• 2018-07
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  • 2019-11
  • br Alcohol and adipose tissue insulin resistance


    Alcohol and adipose tissue insulin resistance, inflammation, and lipolysis Insulin is a hormone produced by pancreatic beta cells. It mediates carbohydrate, lipid, and protein metabolism in multiple organs, including the liver, adipose tissue, and skeletal muscle, to utilize and store Manumycin A from glucose intake. In adipose tissue, insulin primarily increases glucose transport and glycolysis rates, decreases the rate of lipolysis, stimulates FA and triacylglycerol synthesis and TG uptake, and increases the rate of protein synthesis. Insulin resistance refers to the genetic or acquired condition in which the body does not respond well to insulin. As a result, the pancreas produces more insulin, while blood glucose levels remain dysregulated. While insulin resistance often occurs in metabolic disorders, such as type II diabetes and obesity, binge drinking has also been demonstrated to impair whole body insulin sensitivity. Oral or intraperitoneal administration of alcohol in rats for three consecutive days resulted in an impaired insulin response, reflected by higher blood glucose levels and lipolysis rates in adipose tissue. Chronic alcohol consumption has also been suggested to impair insulin sensitivity in adipose tissue. Isolated epididymal and subcutaneous adipocytes from rats treated with ethanol for 4 weeks displayed impaired glucose uptake and a decreased response to insulin-inhibited β-adrenergic agonist-induced glycerol release. Therefore, alcohol-induced adipocyte insulin resistance may also partially contribute to alcohol-induced adipose tissue atrophy by increasing lipolysis. Insulin resistance and obesity are often associated with macrophage infiltration in adipose tissue. Insulin resistance and type II diabetes can often be associated with a switch from M2 (alternatively activated) macrophages secreting anti-inflammatory cytokines, such as IL-6 and TGF-β, to M1 (classically activated) macrophages secreting pro-inflammatory cytokines, such as TNF-α, IL-6, and IL1-β. Furthermore, they are associated with an increased presence of crown-like structures (i.e., macrophages surrounding dead adipocytes). Notably, chronic ethanol consumption for 4 weeks in rats also resulted in increased macrophage infiltration into epididymal adipose tissue. This was accompanied by elevated levels of the genes encoding TNF-α, IL-6, and monocyte chemotactic protein 1 and decreased levels of the genes encoding adiponectin and retinol binding protein 4. Dr. Nagy\'s group has reported that chronic alcohol feeding (25 days) in mice induced apoptosis and inflammation in WAT in a Cyp2E1/Bid/C1q-dependent manner. The same group also reported that chronic alcohol feeding (4 weeks) in rats suppressed adiponectin secretion and enhanced markers of oxidative stress via the Cyp2E1 pathway. This suggests that ethanol metabolism and ethanol-induced adipocyte cell death promote inflammation in adipose tissue. It is well known that elevated intracellular cAMP concentrations and enhanced catecholamine signaling stimulate the β2-adrenergic receptors on adipose tissue to increase lipolysis. Surprisingly, previous work from Dr. Nagy\'s group revealed that chronic ethanol intake suppressed beta-adrenergic receptor-mediated lipolysis in adipocytes. They determined that chronic ethanol consumption decreased beta-adrenergic receptor-stimulated protein kinase A activation and led to decreased perilipin A and HSL phosphorylation. Moreover, chronic ethanol feeding increased phosphodiesterase 4 activity in adipocytes, resulting in decreased cAMP accumulation. In addition, epididymal adipocytes isolated from rats treated with a chronic ethanol liquid diet exhibited similar basal lipolysis but decreased lipolysis in response to β-adrenergic agonist treatment, which was associated with increased phosphodiesterase 4 activity. However, chronic ethanol feeding markedly impaired insulin-mediated suppression of lipolysis in rats and in adipocytes isolated from epididymal and subcutaneous adipose tissue. These data suggest that alcohol-induced adipose tissue atrophy is likely due to a suppression of the anti-lipolytic effects of insulin in adipocytes but may not directly affect the beta-adrenergic receptor.