Exp. Biol. Med. 2009;234:850-859

Alcoholic fatty liver is a major risk factor for advanced liver injuries such as steatohepatitis, fibrosis, and cirrhosis. While the underlying mechanisms are multiple, the development of alcoholic fatty liver has been attributed to a combined increase in the rate of de novo lipogenesis and a decrease in the rate of fatty acid oxidation in animal liver. Among various transcriptional regulators, the hepatic SIRT1 (sirtuin 1)-AMPK (AMPK-activated kinase) signaling system represents a central target for the action of ethanol in the liver. Adiponectin is one of the adipocyte-derived adipokines with potent lipid-lowering properties. Growing evidence has demonstrated that the development of alcoholic fatty liver is associated with reduced circulating adiponectin levels, decreased hepatic adiponectin receptor expression, and impaired hepatic adiponectin signaling. Adiponectin confers protection against alcoholic fatty liver via modulation of complex hepatic signaling pathways largely controlled by the central regulatory system, SIRT1-AMPK axis. This review aims to integrate the current research findings of ethanol-mediated dysregulation of adiponectin and its receptors and to provide a comprehensive point of view for understanding the role of adiponectin signaling in the development of alcoholic fatty liver.

Figure 1. Proposed mechanisms that underlie the protective action of adiponectin against alcoholic fatty liver. Adiponectin protects against development of alcoholic fatty liver through coordination of multiple signaling pathways mediated by various transcriptional regulators including SIRT1, AMPK, SREBP-1, PGC-1 /PPAR , CD36, and UCP2. Abbreviations: AdipoR, adiponectin receptor; AMPK, AMP-activated kinase; ACC, acetyl-coenzyme A carboxylase; CD36, fatty-acid translocase; FA, free fatty acids; MRC, mitochondrial respiratory chain; SIRT1, sirtuin 1; SREBP-1c, sterol regulatory element-binding protein 1c; PGC-1 , peroxisome proliferator-activated receptor co-activator-alpha; PPAR , peroxisome proliferator-activated receptor alpha; TNF , tumor necrosis factor alpha; UCP2, uncoupling protein-2.

Endocrine Reviews 2005; 26 (3): 439-451

Metabolic syndrome is thought to result from obesity and obesity-linked insulin resistance. Obesity in adulthood is characterized by adipocyte hypertrophy. Adipose tissue participates in the regulation of energy homeostasis as an important endocrine organ that secretes a number of biologically active “adipokines.”

Heterozygous peroxisome proliferator-activated receptor- knockout mice were protected from high-fat diet induced obesity, adipocyte hypertrophy, and insulin resistance. Systematic gene profiling analysis of these mice revealed that adiponectin/Acrp30 was overexpressed. Functional analyses including generation of adiponectin transgenic or knockout mice have revealed that adiponectin serves as an insulin-sensitizing adipokine. In fact, obesity-linked down-regulation of adiponectin was a mechanism whereby obesity could cause insulin resistance and diabetes.

Recently, we have cloned adiponectin receptors in the skeletal muscle (AdipoR1) and liver (AdipoR2), which appear to comprise a novel cell-surface receptor family. We showed that AdipoR1 and AdipoR2 serve as receptors for globular and full-length adiponectin and mediate increased AMP-activated protein kinase, peroxisome proliferator-activated receptor- ligand activities, and glucose uptake and fatty-acid oxidation by adiponectin. Obesity decreased expression levels of AdipoR1/R2, thereby reducing adiponectin sensitivity, which finally leads to insulin resistance, the so-called “vicious cycle.” Most recently, we showed that osmotin, which is a ligand for the yeast homolog of AdipoR (PHO36), activated AMPK via AdipoR in C2C12 myocytes. This may facilitate efficient development of adiponectin receptor agonists.

Adiponectin receptor agonists and adiponectin sensitizers should serve as versatile treatment strategies for obesity-linked diseases such as diabetes and metabolic syndrome.