Since 1995, with the discovery of leptin, adipose tissue has been recognized as an active endocrine organ, not only a site for energy storage. The peptide hormones secreted by adipose tissue are collectively called adipocytokines, and include leptin, adiponectin, tumor necrosis factor-α (TNF-α), plasminogen activator inhibitor-1, interleukin-6 (IL-6), and recently described visfatin, apelin, and others. Some adipocytokines including adiponectin, leptin, resistin, TNF-α, IL-6, visfatin and apelin have a close relationship with obesity, insulin sensitivity and type II diabetes.
Adiponectin, also called adipocyte-complement-related protein of 30KD (Acrp 30), is a plasma protein secreted by adipose tissue. Adiponectin mRNA expression is reduced in obese and diabetic mice, and its plasma levels are significantly suppressed in human subjects with obesity, type II diabetes or insulin resistance. A significant increase in plasma adiponectin in obese mice exposed to anti-diabetic thiazolidinediones (TZD) treatment preceded the decrease in plasma glucose levels. Adiponectin is regarded as one of the determinants of insulin sensitivity. It regulates insulin sensitivity and glucose homeostasis via the activation of adenosine monophosphate (AMP)–activated protein kinase (AMPK) in the liver and muscle, which phosphorylates and inactivates acetyl-coenzyme A carboxylase (ACC). There is then a decrease in the production of malonyl CoA, a substrate for fatty acid synthase (FAS) and a potent inhibitor of mitochondria transportation of fatty acids, and therefore decreases in fatty acid synthesis, which promotes fatty acid oxidation and reduces the accumulation of triglycerides in liver and muscle. Adiponectin also reduces the expression of enzymes involved in gluconeogenesis including glucose-6- phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) in the liver, and directly stimulates glucose uptake in muscle and adipocytes by activating AMPK, thus regulating insulin sensitivity and energy homeostasis.
Leptin has been widely accepted as an adiposity signal controlling food intake and energy expenditure. Plasma leptin levels are positively related to the fat mass and are significantly increased in obese, type II diabetic, and insulin resistant patients. Mice that are deficient in leptin (obese, ob/ob) or leptin receptor (diabetic, db/db) exhibit hyperphagia, obesity, and diabetes. Exogenous leptin administration to ob/ob mice reverses these abnormalities. Leptin binds to its receptors located in hypothalamic arcuate nucleus, activates neurons that express proopiomelanocortin (POMC) to release anorexic neuropeptide, α-MSH, and inhibits neurons that express orexigenic neuropeptide Y (NPY) and agoutirelated protein (AgRP), which potently stimulate food intake and metabolic efficiency. α-MSH binds to and acts on melanocortin 4 receptors (MC4R) located in downstream neurons in paraventricular nuclei (PVN) and the lateral hypothalamus (LH), thus decreasing food intake and increasing energy expenditure actions, which are mediated in part by corticotrophin releasing hormone (CRH) and oxytocin. α-MSH also increases the gene expression of uncoupling protein (UCP) 1, UCP2 and UCP3 in adipose tissue, and thus promotes energy expenditure. Leptin treatment enhances the ability of insulin to inhibit endogenous glucose production via suppressing the key enzymes in gluconeogenesis, G6Pase and PEPCK. Thus, leptin plays a pivotal role in regulation of total-body sensitivity to insulin. In addition, by binding to its receptor, leptin initiates a phosphorylation cascade via Janus kinase (Jak)/ signal transducer and activator of transcription-3 (STAT-3) pathway, then phosphorylates and activates AMPK and peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α (PGC- 1α), and thus down-regulates lipogenic enzymes, such as ACC, FAS, upregulates lipid oxidation-related enzymes, such as carnitine palmitoyl transferase 1 (CPT-1), and acyl-CoA oxidase (ACO), and therefore regulates lipogenesis and fatty acid oxidation.
Fig.1 The normal lipid metabolism regulated by leptin.
Resistin is recognized as an anti-adipogenic factor and an inducer of insulin resistance. It inhibits adipocyte differentiation, impairs glucose tolerance, decreases insulin-mediated glucose uptake, and increases hepatic glucose production. Plasma resistin levels were reported to be elevated in the genetic (ob/ob) and high-fat-diet- induced obese mice and in insulin-resistant animals. Resistin administration to normal mice impaired glucose tolerance and action of insulin. Anti-diabetic treatment with thiazolidinediones (TZD) reduced resistin gene expression and protein levels. Mice with resistin deficiency exhibited low hepatic glucose production and low plasma glucose levels after fasting. However, some reports showed that resistin mRNA expression in fat tissue was reduced in obese mice, and there were decreased resistin levels in insulin resistant mice. A recent report showed that there was no correlation between resistin gene expression and plasma insulin levels or insulin resistance, but there was a significant positive correlation between resistin gene expression and plasma glucose levels, indicating that resistin might be involved in the regulation of glucose homeostasis. Thus the role of resistin in insulin resistance and obesity is controversial and remains to be elucidated in future studies.
TNF-α and IL-6, proinflammatory cytokines involved in chronic inflammation and malignancy, now are well documented as adipocytokines contributing to insulin resistance. The mRNA expression of TNF-α is positively correlated with body adiposity, insulin, triglycerides and free fatty acids (FFA) levels. TNF-α impairs the insulin signaling pathway by blocking tyrosine kinase activity of insulin receptors (IRs) and inducing serine phosphorylation of IR substrate (IRS), thus decreasing insulin-induced tyrosine phosphorylation of IRS- 1, and decreasing the activation of PI3 kinase. It also decreases insulin secretion from pancreatic islets. In addition, TNF-α down-regulates glucose transporter 4 (GLUT4) gene expression, induces the expression of suppressor of cytokine signaling (SOCS)-1 and SOCS-3, and suppresses the release of adiponectin. IL-6 not only increases hepatocyte glucose release through inhibition of glycogen synthase and acceleration of glycogen phosphorylase activities, but also influences glucose uptake in muscle and adipocyte by suppressing GLUT4 synthesis. IL-6 inhibits IR signal transduction in liver, which is mediated at least partly by the induction of SOCS-3. It also may increase circulating free fatty acids (FFA) and decrease adiponectin secretion.