Pushing the Inflammatory Response
 IL-6 is present in fat tissue in much higher amounts than is found in the blood. In fact, IL-6 concentrations in fat tissue exceed 100 times the blood level. The signaling mechanism for producing and secreting IL-6 is complex. However, some key players are present that help explain the interrelationship between inflammation and lipolysis.
 Norepinephrine, the excitatory nerve signal that turns on fat loss with products like ephedrine and caffeine, stimulates the inflammatory cascade in fat cells, including IL-6 and tumor necrosis factor alpha (TNF). Interestingly, the amount of IL-6 produced is greater in larger fat cells, which are seen in disease states and obesity. In the presence of the high local concentrations of IL-6, fat cells release stored fat as free fatty acids with greater amounts coming from larger fat cells.
 Other reactions take place in the fat cells, including changes that make the fat cells resistant to insulin. By blocking the fat cell’s response to insulin, less fat is taken into storage from the blood, protecting the body from accumulating too much fat. Unfortunately, this only happens if the diet is controlled. Daily buffets and nightly tubs of ice cream force the fat cells to push the inflammatory response into overdrive. As a consequence, high levels of free fatty acids and IL-6 enter the bloodstream. From the subcutaneous fat (the kind you can pinch), the excess IL-6 and free fatty acids enter the circulating blood and likely account for much of the basal IL-6 seen at rest. However, the real problem comes from the visceral fat (the fat inside your abdominal cavity and that lines the organs of your gut). Visceral fat has a much higher rate of production of IL-6 and is more fibrovascular. This is important because it’s been determined that as much as 90 percent of fat-associated IL-6 actually comes from the fibrous tissues and blood vessels that support the structure. The obese also seem to collect inflammatory cells within fat, which further stimulate and generate inflammatory cytokines. Making the matter worse is the fact that visceral fat drains directly into the liver, rather than being diluted in the circulating bloodstream.
 The liver is a critical organ. It plays a vital role in controlling the amount of sugar and fat circulating in the body. It’s also the site of production for many important proteins. When high levels of free fatty acids enter the portal circulation (the primary bloodstream for the liver), the liver packages them up into triglycerides and sends them into the circulating bloodstream to be taken up by fat cells or working tissue (like muscle). However, when present in excess, triglycerides can build up in the bloodstream and may cause plaques, which can block blood flow and lead to heart attacks or strokes.

 The liver also gets assaulted by high levels of IL-6, which can induce inflammation in the liver, causing cellular damage or scarring, and damage the liver’s ability to respond to insulin. When the liver becomes insulin resistant, it fails to properly control the body’s supply of sugar. Sensing a need for more sugar, it turns off sugar storage, breaks down Amino Acids to create new sugar and pumps out the newly created sugar into the bloodstream, which already has sufficient or high sugar levels.  Normally, this process is turned off by the insulin surge that accompanies meals, but as the liver no longer responds properly to insulin, muscle is robbed of Amino Acids to feed the sugar-producing process and new sugar continues to enter the bloodstream, even as a meal is being consumed. Correcting the insulin-resistant state of the liver is believed to be one mechanism for the success of metformin in reducing body fat.