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  • GPR shares a amino acid

    2022-01-14

    GPR81 shares a 52% amino myd88 inhibitor sequence identity in humans to GPR109A [1], [2], [3]. In addition, GPR81 is localized more specifically to the adipose tissue [3]. In 2008, lactate was discovered to be the endogenous ligand for GPR81 [9], [10]. Plasma lactate levels reach concentrations capable of activating the receptor during bouts of intense exercise, with an EC50 of ∼5mM [10]. Infusion of lactate reduces lipolysis in vivo[11], [12], [13] as does treatment of adipocytes in vitro[14], [15]. The effect of lacate to reduce lipolysis is mediated through activation of GPR81 [9], [10]. However, these effects are somewhat controversial, as studies have demonstrated that the receptor is not involved in the regulation of lipolysis during intensive exercise when lactate concentrations are elevated [16]. Both GPR109A and GPR81 are located on chromosome 12q24 [3] and mediate anti-lipolytic effects through coupling to Gi-type G proteins [17]. It is important to note that with the recent deorphanization of these receptors, there has been a recommendation to the International Union of Basic and Clinical Pharmacology (IUPHAR) to rename GPR81, GPR109A, and GPR109B (a human-specific, low-affinity niacin receptor) as hydroxy-carboxylic acid (HCA) receptor family members, whereby GPR81 is HCA1, GPR109A is HCA2, and GPR109B is HCA3[18]. Studies have revealed that all three receptors bind hydroxy-carboxylic acids as their endogenous ligands, leading to the proposed nomenclature for this receptor family. G protein-coupled receptor synthesis is regulated by gene transcription, translation, and posttranslational processing, which may be regulated by the ligand itself and by other hormones and factors [19]. GPR109A gene expression in adipocytes is reduced with age in mice [20]. While the regulation of GPR109A gene expression in the adipose tissue in various disease states (including diabetes or obesity) has not been demonstrated, a down-regulation of GPR81 mRNA expression in mouse adipose tissue has been demonstrated in response to acute treatment with inflammatory stimuli [21]. In addition, ob/ob mice, a mouse model of obesity and type 2 diabetes, demonstrate reduced adipose tissue expression of GPR81 [21]. Our objectives were to investigate the effects of high fat diet-induced obesity and inflammation on gene expression of GPR109A and GPR81.
    Materials and methods
    Results
    Discussion Here, we demonstrate, for the first time, that HFD reduces adipose tissue GPR109A and GPR81 gene expression. Downregulation of GPR109A and GPR81 during states of obesity may contribute to the disruption of normal regulation of adipocyte lipolytic function often seen in obesity, such as elevated basal lipolysis and reduced catecholamine-induced lipolysis [23], [24]. GPR109A and GPR81 give adipocytes the ability to “sense” metabolic changes in the surrounding environment and respond through lipolytic regulation and release of products including free fatty acids and pro- or anti-inflammatory adipokines. Regulation of expression of these receptors is crucial for the metabolic sensing ability of the adipocyte and ultimately whole body energy homeostasis. Obesity is associated with a chronic low-grade inflammation of the adipose tissue, characterized by increased production of pro-inflammatory cytokines and chemokines including MCP-1, TNF-α, IL-1β, and IL-6. GPR81 downregulation in adipose tissue of ob/ob mice (a mouse model of obesity) has previously been demonstrated [21]. Others have demonstrated that adipose tissue GPR81 expression is downregulated in response to the inflammatory stimuli LPS, zymosan, and turpentine [21]. However, its expression does not appear to be regulated by the usual cytokines that induce metabolic changes during obesity-associated inflammation. Specifically, treatment of adipocytes with the pro-inflammatory cytokines typically elevated in the adipose tissue during obesity, including TNF- α, IL-1 β, IL-6, or interferon γ failed to reduce the expression of GPR81 in vitro[21]. Here, we demonstrate for the first time that HFD-induced obesity also reduces GPR81 gene expression. The exact mechanism for the down-regulation of GPR81 in obesity has yet to be fully elucidated, but it does not appear to be mediated through the increased production of pro-inflammatory cytokines produced abundantly in adipose tissue of obese subjects.