One way in which leptin aids in fat loss is by its direct effects on skeletal and cardiovascular muscle. Let’s read about leptin and muscle tissue. Muscle cells express the long-form leptin receptor (Ob-R). This is the receptor that is responsible for initiating leptin’s signaling cascade through the JAK pathway when it interacts with various tissues. In very simple terms, leptin causes your muscle cells to utilize fat instead of carbohydrates for energy. To properly address this phenomenon we must digress for a moment to briefly describe the system that regulates substrate utilization at the cellular level.
What Will You Read Here?
Leptin and Muscle Tissue
Inside the muscle cells in your body are small organelles called mitochondria. The mitochondria create the majority of the energy our cells need to operate, in the form of ATP. For various reasons that are to complex to delve in to in this article, our mitochondria tend to use mostly fat or mostly carbohydrates for energy production, but they tend not to use both of them at the same time. This issue is an interesting one that I hope to provide a full examination of in the future, but for now you will just have to take your humble author’s word for it. In essence, your cells will use fat or carbohydrates but not both at the same time.
The choice of fuel selection is controlled in large part by a protein called, acetyl-CoA carboxylase (ACC) (1). On the surface of the mitochondria’s membrane is another protein called carnitine palmitoyl transferase (CPT). You can think of CPT as a doorway for long-chain fatty acids to get inside the mitochondria. If CPT can’t get those long-chain fatty acids in to the mitochondria, then they can’t be oxidized (2). CPT transfers a fatty acid in to the mitochondria by binding to the acyl end of a fatty acid acyl complex.
Essentially, there is this substance called acytal-CoA that is floating around in your cells. When it comes time to burn fat the acytal-CoA is grafted on to the end of a fatty acid, forming an acyal-FAT complex. CPT latches on to the acyl part and transports the fat into the mitochondria to create around 140 ATP molecules per fatty acid. ACC creates a product called malonyl-CoA by acting on acytal-CoA. Malonyl-CoA is a competitive inhibitor of the acyal-FAT complex. It binds to CPT, thus preventing CPT from doing its job of transporting the real fat into the mitochondria.
As you can see, if we wish for our cells to keep burning fat, we need to make sure there is as little malonyl-CoA as possible. To keep malonyl-CoA content low we need to stop ACC from creating this compound. Luckily our body has a way of doing just that. There is yet another protein called AMP-Activated Protein Kinase (AMPK). This proteins job is to deactivate ACC. In other words:
AMPK activation = ACC deactivation = less malonyl-CoA = more fat oxidation.
AMPK deactivation = ACC activation = more malonyl-CoA = less fat oxidation.
Great, this is just what we were looking for. Now we are ready to see how leptin affects these enzymes and optimizes fatty acid oxidation.
When skeletal muscle was incubated in a serum with leptin, AMP-activated protein kinase (AMPK) was activated (12,13). When AMPK is activated it inhibits ACC thus reducing malonyl-CoA. This reduction in malonyl-CoA frees CPT to do its thing and transfer long chain fatty acids in to the mitochondria where they can be used to produce ATP.
Additionally, chronic leptin administration not only activated AMPK but also increased the amount of AMPK in muscle cells. So you can see this is of great benefit. This also makes sense from a physiological perspective, as leptin is signaling the rest of the body that there is ample fuel stored in your fat cells. This signal lets the muscle know that there is ample fat so it should use fat as its primary energy source.
Leptin’s activation of AMPK and concurrent increase of AMPK concentration also promotes a lean physique through mechanisms other than just short-term usage of fat for fuel. Chronic AMPK activation is also implicated in the mechanisms responsible for several of the adaptations muscles undergo in response to chronic exercise. Specifically, chronic AMPK activation upregulates a protein called nuclear respiratory factor-1 (NRF-1).
NRF-1 is one of the primary proteins involved in mitochondrial neobiogenesis (16,18). In other words chronic AMPK activation causes cells to grow more mitochondria, thereby increasing ones oxidative potential. Clearly AMPK is not the only protein involved in mitochondrial biogenesis, but it does play a key role.
This behavior is to be expected. You see when you first start a bout of exercise (as in the first few seconds of the first muscle contraction) there is a sharp increase in demand for ATP. This demand cannot be met by oxidative phosphorylation in the mitochondria. So there is a very temporary but very real energy deficit. As AMP-Activated Protein Kinase’s (AMPK) name implies it activated by Adenosine Mono-Phosphate (AMP).
More specifically, it’s activated by the AMP/ATP ratio. Or even more simply: AMPK is activated when there is an energy deficit. This temporary deficit activates AMPK, which then promotes NRF-1 and PGC-1 production, leading to mitochondrial biogenesis. The entire process of mitochondrial biogenesis is not yet completely understood, but this is certainly an area of interest and something to keep one’s eye on.
AMPK activation also increases cellular concentration of GLUT4 protein (9). The GLUT family of proteins is responsible for transporting carbohydrates into cells. Activation of AMPK may therefore help lower insulin resistance. AMPK is so important for GLUT regulation that its role cannot be overstated. Mice that have their AMPK artificially deactivated are known as “lazy mice” for a reason—there skeletal muscle cannot maintain a store of glycogen and they become incredibly fatigued with even the slightest exertion (10).
Additionally AMPK activation results in the upregulation of Fatty Acid Translocase (FAT/CD36). This protein is to fat as GLUT is to carbohydrates. Its function is to transport free fatty acids across the cellular membrane where they can be used as fuel (3).
An entire article could easily be written about all of AMPK’s various functions. However, considering this article is about leptin and not AMPK we will have to just leave it the explanation where it stands, as further exploration into AMPK is beyond the scope of this article.
Leptin and Metabolism
Leptin further enhances metabolism by activating the Krebs (TCA) cycle in muscle, as well as pyruvate-dehydrogenase (PDH). PDH is the bridge linking pyruvate decarboxylation to the citric acid cycle. To my knowledge it is not known at this time if this is a direct effect or an indirect one brought about by increased mitochondrial uncoupling (6). Leptin also appears to promote fat oxidation and increased oxygen utilization by some yet undiscovered mechanisms. Specifically, leptin administration induced a large increase in both fat oxidation and oxygen consumption without effecting glucose utilization, AMPK, or ACC in cardiac muscle (5). So, it appears as though all of the pieces of the puzzle have yet to be uncovered.
Leptin and Fatty Acid Oxidation
Furthermore, leptin enhances fatty acid oxidation through some mechanism related to PPAR-alpha. PPAR-alpha is for the most part the opposite of PPAR-gamma. PPAR-alpha, when activated, causes a host of enzymes to be created that elevate fatty acid oxidation. In in vivo studies, PPAR-alpha seems to be linked to leptin’s effects by a yet to be determined mechanism. Specifically, leptin administration to rats increases PPAR-alpha content as well as CPT; it also lowers intra-cellular TAG stored in the muscles and liver. Additionally leptin lowered the amount of ACC present in said tissues.
Concluding Leptin and Muscle Tissue
Clearly this is a near perfect scenario. Leptin is literally priming the pump for fat oxidation to take place. This link between PPAR-alpha and leptin can be verified by experiments conducted on PPAR-alpha knockout mice. When leptin is administered—even at incredibly high level—to these special mice they fail to respond. No increase in fat oxidation, no weight loss, no decrease in ACC, and no decrease in cellular TAG.
Now that’s much better news isn’t it? You can officially stop plotting my assassination now, thank you.
References for 'Leptin and Muscle Tissue'
(1) Jeukendrup AE. Regulation of fat metabolism in skeletal muscle. Ann N Y Acad Sci. 2002 Jun;967:217-35. doi: 10.1111/j.1749-6632.2002.tb04278.x. PMID: 12079850.
(2) Tunstall RJ, Mehan KA, Wadley GD, Collier GR, Bonen A, Hargreaves M, Cameron-Smith D. Exercise training increases lipid metabolism gene expression in human skeletal muscle. Am J Physiol Endocrinol Metab. 2002 Jul;283(1):E66-72. doi: 10.1152/ajpendo.00475.2001. PMID: 12067844.
(3) Minokoshi Y, Kahn BB. Role of AMP-activated protein kinase in leptin-induced fatty acid oxidation in muscle. Biochem Soc Trans. 2003 Feb;31(Pt 1):196-201. doi: 10.1042/bst0310196. PMID: 12546684.
(4) Steinberg GR, Rush JW, Dyck DJ. AMPK expression and phosphorylation are increased in rodent muscle after chronic leptin treatment. Am J Physiol Endocrinol Metab. 2003 Mar;284(3):E648-54. doi: 10.1152/ajpendo.00318.2002. Epub 2002 Nov 19. PMID: 12441311.
(5) Atkinson LL, Fischer MA, Lopaschuk GD. Leptin activates cardiac fatty acid oxidation independent of changes in the AMP-activated protein kinase-acetyl-CoA carboxylase-malonyl-CoA axis. J Biol Chem. 2002 Aug 16;277(33):29424-30. doi: 10.1074/jbc.M203813200. Epub 2002 Jun 10. PMID: 12058043.
(6) Ceddia RB, William WN Jr, Curi R. The response of skeletal muscle to leptin. Front Biosci. 2001 Jan 1;6:D90-7. doi: 10.2741/ceddia. PMID: 11145919.
(7) Zong H, Ren JM, Young LH, Pypaert M, Mu J, Birnbaum MJ, Shulman GI. AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):15983-7. doi: 10.1073/pnas.252625599. Epub 2002 Nov 20. PMID: 12444247.
(8) Bergeron R, Ren JM, Cadman KS, Moore IK, Perret P, Pypaert M, Young LH, Semenkovich CF, Shulman GI. Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis. Am J Physiol Endocrinol Metab. 2001 Dec;281(6):E1340-6. doi: 10.1152/ajpendo.2001.281.6.E1340. PMID: 11701451.
(9) Ojuka EO, Jones TE, Nolte LA, Chen M, Wamhoff BR, Sturek M, Holloszy JO. Regulation of GLUT4 biogenesis in muscle: evidence for involvement of AMPK and Ca(2+). Am J Physiol Endocrinol Metab. 2002 May;282(5):E1008-13. doi: 10.1152/ajpendo.00512.2001. PMID: 11934664.
(10) Mu J, Barton ER, Birnbaum MJ. Selective suppression of AMP-activated protein kinase in skeletal muscle: update on ‘lazy mice’. Biochem Soc Trans. 2003 Feb;31(Pt 1):236-41. doi: 10.1042/bst0310236. PMID: 12546693.