The cause of obesity is not fully understood, but it is becoming clear that metabolic dysfunction leading to insulin resistance is a contributory factor. Obesity is characterised by chronic systemic inflammation, because as white adipose tissue accumulates, pro-inflammatory cytokines are released into circulation from adipocytes. Tumour necrosis factor alpha, interleukin-1, interleukin-1β and interleukin-6 are all released from adipocytes, because of an influx of macrophages to adipose tissue. This resultant inflammation may cause the development of atherosclerosis and cardiovascular disease which are both associated with obesity. Adiponectin is another cytokine produced by adipose tissue (an adipokine), but unlike other cytokines its levels fall as white adipose tissue accumulates. Patients with diabetes and cardiovascular disease have suppressed levels on adiponectin, and this may be because low adiponectin is strongly associated with insulin resistance.
Adiponectin is able to cause cellular changes in both the liver and skeletal muscle because it acts via the adenosine monophosphate-activated protein kinase (AMPK) second messenger system. Adiponectin stimulated phosphorylation of AMPK causes the conversion of the active form of acetyl CoA carboxylase to the inactive form, and this results in a decrease in fatty acid synthesis. The resultant reduction in the cellular concentrations of malonyl CoA remove the inhibition from the enzyme carnitine palmitoyl transferase, and thus increases transport of fatty acids into the mitochondria for β-oxidation. Increased cellular levels of AMPK also increase the expression of the enzymes involved in β-oxidation. Adiponectin therefore plays a stimulatory role in the utilisation of fatty acids as a fuel source, which reduces their circulating levels. The reduction in the circulating fatty acids reduces their interfering effect with the insulin receptor and thus increases insulin sensitivity (figure 1).
Figure 1. Effects of adiponectin on glucose and fat metabolism. ACC = acetyl CoA carboxylase; PEPCK = phosphoenolpyruvate carboxylase; G6-P = glucose 6-phosphate; AMPK = adenosine monophosphate activated protein kinase; VLDL = very low density lipoprotein.
The up regulation of fatty acid oxidation as a result of adiponectin release also causes alterations in the circulating levels of lipoproteins, in particular a decrease of very low density lipoprotein (VLDL). This occurs because the inhibition of acetyl CoA carboxylase causes a decrease in the rate of de novo lipogenesis. Coupled to the reduction in the delivery of fatty acids from peripheral tissues, the reduced fatty acid synthesis causes a decrease in fatty acid esterification and therefore a reduction in very low density lipoprotein formation. Lower levels of circulating VLDL reduce triglyceride delivery to peripheral tissues such as the skeletal muscles, and therefore increases insulin sensitivity. Insulin sensitivity is increased further because adiponectin decreases flux through gluconeogenesis to limit cellular glucose production. This occurs via direct inhibition by adiponectin of the rate limiting gluconeogenic by-pass enzymes glucose 6-phosphatase and phosphoenolpyruvate carboxylase.
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