Abstract
Obesity-linked type 2 diabetes is one of the paramount causes of morbidity and mortality worldwide, posing a major threat on human health, productivity, and quality of life. Despite great progress made towards a better understanding of the molecular basis of diabetes, the available clinical counter-measures against insulin resistance, a defect that is central to obesity-linked type 2 diabetes, remain inadequate. Adiponectin, an abundant adipocyte-secreted factor with a wide-range of biological activities, improves insulin sensitivity in major insulin target tissues, modulates inflammatory responses, and plays a crucial role in the regulation of energy metabolism. However, adiponectin as a promising therapeutic approach has not been thoroughly explored in the context of pharmacological intervention, and extensive efforts are being devoted to gain mechanistic understanding of adiponectin signaling and its regulation, and reveal therapeutic targets. Here, we discuss tissue- and cell-specific functions of adiponectin, with an emphasis on the regulation of adiponectin signaling pathways, and the potential crosstalk between the adiponectin and other signaling pathways involved in metabolic regulation. Understanding better just why and how adiponectin and its downstream effector molecules work will be essential, together with empirical trials, to guide us to therapies that target the root cause(s) of type 2 diabetes and insulin resistance.
Highlights
Adiponectin enhances the secretion of the anti-inflammatory cytokine IL-10 by cultured human monocyte-derived macrophages and stromal vascular fraction cells prepared from human adipose tissue (Kumada et al, 2004)
Macrophage polarization phenotype regulates the expression of adiponectin receptors (AdipoRs) in ways that classical activation (M1) of macrophages suppresses the expression of AdipoRs, and alternative activation (M2) preserves it
APPL1 directly binds to the intracellular domains of AdipoR1 and AdipoR2 via its C-terminal PTB and coiled coil (CC) domains, thereby mediating the actions of adiponectin in the regulation of energy metabolism and insulin sensitivity (Figure 2)
Summary
Overview Adiponectin, known as Acrp30 (Scherer et al, 1995), AdipoQ (Hu et al, 1996), GBP-28 (Nakano et al, 1996), and apM1 (Maeda et al, 1996), and independently identified by four groups using different approaches (Scherer et al, 1995; Hu et al, 1996; Maeda et al, 1996; Nakano et al, 1996), was originally cloned as an adipocyte-enriched protein highly induced upon 3T3-L1 adipocyte differentiation (Scherer et al, 1995). Adiponectin signaling and function in insulin target tissues | 103 carboxykinase and glucose-6-phosphatase (Yamauchi et al, 2002), thereby suppressing gluconeogenesis. Another independent study showed that adiponectin administration increases fatty acid oxidation in skeletal muscle, and suppresses lipid accumulation in the liver by activating AMPK, thereby reducing triglyceride content in the liver and muscle and improving overall in vivo insulin sensitivity (Yamauchi et al, 2001, 2002).
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