The physiological role of lactate induced antilipolytic effe
The physiological role of lactate-induced antilipolytic effects is less clear. It has been speculated that GPR81 mediates the inhibition of lipolysis during intensive exercise, a condition which results in high systemic lactate plasma concentrations 9, 10. Owing to oxygen shortage resulting from intensive exercise, skeletal muscle cannot utilize free fatty acids as an energy substrate. Therefore, an inhibition of lipolysis mediated by lactic thyroid hormone receptor and GPR81 would be a plausible mechanism. However, the concept of a link between elevated lactate plasma levels and a decreased fatty acid formation during anaerobic exercise has been somewhat controversial 39, 40. In light of the very specific expression of GPR81 in adipocytes, it is intriguing that adipocytes can produce and release considerable amounts of lactate . Thus lactate may function in an autocrine manner to regulate triglyceride storage in adipocytes via GPR81.
The striking expression of GPR109A and GPR109B in various immune cells raises the question which physiological or pathophysiological role these receptors have in leukocytes. Although the expression of GPR109A in immune cells of the skin is responsible for the nicotinic acid-induced flushing phenomenon and potentially also for the beneficial effects of monomethylfumarate in the treatment of psoriasis 7, 14, 42, the physiological role of the receptors in immune cells is unclear. It is conceivable that GPR109A and GPR109B mediate the effect of an unknown epidermal mediator, which via activation of Langerhans cells and subsequent release of prostanoids induces under certain conditions a localized erythema and other inflammatory symptoms thereby regulating immunological responses of the skin as well as local dermal blood flow.
GPR109A is also activated by high concentrations of butyrate which is produced in large quantities by bacterial fermentation of dietary fibers in the colon. Recent data show that GPR109A is present in the apical membrane of intestinal epithelial cells and that it might function as a tumor suppressor and an anti-inflammatory receptor in the large intestine by mediating effects of butyrate .
Therapeutic potential The nicotinic acid receptor GPR109A is an established drug target, although it is not yet completely clear whether the receptor alone is responsible for the wanted antidyslipidemic effects of nicotinic acid 27, 43. Nevertheless, the major unwanted effect of nicotinic acid, the flushing reaction, is mediated by GPR109A . The involvement of GPR109A in wanted and unwanted effects of nicotinic acid makes it difficult to develop drugs based on GPR109A agonism which have an improved ratio of wanted vs. unwanted effects. However, evidence has been provided that unwanted effects of nicotinic acid are mediated by the activation of G protein-independent pathways, whereas antilipolytic effects are mediated by Gi15, 44. Thus, differences in the post-receptor mechanisms mediating wanted and unwanted effects might be exploited to improve the pharmacological profile of drugs acting through GPR109A. In this regard, it is interesting that some partial agonists of GPR109A have full antilipolytic activity, whereas their ability to induce flushing appears to be reduced when compared with nicotinic acid 15, 16. Given that GPR109B has an expression pattern very similar to GPR109A, it is unlikely that selective agonists of GPR109B have a better profile than GPR109A agonists. Provided that the induction of antilipolytic effects via Gi-coupled receptors on adipocytes is the primary mechanism which mediates the beneficial effects of nicotinic acid, the receptor GPR81 might be an interesting drug target as its expression is restricted to adipose tissue. In this case, synthetic agonists of GPR81 are expected to lack unwanted effects of nicotinic acid such as the flushing response while preserving wanted effects mediated by their antilipolytic effects on adipocytes. Recently, monomethylfumarate, an established drug for the treatment of psoriasis, has been shown to be an agonist of GPR109A . Because GPR109A is expressed in epidermal Langerhans cells, GPR109A will probably mediate the antipsoriatic effects of monomethylfumarate. Given the broad expression of GPR109A and GPR109B in various immune and inflammatory cells, it will certainly be interesting to explore the potential of GPR109A and GPR109B agonists to treat immune disorders of the skin but also of other organs.