Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0948265 (metabolic syndrome)
 24,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adiponectin, an adipocyte secretory hormone, has been causally linked to insulin resistance in the metabolic syndrome and diabetes. A recent paper (Mao et al., 2006) shows that the APPL1 adaptor protein binds to the intracellular domain of adiponectin receptors and mediates some of adiponectin's actions, identifying a novel mechanism linking adiponectin to insulin sensitization.
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PMID:APPLied mechanics: uncovering how adiponectin modulates insulin action. 1681 26

Adiponectin, an adipokine secreted by the white adipose tissue, plays an important role in regulating glucose and lipid metabolism and controlling energy homeostasis in insulin-sensitive tissues. A decrease in the circulating level of adiponectin has been linked to insulin resistance, type 2 diabetes, atherosclerosis, and metabolic syndrome. Adiponectin exerts its effects through two membrane receptors, AdipoR1 and AdipoR2. APPL1 is the first identified protein that interacts directly with adiponectin receptors. APPL1 is an adaptor protein with multiple functional domains, the Bin1/amphiphysin/rvs167, pleckstrin homology, and phosphotyrosine binding domains. The PTB domain of APPL1 interacts directly with the intracellular region of adiponectin receptors. Through this interaction, APPL1 mediates adiponectin signaling and its effects on metabolism. APPL1 also functions in insulin-signaling pathway and is an important mediator of adiponectin-dependent insulin sensitization in skeletal muscle. Adiponectin signaling through APPL1 is necessary to exert its anti-inflammatory and cytoprotective effects on endothelial cells. APPL1 also acts as a mediator of other signaling pathways by interacting directly with membrane receptors or signaling proteins, thereby playing critical roles in cell proliferation, apoptosis, cell survival, endosomal trafficking, and chromatin remodeling. This review focuses mainly on our current understanding of adiponectin signaling in various tissues, the role of APPL1 in mediating adiponectin signaling, and also its role in the cross-talk between adiponectin/insulin-signaling pathways.
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PMID:APPL1: role in adiponectin signaling and beyond. 1885 21

The decrease in adiponectin levels are negatively correlated with chronic subclinical inflammation markers in obesity. The hypertrophic adipocytes cause obesity-linked insulin resistance and metabolic syndrome. Furthermore, macrophage polarization is a key determinant regulating adiponectin receptor (AdipoR1/R2) expression and differential adiponectin-mediated macrophage inflammatory responses in obese individuals. In addition to decrease in adiponectin concentrations, the decline in AdipoR1/R2 mRNA expression leads to a decrement in adiponectin binding to cell membrane, and this turns into attenuation in the adiponectin effects. Within the receptor complex, adaptor protein-containing pleckstrin homology domain, phosphotyrosine-binding domain, and leucine zipper motif 1 (APPL1) is the intracellular binding partner of AdipoR1 and AdipoR2. The expression levels of APPL1 or APPL2 lead to an altered adiponectin activity. Despite normal or high adiponectin levels, an impaired post receptor signaling due to APPL1/APPL2 may alter adiponectin efficiency and activity. However, APPL2 blocks adiponectin signaling through AdipoR1 and AdipoR2 by competitive inhibition of APPL1. APPL1 is also an important mediator of adiponectin dependent insulin sensitization. In this context, adiponectin resistance is associated with insulin resistance and is thought to be partly due to the down-regulation of the AdipoRs in high-fat diet fed subjects. Actually, adiponectin resistance occurs very rapidly after saturated fatty acid feeding, this metabolic disturbance is not due to a decrease in AdipoR1 protein content. Intra-abdominal adipose tissue-AdipoR2 expression is reduced in obesity, whereas AdipoR1 expression is not changed. Adiponectin resistance together with insulin resistance forms a vicious cycle. The elevated adiponectin levels with adiponectin resistance is a compensatory response in the condition of an unusual discordance between insulin resistance and adiponectin unresponsiveness.Additionally, different mechanisms are involved in vascular adiponectin resistance at different stages of obesity. Nevertheless, diet-induced hyperlipidemia is the leading cause of vascular adiponectin resistance. Leptin/adiponectin imbalance may also be an important marker of the elevated risk of developing abdominal obesity-associated cardiovascular diseases.
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PMID:Adiponectin-Resistance in Obesity. 2858 10