SEARCH

SEARCH BY CITATION

Why are obesity and insulin resistance associated with hemostatic and metabolic abnormalities?

  1. Top of page
  2. Why are obesity and insulin resistance associated with hemostatic and metabolic abnormalities?
  3. References

We are increasingly aware that obesity is burgeoning and that we are facing a serious public health issue. Obesity is now known to be intimately linked with insulin resistance, Type 2 diabetes, and cardiovascular disease, and investigation into the mechanisms surrounding this has led to an increased understanding of the adipocyte. Although traditionally thought of as a passive storage cell, it is now clear that it has a critical role to play in the manifestation of the features of insulin resistance [1]. In the last decade several novel (leptin, adiponectin, resistin) and previously known proteins [tumor necrosis factor (TNF)-α, C-reactive protein, plasminogen activator inhibitor (PAI)-1, renin, angiotensinogen] have been identified as being produced by the adipocyte, and through the actions of these proteins, the adipocyte itself is central to the development of insulin resistance and vascular disease [2,3].

By releasing TNF-α the adipocyte directly suppresses insulin signaling, induces insulin resistance and has direct inflammatory effects on the macrophage and the endothelial cell, which promote the development of atherosclerosis. PAI-1 is a prothrombotic factor that inhibits plasmin preventing the breakdown of fibrin clots and circulating levels of PAI-1 increase with increasing obesity and predict cardiovascular events and mortality [2]. Renin and angiotensinogen are involved in blood pressure control causing vasoconstriction. The fact they are produced by the adipocyte may explain the link between obesity and hypertension. Leptin exerts an effect on the central nervous system to increase energy expenditure and reduce food intake. Obesity is associated with leptin resistance and increased leptin secretion. Leptin is involved in regulating insulin action within the liver and also has anti-inflammatory actions. Adiponectin secretion is reduced in obesity, which further increases insulin resistance and inflammation [3].

One has to ask, why does the adipocyte develop an insulin-resistant, prothrombotic, proinflammatory phenotype? The human body has evolved to conserve nutrition in times of plenty and then to make the stored energy available in times of need. It can be seen that there would be a distinct survival advantage for those who most effectively stored energy in times of excess and conserved energy during times of famine. It is only in the last century that an abundance of nutrition has been freely available and it would seem likely that these individuals have become those most prone to the onset of obesity brought on by excess consumption and a reduction in energy expenditure associated with modern day living. The response to this energy imbalance is adipocyte hypertrophy (increased cell size) and hyperplasia (increased cell number) [4], leading to increased secretion of adipocyte proteins and their attendant effects leading to insulin resistance, inflammation and thrombosis.

Perhaps there may also be some answers as to why the adipocyte produces these particular proteins by examining the metabolism of the hibernating mammal [5,6]. In anticipation of winter, hibernating animals lay down fat in their existing fat cells. This is associated with the development of peripheral insulin resistance, decreased glucose utilization, leptin resistance, and (in some mammals) a prothrombotic state. The benefits of these physiological changes to the mammal are that it has increased resistance to hypothermia, ischemia, and bacterial infection. During hibernation these mammals gradually utilize their fat stores and emerge from winter lean and healthy. Perhaps individuals with obesity are effectively preparing to hibernate but then not doing so and as a result become chronically insulin resistant. Under such circumstances the response that is so protective in the short term may chronically become the cause of insulin resistance Type 2 diabetes and increased vascular risk clustering in the long term.

References

  1. Top of page
  2. Why are obesity and insulin resistance associated with hemostatic and metabolic abnormalities?
  3. References