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    • The lactic acid receptor HCA is primarily

    2022-02-22

    The lactic A-1155463 australia receptor HCA1 is primarily expressed in white and brown adipocytes 11, 12, 17, 18 (Table 1). Only relatively low expression levels of HCA1 have been described in several other tissues 16, 19, and it is not clear whether this is due to the presence of adipocytes in these tissues or whether it reflects expression by other resident cell types. In contrast to HCA1, HCA2 and HCA3 are more widely expressed (Table 1). HCA2 also shows relatively high expression in white and brown adipocytes 14, 15, 16. In addition, HCA2 is expressed by immune cells including neutrophils, macrophages, and epidermal Langerhans cells, but not in lymphocytes 20, 21, 22, 23. Several types of epithelial cells including intestinal epithelial cells, retinal pigment epithelial cells, as well as keratinocytes also express HCA25, 6, 23, 24, 25, 26. HCA3 is only expressed in higher primates, and its expression has not been studied in-depth. However, HCA3 appears to be present in most tissues which also express HCA2, including adipocytes, immune cells such as neutrophils, monocytes, and macrophages, as well as in intestinal epithelial cells 14, 16, 24, 27, 28, 29, 30.
    HCA Receptors in the Adipose Tissue All three HCA receptors are highly expressed in white and brown adipocytes. Expressions of HCA1 and HCA2 have been shown to increase during differentiation of adipocytes from preadipocytes as well as after activation of peroxisome proliferator-activated receptor-gamma 11, 17, 18. Both high-fat diet (HFD) feeding and exposure to various inflammatory stimuli result in decreased expression of HCA1 in the adipose tissue 31, 32. While HCA2 expression in the adipose tissue is also decreased after HFD feeding, inflammatory stimuli increase expression of HCA220, 31. It has been shown that lactic acid inhibits adipocyte lipolysis in an HCA1-dependent manner 10, 11, 13. While basal plasma levels of lactic acid are too low to activate HCA1, during intensive exercise lactic acid levels reach 10–20mM [33], which would be sufficient to fully activate HCA1. Although it seems plausible that elevated lactic acid levels during intensive exercise would reduce lipolysis, since skeletal muscle does not use free fatty acids (FFAs) as an energy source under anaerobic conditions, studies in mice lacking HCA1 did not support a role for HCA1 in lipolysis regulation during intensive exercise [13]. Another source for lactic acid acting on HCA1 in the adipose tissue is adipocytes themselves; glucose is taken up under basal or insulin-stimulated conditions, and lactate is produced from pyruvate during glycolysis [34]. Subsequent release of lactate from adipocytes increases the local lactate concentration in the adipose tissue by several folds, but lactate also enters the circulation and serves as a substrate for gluconeogenesis in the liver 13, 35, 36. Given that the lactic acid concentration in the interstitium of the adipose tissue strongly increases after insulin-induced glucose uptake, lactic acid may act in an autocrine and/or paracrine fashion to mediate the antilipolytic effects of insulin by activating HCA1 followed by Gi-dependent inhibition of the cAMP-forming enzyme adenylyl cyclase. In fact, a reduced insulin-induced inhibition of lipolysis can be seen in mice lacking HCA1[13]. Thus, insulin exerts its antilipolytic effects not only through the classic pathway resulting in activation of phosphodiesterase 3B and subsequent stimulation of the degradation of cAMP [37], but also through the inhibition of the formation of cAMP induced by lactic acid acting through HCA1 (Figure 1A). While HCA1 deficiency has no effect on body weight under normal chow-feeding conditions, HCA1-deficient mice fed an HFD gain significantly less weight than their wild-type counterparts [13]. The reason for the reduced weight gain in the absence of HCA1 is unclear but may result from a slight disinhibition of adenylyl cyclase activity resulting in chronically elevated cAMP levels, which in turn may lead to increased lipolysis in white adipose tissue and increased heat production and browning in brown and white adipose tissues 38, 39.