Editors' ChoiceMetabolism

Fat Feedback

Science Signaling  03 Feb 2009:
Vol. 2, Issue 56, pp. ec34
DOI: 10.1126/scisignal.256ec34

Liu et al. used a classical biochemical purification approach to identify a ligand in extracts of porcine brain that could activate the heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptor (GPCR) GPR81 from various species when those receptors were expressed in Chinese hamster ovary cells. GPR81 is found most abundantly in adipose tissue. Nuclear magnetic resonance analysis revealed that the activating fractions contained highly purified L-lactate. L-Lactate activated GPR81, as detected by assays of guanosine triphosphate-γS binding, inhibition of accumulation of adenosine 3′,5′-monophosphate, or receptor internalization with a median effective concentration (EC50) of 5 mM, which is much higher than that required for most ligands of GPCRs. However, the authors point out that resting concentrations of lactate in human plasma are 0.5 to 2 mM and can increase to 20 mM after intense anaerobic exercise. L-Lactate inhibited lipolysis in differentiated mouse 3T3-L1 cells (an adipocyte cell line) and in primary cultures of human adipocytes. Adipocytes from GPR81 knockout mice showed no effect of L-lactate on lipolysis, but lipolysis in these cells remained responsive to insulin and other stimuli. The authors conclude that GRR81 is a receptor for lactate that may account for roles of lactate in metabolic regulation. It has been proposed that lactate produced during extreme exercise may act to limit lipolysis. This could be helpful because production of adenosine triphosphate from free fatty acids is less efficient than that from pyruvate (in term of amounts of oxygen required). Thus, limiting the release of free fatty acids would be appropriate when the rate of glycolysis (which produces lactate) exceeds that of mitochondrial respiration. Lactate is also produced by adipocytes under metabolic load—for example, after a meal, when glucose is abundant. The authors note that in this case, L-lactate may act as an autocrine signal to suppress lipolysis.

C. Liu, J. Wu, J. Zhu, C. Kuei, J. Yu, J. Shelton, S. W. Sutton, X. Li, S. J. Yun, T. Mirzadegan, C. Mazur, F. Kamme, T. W. Lovenberg, Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor, GPR81. J. Biol. Chem. 284, 2811–2822 (2009). [Abstract] [Full Text]

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