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    • Adiponectin also works on AdipoR inducing extracellular Ca i

    2024-01-22

    Adiponectin also works on AdipoR1, inducing extracellular Ca2+ influx necessary for activation of Ca2+/calmodulin-dependent protein kinase kinase (CaMKK)β, AMPK (Fig. 1). This step is then followed by activation of SirT1 and increased expression and decreased acetylation of PPARγ coactivator (PGC)-1α, and increased mitochondria in myocytes. Specifically disrupting the AdipoR1 in muscle results in suppression of the adiponectin-mediated increase in intracellular Ca2+ concentration, and decreases the adiponectin-activation of CaMKK, AMPK and SirT1. Suppression of AdipoR1 also decreases the expression and deacetylation of PGC-1α, decreases mitochondrial content and enzymes, decreases oxidative type I myofibers, and decreases oxidative stress-detoxifying enzymes in skeletal muscle, which are associated with insulin resistance and decreased exercise endurance. These results support the proposal that decreased adiponectin and AdipoR1 levels in obesity may be causally associated with the mitochondrial dysfunction and insulin resistance seen in diabetes [14]. In addition to adiponectin activating AMPK, Ca2+, and PPARα signaling pathways, it is also likely to be involved in other signaling pathways, possibly including ceramide signaling [12]. Adiponectin lowers cellular ceramide levels via activation of ceramidase, which is associated with an increase in sphingosine, leading to reduced hepatic ceramide levels and improved insulin sensitivity. Conversely a reduction in adiponectin levels increases hepatic ceramide, which may be implicated in insulin resistance (Fig. 1). The increased levels of sphingosine 1-phosphate (S1P) seen with increased levels of adiponectin, protect etravirine sale from apoptosis induced by either palmitate or C2-ceramide in cardiac myocytes and pancreatic beta cells [12] (Fig. 1). Either an inhibitor of ceramide biosynthesis or S1P itself reverses this effect. Therefore, adiponectin-induced S1P is likely to protects cardiac myocytes and beta cells from cell death. The importance of this ceramide pathway is supported by evidence the fact that it showing it to be totally dependent on adiponectin activating AdipoR1/AdipoR2, with an overexpression in adiponectin, AdipoR1 and AdipoR2 reducing hepatic ceramide levels, with improved insulin sensitivity.
    Pathway regulation AdipoR1 is found in many tissues, being particularly abundant in skeletal muscle, whereas AdipoR2 is most commonly found in the liver. The expression of these receptors in insulin target organs, such as skeletal muscle and liver, significantly increases in fasted mice and decreases in refed mice and in vitro studies have shown the expression of AdipoR1/R2 is reduced by insulin via the phosphoinositide 3-kinase/FoxO1-dependent pathway. AdipoR1 and AdipoR2 levels are significantly decreased in the muscle and adipose tissue of insulin-resistant ob/ob mice, probably partly due to obesity-linked hyperinsulinemia via FoxO [20] (Fig. 2). Additionally, adiponectin-induced activation of AMPK is reduced in the skeletal muscle of ob/ob mice, suggesting that the reduced expression of AdipoR1 and AdipoR2 seen in ob/ob mice is associated with insulin resistance [20]. This indicates that obesity not only decreases plasma adiponectin levels but also AdipoR1/R2 expression, thereby reducing adiponectin sensitivity and leading to insulin resistance, creating a “vicious cycle” [20].
    Genetic factors Data from the Québec Family Study has been used to investigate the association between ADIPOR1 and ADIPOR2 polymorphisms with energy metabolism and adiposity. One single-nucleotide polymorphism (SNP) each in the putative promoter of ADIPOR1 (i.e., −3882T→C) and ADIPOR2 (i.e., IVS1 −1352G→A) was associated with RQ (P = 0.03 and 0.04, respectively), and the association was even stronger in nonobese persons (P = 0.02 and 0.003). Carriers of the common alleles (ADIPOR1 T and ADIPOR2 G alleles) had a lower RQ than did the rare homozygotes. A significant genotype-by-genotype interaction (P = 0.0002–0.02) was found between SNPs in the promoters of ADIPOQ (−3971A→G) and ADIPOR1 (−3882T→C). Subjects carrying the minor ADIPOQ allele (G allele) who were rare homozygotes (C/C) for the ADIPOR1 SNP had a higher RQ (P = 0.003) and greater overall (P < 0.03) and abdominal (P < 0.05) adiposity than did persons with other genotype combinations. Thus variants in the promoter region of both ADIPOR genes contribute to substrate oxidation.