INFLAMAÇÃO, TECIDO ADIPOSO E DIABETES T2 (INGLÊS) - Monash University

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© Monash University 2016 FutureLearn 1 
 
 
Inflammation in adipose tissue 
and type 2 diabetes 
 
 
 
Fat stores in the body provide a means of storing energy, providing insulation 
against the cold and give some protection for vital organs. Fat is stored at many 
locations in the body including under the skin (subcutaneous adipose tissue) and 
internally around body organs like the kidneys (visceral adipose tissue). When 
people have excess fat (and are clinically classified as obese), most adipocytes 
(cells that store fat) have become full of lipid so that free fatty acid levels rise in 
the blood and fat begins to become deposited in body tissues like the skeletal 
muscle, liver and pancreas whose normal function is not fat storage. The presence 
of abnormally high fat levels in these tissues is highly damaging. 
 
The pathway towards this more general tissue damage starts with damage within 
the adipose tissue itself. In the obese condition, the fat cells gradually become 
overloaded with lipid. Some divide to make more fat cells to contain all the fat, 
which is the less harmful response. But most fat cells just become larger and larger 
(hypertrophy). Small blood vessels then grow into the fat tissue to provide enough 
nutrients for the enlarging cells. As very large fat cells become more and more 
metabolically stressed due to their lipid overload, they begin to die. As they die, 
they signal their stressed state by secreting molecules such as monocyte 
chemoattractant protein 1 (MCP-1) which attract monocytes in to the adipose tissue 
from the blood. 
 
Entering the adipose tissue, these monocytes turn into adipose tissue macrophages. 
They encounter stressed adipocytes that are starting to release their stored fat as 
free fatty acids, because they can not expand to store any more fat. Free fatty 
acids and some toxic products such as ceramide, are released into the blood 
stream. The macrophages at first appear to try and help the adipocytes with their 
lipid overload by taking up some of the lipid themselves. But since macrophages are 
not well designed for lipid storage, much of this fat is soon released. As obesity 
continues, macrophages continue to accumulate in adipose tissue, along with other 
immune cells, initiating chronic low grade inflammation. Interestingly, the type of 
fat stored in the adipocytes can affect the level of inflammation. High levels of 
saturated fatty acids stored in enlarging adipocytes is most likely to result in the 
infiltration of macrophages with high inflammatory activity. Fat stored in adipose 
tissue reflects the fat eaten in the diet. So people who eat a lot of saturated fat 
will store more saturated fat in their adipocytes. 
	
FutureLearn	 2 
 
In badly inflamed adipose tissue up to 60% of the total number of cells can be 
made up of macrophages. This is a very unhealthy situation which leads to an 
outpouring not only of free fatty acids but also of pro-inflammatory signals, 
released by the stressed adipocytes into the blood. One of the most important of 
these signals is Tumour Necrosis Factor alpha (TNF-⍺). In this way the state of 
chronic inflammation can spread through the body. 
 
Fat in adipose tissue is usually stored in fat droplets in the form of stable 
triglycerides (formed as complexes of three fatty acids). When blood sugar levels 
are sufficient to provide the skeletal muscle with sufficient energy, the hormone, 
insulin signals to prevent any breakdown of these triglycerides stored in adipocytes 
as fat is not needed for body energy when there is sufficient sugar available. But 
when adipocytes become stressed and TNF-⍺ levels rise, the adipocytes fail to 
respond to this insulin signal and will break down triglycerides and release free 
fatty acids into the blood even if this is in large excess to what is needed for body 
energy. Important metabolic tissues, notably the liver and the skeletal muscle then 
become exposed to excessively high levels of free fatty acids. 
 
In the liver, the arrival of excessive amounts of free fatty acids released from 
adipose tissue results in the deposition of fat droplets within the hepatocytes (liver 
cells). This is ectopic fat deposition i.e. fat deposition that occurs in a tissue not 
designed to store fat. At the same time these fatty acids can damage the liver cells. 
This is particularly likely if the free fatty acids are made up largely of saturated fat. 
The presence of ectopic fat in the liver soon triggers an inflammatory response. One 
of the main types of cell involved is the Kupffer cell, which is a specialised liver 
macrophage. The normal function of Kupffer cells is to engulf and destroy any 
foreign organisms that may get into the liver. However, as liver tissue gets 
increasingly fatty, the Kupffer cells begin to multiply, and like activated 
macrophages in the adipose tissue they release many pro-inflammatory signals. 
These in turn trigger infiltration of immune cells which increasingly harms liver cells 
and alters their metabolism. If all these changes continue and ectopic fat continues 
to accumulate in liver cells, causing inflammation, the result over the longer term is 
non-alcoholic fatty liver disease (NAFLD). This is the most common form of liver 
disease world-wide. 
 	 
	
© Monash University 2016 FutureLearn 3 
One normal function of the liver is to produce glucose and release it into the blood, 
something that is very useful during the night when blood glucose levels tend to 
fall while the body is asleep. During the day, the action of insulin stops hepatic 
glucose production. It is not required now because sufficient glucose can readily be 
absorbed from foods consumed. However, when the liver is burdened with excess 
fat, the liver cells become less and less able to respond to insulin. They continue to 
make glucose at an inappropriate time releasing it into the circulation causing blood 
glucose levels to rise. 
 
Release of excess free fatty acids from adipose tissue also results in deposition of 
ectopic fat in skeletal and cardiac muscle. The deposition of lipid droplets within 
muscle makes the muscle tissue work much less efficiently and as with the liver, the 
presence of this ectopic fat makes the muscle more resistant to signals from insulin. 
As skeletal muscle is responsible for clearing about 80% of glucose from the blood. 
So when muscle cells are much less able to respond to a rise in insulin levels by 
taking in blood glucose and using it for energy. This insulin resistance in skeletal 
muscle again means that blood sugar levels will rise. 
 
If conditions of fatty liver and/or fatty muscle continue over time, type 2 diabetes 
may eventually develop in genetically susceptible individuals. There is therefore a 
link between becoming very overweight, onset of inflammation in adipose tissue, fat 
spillover and the deposition of ectopic fat (particularly in muscle and liver) and the 
development of type 2 diabetes. 
 
Not all people who are obese however, will develop diabetes. Interest has grown as 
to why this is so. Up to about 30% of obese individuals are ‘metabolically healthy’. 
They seem to have adipose tissue that is more readily able to expand to store 
additional fat and that therefore does not become infiltrated with macrophages and 
never becomes very inflamed. Obese individuals who are physically active are more 
likely to be in this ‘metabolically healthy’ condition. They are also more likely to 
deposit fat in subcutaneous stores than as visceral fat.