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  • Also the decrease in adipocyte cAMP levels seen

    2022-05-21

    Also, the decrease in adipocyte cAMP levels seen after an acute glucose challenge in wild-type mice was strongly reduced in mice lacking GPR81, indicating that the activation of PDE3B alone was not sufficient to mediate the effect of insulin on cAMP levels and lipolytic activity. The fact that insulin-dependent antilipolysis is strongly inhibited after blockade of PDE3B or in the absence of PDE3B in PDE3B-deficient mice (Choi et al., 2006, Eriksson et al., 1995) does not speak against the mechanism described here, since PDE3B inhibition or elimination does not only block the effect of insulin on cAMP degradation but also results in an increase in basal cAMP levels. The latter effect is unlikely to be overcome by insulin-induced inhibition of cAMP formation via lactate and GPR81. Thus, a dual regulation of adipocyte cAMP levels through the stimulation of cAMP degradation via PDE3B and the inhibition of cAMP formation via lactate and GPR81 (Figure 7) is necessary for the rapid and efficacious antilipolytic effect of insulin on adipocytes. This mechanism explains the long-known phenomenon that lactate can potentiate the antilipolytic effect of insulin (Green and Newsholme, 1979) and is the basis for a well-controlled switch of energy sources from lipids to carbohydrates upon feeding. A lack of insulin-dependent antilipolytic effects has been shown in adipocyte-specific insulin receptor-deficient mice to strongly reduce the increase in fat mass under the condition of a hypercaloric diet (Bluher et al., 2002). Consistent with this, GPR81-deficient mice had a reduced weight gain compared to wild-type mice under high-fat diet. The reduced weight gain was not accompanied by an increase in glucose tolerance compared to wild-type animals. This may be due to transient elevations in free fatty BIX 02565 levels in GPR81-deficient mice, which may negatively influence insulin sensitivity. These data also indicate that lactate which has traditionally been viewed primarily as a product of glucose metabolism and as a source for hepatic gluconeogenesis exerts by itself hormone-like effects by activating a specific G protein-coupled receptor. Together with the recently discovered G protein-coupled receptors for free fatty acids, ketone bodies, β-oxidation intermediates, or citric acid cycle intermediates (Ahmed et al., 2009, Brown et al., 2005, He et al., 2004, Taggart et al., 2005), the lactate receptor GPR81 forms a group of metabolic sensors, which detect local and systemic concentrations of key metabolites in order to adjust metabolic fluxes to varying metabolic states. Within this general concept, adipocytes use GPR81 to indirectly sense the availability of sufficient amounts of glucose, since high glucose levels result in increased insulin-dependent glucose uptake and subsequent conversion of glucose to lactate, which then activates GPR81. Activation of GPR81 decreases the net rate of lipolysis in order to save energy stored in adipocytes when glucose is available as an energy source. Alterations in GPR81 expression or function may contribute to dysfunctions of the metabolic system.
    Experimental Procedures
    Acknowledgments
    Introduction Adipocytes express a number of cell surface receptors that contribute to their ability to sense metabolic changes in the surrounding environment, including GPR109A and GPR81. In 2003, GPR109A was identified as the receptor for the beneficial lipid-altering drug, niacin [1], [2], [3]. However, under physiological conditions, plasma concentrations of niacin do not reach levels high enough to activate the receptor, making it unlikely to be the endogenous ligand. In 2005, Taggart et al. demonstrated that β-hydroxybutyrate, a ketone body produced by the liver, is an endogenous ligand for GPR109A [4]. β-Hydroxybutyrate activates GPR109A and inhibits adipocyte lipolysis at concentrations seen during a 2–3day fast, with an EC50 of 767±57μM [4]. β-Hydroxybutyrate may represent a homeostatic mechanism for surviving starvation by acting in a negative feedback manner to inhibit lipolysis. In this manner, β-hydroxybutyrate can regulate its own production by decreasing the serum level of fatty acid precursors available for hepatic ketogenesis [4] and possibly preserving lipid stores during a prolonged fast [5]. GPR109A is predominantly expressed in adipocytes of white and brown adipose tissue, and is expressed to a lesser extent in keratinocytes and immune cells, including dermal dendritic cells, monocytes, macrophages and neutrophils [1], [2], [3], [6], [7], [8].