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Reply to Xu: Role of Lactate in Lipid Metabolism, Just Always Inhibiting Lipolysis?

Open AccessPublished:July 31, 2009DOI:https://doi.org/10.1074/jbc.N806409200
      This is a response to the letter by Hai-jun Xu (
      • Xu H.
      Role of lactate in lipid metabolism, just always inhibiting lipolysis?.
      ).
      Regarding the question of whether l-lactate indeed plays a role in inhibiting lipolysis, we think that we have adequately addressed the question in our original JBC paper. In adipocytes, it is very well studied and documented that reagents such as adrenaline and forskolin (stimulating cAMP synthesis) or isobutylmethylxanthine (IBMX) (inhibiting cAMP hydrolysis) that up-regulate cAMP levels in adipocytes increase lipolysis. In contrast, reagents such as insulin (increase cAMP hydrolysis by stimulating phosphodiesterase) or niacin and propionate etc. (inhibiting cAMP synthesis through Gi-protein-coupled GPCRs) that down-regulate cAMP levels in the adipocytes inhibit lipolysis. That lactate stimulates GPR81 and inhibits cAMP synthesis in GPR81-expressing cells strongly suggests that lactate may play a role in suppressing lipolysis in adipocytes, which express high levels of GPR81. Our results from differentiated 3T3L1 cells as well as primary adipocytes from mouse, rat, and human demonstrated that l-lactate indeed inhibits lipolysis in those adipocytes. This hypothesis is further supported by our results using adipocytes from GPR81 knock-out mice, which are completely unresponsive to l-lactate in lipolysis assays. Of course, our results are in isolated cells and are well controlled. In our experiments we always compare the samples with and without added lactate while keeping all of the other elements the same. However, this does not mean that under physiological conditions both lactate and glycerol concentrations can't be elevated since in vivo lactate certainly is not the only regulator for lipolysis. For instance, under hypoglycemic conditions, it is very well known that epinephrine, glucagon, cortisol, and many other hormones are released. Some of those hormones including epinephrine and glucagon are known to increase lipolysis. Therefore, lactate may still play an inhibitory role for lipolysis in adipocytes even under hypoglycemic conditions, but at the same time, there are many other hormones that are stimulating the lipolysis. In addition, those hormones may also stimulate lipolysis in cells (such as liver cells) that do not express GPR81 and therefore won't be suppressed by l-lactate. Overall, what has been observed under hypoglycemic conditions is a result of the body's response to many different hormones, and we should not conclude that l-lactate is not playing an inhibitory role for lipolysis because both lactate and glycerol concentrations are raised under hypoglycemic conditions.
      Regarding the question of whether the only role of lactate in lipid metabolism is inhibiting lipolysis, so far we can only conclude that l-lactate inhibits lipolysis in adipocytes that express GPR81. Lactate is a metabolite of glucose. A growing number of studies show that lactate is also an energy source. Lactate can also be a signaling molecule through pathways other than GPR81. Therefore, in addition to GPR81, lactate can certainly affect the body's metabolism (including lipid metabolism) either directly or indirectly.
      Mr. Xu also proposed a hypothesis that lactate could actually promote lipolysis under certain situations because lactate produced by anaerobic glycolysis might relieve the inhibition of glucose aerobic oxidation on fatty acid oxidation or adjust intracellular redox state via lactate shuttle in skeletal muscle and adipose tissues and thus promote fatty acid oxidation. We think this is an interesting proposal but it needs to be supported by experiments and evidence.

      References

        • Xu H.
        Role of lactate in lipid metabolism, just always inhibiting lipolysis?.
        J. Biol. Chem. 2009;

      Linked Article

      • Role of Lactate in Lipid Metabolism, Just Always Inhibiting Lipolysis?
        Journal of Biological ChemistryVol. 284Issue 31
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          I appreciate the mechanism underlying the role of lactate in lipid metabolism proposed by Liu et al. (1). They found that lactate suppresses lipolysis in adipose tissue through a direct activation of GPR81. However, the argument that lactate suppresses lipolysis might be worthy of further consideration. Several studies have shown that there exists a substrate cycle or futile cycle in skeletal muscle as well as in adipose tissue, which dissipates redundant energy as heat via the cycle of synthesis, hydrolysis, and oxidation of triglyceride (2, 3).
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      • Lactate Inhibits Lipolysis in Fat Cells through Activation of an Orphan G-protein-coupled Receptor, GPR81
        Journal of Biological ChemistryVol. 284Issue 5
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          Lactic acid is a well known metabolic by-product of intense exercise, particularly under anaerobic conditions. Lactate is also a key source of energy and an important metabolic substrate, and it has also been hypothesized to be a signaling molecule directing metabolic activity. Here we show that GPR81, an orphan G-protein-coupled receptor highly expressed in fat, is in fact a sensor for lactate. Lactate activates GPR81 in its physiological concentration range of 1–20 mm and suppresses lipolysis in mouse, rat, and human adipocytes as well as in differentiated 3T3-L1 cells.
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