Here we show that lactate activates the Gi

Here we show that lactate activates the Gi-coupled receptor GPR81, which is exclusively expressed on adipocytes, and that lactate released from adipocytes in response to glucose and insulin mediates insulin-induced antilipolysis by activation of GPR81.
Results
Discussion Nutrients and their metabolites provide energy and substrates for multiple metabolic processes. However, they can also exert regulatory effects by activating specific membrane receptors. Recently it has become clear that eukaryotes use membraneous G protein-coupled receptors to sense the concentration of nutrients and their metabolites in the metabolic or gustatory system (Brown et al., 2005, Chandrashekar et al., 2006, He et al., 2004, Holsbeeks et al., 2004). Here we report that the orphan G protein-coupled receptor GPR81 functions as a receptor for lactate, a central intermediate of energy metabolism. GPR81 couples to Gi-type G proteins and is expressed on adipocytes where it mediates lactate-induced antilipolytic effects. We show that insulin-dependent glucose uptake in adipocytes results in the local release of lactate, which in an autocrine fashion induces inhibition of lipolysis. In animals lacking GPR81, insulin-dependent inhibition of lipolysis as well as insulin-induced decreases in cAMP levels are almost completely abrogated. Thus, besides its well-established role as an intermediate of the energy metabolism, lactate functions as an autocrine or paracrine signaling molecule that mediates insulin-induced inhibition of adipocyte lipolysis and thereby critically contributes to the change in metabolic fluxes during the transition from the fasted to the fed state. Especially during exercise, the skeletal muscle is the major site of lactate production in the body. During low-intensity exercise, fatty Nocodazole synthesis oxidation is the major source of energy. However, with increasing exercise intensity, the anaerobic degradation of carbohydrates via increased glycogenolysis and glycolysis to lactate prevails (Brooks and Mercier, 1994, Romijn et al., 1993). Since the accumulation of lactate in the blood during intensive exercise coincides with the decrease in fatty acid oxidation, a direct effect of lactate on fatty acid release from adipocytes has been suggested (Boyd et al., 1974, Fredholm, 1971, Issekutz and Miller, 1962). While a causal link between elevated lactate levels and a decreased fatty acid formation and oxidation is plausible, no clear proof for this concept has been provided, and the issue has remained controversial (Trudeau et al., 1999). Since GPR81 would be in an ideal position to mediate lactate-induced antilipolytic effects during exercise, we tested whether GPR81 deficiency has an effect on free fatty acid and glycerol plasma levels of exercising mice. When mice were trained to exercise resulting in lactate plasma levels, which are able to induce strong antilipolytic effects, free fatty acid plasma concentrations remained on comparable levels in wild-type and GPR81-deficient animals. Thus, although lactate has an antilipolytic activity under resting conditions which involves GPR81, during intensive exercise this effect may not be sufficient to overcome the strong stimulation of lipolysis via sympathetic activation (Horowitz, 2003). Alternatively, it is also conceivable that GPR81-independent mechanisms are involved in the relative reduction of the lipolytic rate during intensive exercise. The rapid decrease in lipolytic activity in the presence of sufficient supply of carbohydrates after a meal is an important metabolic regulatory process which preserves energy stores in adipocytes. Food uptake inhibits net lipolysis primarily through the action of insulin, which by binding to its receptor on adipocytes increases glucose uptake and exerts a strong and potent antilipolytic effect that is primarily mediated by a decrease in intracellular cAMP levels (Duncan et al., 2007, Wang et al., 2008). The classic pathway linking insulin receptor activation in adipocytes with the suppression of cAMP levels involves the PI-3-kinase-dependent activation of protein kinase B/Akt, which in turn phosphorylates and activates PDE3B, the major phosphodiesterase isoform responsible for cAMP degradation in adipocytes (Degerman et al., 1998). Our data indicate that the mechanism underlying the insulin-induced drop in adipocyte cAMP levels is more complex and involves insulin-stimulated release of lactate from adipocytes. Adipocytes have been shown to be a major site of lactate production by conversion of glucose (DiGirolamo et al., 1992), a process strongly increased by insulin (Hagstrom et al., 1990, Henry et al., 1996). Lactate released from adipose tissue has been regarded primarily as a source for hepatic gluconeogenesis and glycogen synthesis. The fact that the lactate receptor GPR81 is specifically expressed on adipocytes suggested that an increased lactate release upon insulin-stimulated glucose uptake would in an autocrine fashion result in Gi-mediated inhibition of adenylyl cyclase, thereby contributing to the antilipolytic effect of insulin. Indeed, while local free fatty acid levels in the adipose tissue as well as systemic free fatty acid levels dropped after an acute glucose challenge of wild-type mice, this effect was greatly diminished in animals lacking the lactate receptor GPR81. Comparable effects could be observed in isolated wild-type and GPR81-deficient adipose tissue treated with insulin.