount of glucose, later the pendulum will swing the other way resulting in the oxidation of a large number of fatty acids. This back and forth regulation can be seen at the cellular level.
When excess amounts of fatty acids are oxidized, large amounts of acetyl-CoA are produced. Acytal-CoA inhibits phosphofurctokinase-1 (PFK1), which is the rate-limiting step in the utilization of glucose-6-phosphate (G6P). It’s important to note that transport into the cell, not PFK, is the rate-limiting step in glucose utilization. Once inside the cell however, glucose is converted to G6P, at which point it is added to the pool. PFK-1 does limit the utilization of G6P. So, fatty acid oxidation can inhibit glucose utilization so long as excess glucose is not entering the cell (1).
Glucose oxidation also inhibits fat oxidation. Excess glucose oxidation results in the production of citrates. Citrates inhibit AMPK and thus promote the action of ACC. ACC takes the acytal-CoA that was antagonizing PFK-1 and turns it in to malonyl-CoA, which then inhibits CPT, preventing fat oxidation. It is the acytal/malonyl ratio that determines nutrient usage at rest (2). This ratio is largely mediated by concentration, with glucose being generally favored (thought as we will see this is not always the case).
Obese subjects often begin to store fatty acids in their muscle cells. Known as intra-myocellular lipids (IML), these muscle resident fatty acids are the bane of an obese person’s physiology. Through increased oxidation these fats lead to insulin resistance. What’s more, because of the elongated shape of these fatty acids, storage in the muscle cell often gets in the way of enzymatic reactions. Additionally, increased IML peroxidation by peroxisomes produces cellular hydrogen peroxide and reactive oxygen species that attenuate insulin signaling even further. Coupled with the fact that excessive leptin levels tend to cause insulin resistance, and we are left with a truly frightful scenario.
Excess glucose influx into muscle cells inhibits further uptake by two distinct mechanisms. First, it results in glucose being directed into the hexosamine pathway. Hexosamines then inhibit GLUT4 translocation to the cell membrane and prevent further glucose uptake (3). Second, excess glucose influx sends large amounts of glucose through the glycolytic pathways. This results in a spike in reactive oxygen species—specifically hydrogen peroxide (5). The excessive cellular hydrogen peroxide then inhibits insulin’s signalling cascade and further prevents glucose uptake. This attenuation remains until hydrogen peroxide is buffered by glutathione, cystine or dihydrolipoate (the metabolite of alpha-lipoic acid) (6).
Muscle contraction, NE, and glucagon serve to activate AMPK. This results in non-insulin-dependent glucose uptake in the muscle cells. However, activation of AMPK actually slows cellular metabolism. So in the short term, it mediates glucose disposal, however, in the long term, it can decrease glucose disposal by reducing cellular energy requirements.
Let’s take a moment to step back and summarize. Obviously, the system is meant to operate like a pendulum, vacillating throughout the day between hypoglycemia and hyperglycemia. Problems start to arise when we eat too much food, and in particular when we eat too much fat. As fat cells fill they start to become cholesterol depleted. This promotes VAT growth and causes high blood pressure and poor cortisol metabolism. This results in blood sugar control issues. This subject (even if not yet obese) is spending less and less time each day in the hypoglycemic state, resulting in a suppressed metabolism. However, this situation is still reconcilable. The situation does not go totally awry until leptin resistance sets in. With the onset of leptin resistance, the subject in many ways crosses a point of no return.
Leptin resistance is very interesting; its very existence has in the past been hotly debated, though now it is generally accepted that it does indeed occur. Why was this ever debated ?—because though some of the leptin’s effects disappear with obesity (hence resistance), some are enhanced and/or never completely disappear. This apparent disparity can basically be divided into effects that are caused by transcription (exhibit resistance) and those that are induced by ion channel modulation (don’t exhibit resistance). This should not be surprising. As we discussed earlier, there is a negative feedback path in the STAT signalling cascade (though leptin’s effects on ion channels are not necessarily mediated through the JAK/STAT pathway).
Let’s use the above model to walk through what happens when leptin resistance manifests itself. Leptin’s signalling in the VMH is not dependent on the JAK pathway. In fact, even in the obese, VMH signalling is still reduced by leptin. However, in obesity, there exists so much leptin, even after accounting for reduced BBB transport, that it constantly suppresses firing in the VMH. This totally removes the brakes on the PVN.
Essentially, the VMH-PVN link construes blood glucose to be constantly low. Even though obese people often exhibit hyperglycemia, their brains can’t decipher what’s going on because high leptin concentrations are totally overpowering the glucose signal in the VMH. This is why leptin injections do not do anything for the obese.
So at this point, we have a hyperactive PVN that is just itching to activate the SNS and HPA. Now the PVN can operate in either TRH or CRF mode, an outcome that (as stated before) is controlled by NPY. Now you will recall that NPY creation in the LH is not mediated by leptin directly, as the LH does not possess leptin receptors. Leptin and insulin work together through the ARC to make alpha-MSH, which itself acts to reduce NPY. As you will recall the creation of alpha-MSH is not performed though ion channel modulation, but is instead regulated by PMOC protein transcription. Because of this, it is subject to leptin and insulin resistance. Bingo!
NPY is downregulated, and again the body thinks your starving. NPY interacts with the PVN and switches it into CRF mode. The fact that alpha-MSH is lowered also reduces TRH production, resulting in lowered thyroid hormone. This time around the TRH-TSH systems are indeed the prime determiners of thyroid function, as leptin resistance in the thyroid gland has stopped its regulation at that site. At the same time the PVN is primed to overactivate the HPA. This results in massive increases in cortisol, epinephrine, and in women, elevated androgen levels—symptoms that resemble PCOS or adrenal hyperplasia.
Role of Cortisol and Androgen
Both cortisol and elevated androgen levels promote VAT growth—vicious cycle number one. Elevated epinephrine results in increased blood pressure, which again alters vasculature and ensures that the subject spends more time each day with elevated blood glucose. Epinephrine also reduces insulin-simulated glucose disposal, again keeping blood glucose elevated—vicious cycle number two. Excess cortisol increases muscle protein breakdown, and further slows metabolism—vicious cycle number three.
With the PVN firing constantly the SNS is innervated, releasing NE into the blood stream. Eventually the SNS is over innervated and it receives too much dopamine. This results in the slowing of NE outflow from the SNS so commonly seen in the obese. However, some segments in the SNS that are rarely activated normally, are now getting just the right amount of dopamine to activate—specifically the segments feeding the kidneys. This further promotes high blood pressure, especially in men.
The near constant elevation of CRF brought about by increased NPY causes reduced sex hormone secretion as evidenced above. What makes this state so sad is that ironically all of these changes actually promote more leptin synthesis. Beta-adrenoreceptors (B-AR) are primarily mediated by androgens and thyroid hormone. Androgens determine B-AR density, and thyroid hormone determines their activity at the cellular membrane. Thus the reduction in thyroid hormone and androgens lowers basal lipolysis.
This reduction in lipolysis, accompanied with elevated plasma glucose levels, leads to even more leptin synthesis. So as you can now see, the ridiculously leptin levels are actually sustaining an obese person’s weight. In order to step out of this vicious cycle, the obese subject needs desperately to reduce plasma leptin levels.
References for 'Leptin and Skeletal Muscle'
(1) Hawkins M, Barzilai N, Liu R, Hu M, Chen W, Rossetti L. Role of the glucosamine pathway in fat-induced insulin resistance. J Clin Invest. 1997 May 1;99(9):2173-82. doi: 10.1172/JCI119390. PMID: 9151789.
(2) Winder WW, Holmes BF. Insulin stimulation of glucose uptake fails to decrease palmitate oxidation in muscle if AMPK is activated. J Appl Physiol (1985). 2000 Dec;89(6):2430-7. doi: 10.1152/jappl.2000.89.6.2430. PMID: 11090599.
(3) Diabetes 50:418-424, 2001 Free Fatty Acids Induce Peripheral Insulin Resistance Without Increasing Muscle Hexosamine Pathway Product Levels in Rats Cheol S. Choi, Felix N. Lee, and Jang H. Youn
(4) Salmeen A, Andersen JN, Myers MP, Meng TC, Hinks JA, Tonks NK, Barford D. Redox regulation of protein tyrosine phosphatase 1B involves a sulphenyl-amide intermediate. Nature. 2003 Jun 12;423(6941):769-73. doi: 10.1038/nature01680. PMID: 12802338.
(5) Xu L, Badr MZ. Enhanced potential for oxidative stress in hyperinsulinemic rats: imbalance between hepatic peroxisomal hydrogen peroxide production and decomposition due to hyperinsulinemia. Horm Metab Res. 1999 Apr;31(4):278-82. doi: 10.1055/s-2007-978733. PMID: 10333085.
(6) Bunik VI. 2-Oxo acid dehydrogenase complexes in redox regulation. Eur J Biochem. 2003 Mar;270(6):1036-42. doi: 10.1046/j.1432-1033.2003.03470.x. PMID: 12631263.