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    • The direction of research then turned to investigating the l

    2024-03-21

    The direction of research then turned to investigating the long-term effects of adiponectin on insulin resistance. Adiponectin transgenic mice showed a reduction in insulin resistance and diabetes [5,6], while adiponectin-deficient mice showed mild insulin resistance with glucose intolerance, as well as dyslipidemia and hypertension [7–10].
    Adiponectin receptors; structure and functions Full length adiponectin undergoes proteolytic cleavage to form globular adiponectin, which has increased binding in myocytes and skeletal muscle membranes, but reduced binding in hepatocytes and liver membranes. The cDNA for adiponectin receptors was isolated from retrovirally infected Ba/F3 PF-CBP1 hydrochloride and was shown to encode a protein called AdipoR1 (Fig. 1). Two types of adiponectin receptor were identified with different binding affinities for globular or full-length adiponectin (AdipoR1 and AdipoR2) with human and mice sharing 96.8% and 95.25 of AdipoR1 and AdipoR2 identity, respectively. Human and mouse AdipoR1 is located at chromosome 1p36.13-q41 and 1 E4, whereas AdipoR2 is located at chromosome 12p13.31 and 6 F1, respectively. The molecular structure of both receptor forms are significantly homologous, with an internal N-terminus and external C-terminus [11]. AdipoR1 and AdipoR2 are part of the progesterone and adiponectin Q receptor (PAQR) family, some members of which contain sequence homology with alkaline ceramidase [12]. Mice studies have confirmed that AdipoR1 and AdipoR2 are major adiponectin receptors in vivo[13] and mediate metabolic actions of adiponectin. These effects have been confirmed, with AdipoR1·AdipoR2 double knockout mice shown to be glucose intolerant and hyperinsulinemic, indicating that AdipoR1 and AdipoR2 help to regulate normal glucose metabolism and insulin sensitivity. These effects are also dependent on specific tissues with liver AdipoR1 involved in activating AMP-activated kinase (AMPK), while AdipoR2 is involved in activation of PPARα, leading to increased insulin sensitivity. Therefore AdipoR1 and AdipoR2 serve as receptors for globular and full-length adiponectin and mediate increased AMPK, PPARα ligand activities, fatty-acid oxidation, and glucose uptake by adiponectin ([13]; unpublished observations). At present it is not clear whether the ceramidase activity exhibited by these receptors is integral to their structure or occurs via activation of another pathway. It has been proposed that the potential signal mechanisms are downstream of AdipoR1 and AdipoR2, which collectively lead to pleiotropic biological actions; adiponectin appears to regulate more diverse and complex pathways, such as ceramide and S1P downstream of AdipoR1 and AdipoR2, in addition to those originally identified, such as AMPK, Ca2+, and PPARα [11–16] (Fig. 1).
    Signaling mechanisms outlined Full-length adiponectin stimulates the phosphorylation and subsequent activation of AMPK in both skeletal muscle and the liver, compared to globular adiponectin which only exerts its effect in skeletal muscle [17] (Fig. 1). When AMPK activation is blocked, glucose utilization and fatty-acid combustion is also inhibited, indicating that the action of adiponectin occurs through activation of AMPK [17]. In addition, muscle fat oxidation and glucose transport are enhanced by globular adiponection causing AMPK activation and acetyl-CoA carboxylase inhibition [18]. Studies have also shown that the reduced expression of gluconeogenic enzymes such as phosphoenolpyruvate carboxylase and glucose-6-phosphatase that are found in adiponectin transgenic mice are associated with elevated phosphorylation of hepatic AMPK [6]. Results following deletion of LKB1 indicate that adiponectin suppresses hepatic SREBP1c expression in an AdipoR1/LKB1/AMPK dependent pathway. Investigating this pathway in more detailt hasdemonstrated that LKB1- and AMPK-dependent and independent signaling pathways may exist in vivo[19]. Adiponectin, via AdipoR2, activates and increases the expression of PPARα ligands [5] (Fig. 1) and increases fatty-acid combustion and energy consumption [11,13]. This is partly done via increased expression of ACO and UCP, because the ACO and UCP genes possess peroxisome proliferator response element (PPRE) in their promoter regions.