Inflammation and obesity...

Abstract.

Obesity and excess weight resulting from inflammation is a radical departure from orthodox thinking that is dominated by the energy imbalance theory.  The muscle cell is responsible for converting food, in the form of glucose and fat, into energy.  Muscle cell efficiency can be diminished by inflammation resulting in a loss of efficiency.  Glut4 is required to facilitate transport of glucose through the muscle cell membrane, if it cannot enter the cell, it will be stored in the adipocytes.  Lipolysis is dependent upon LPL, for delivery of fat to the adipocytes, the delivery of free fatty acids to the muscle cells and the conversion of serum triacylglycerols into free fatty acids.  Oxygen is required to allow the cell to operate aerobically; while the cell can operate anaerobically this reduces energy output significantly.

 Glut4, LPL and oxygen are all adversely affected by inflammation, contributing to insulin resistance, in particular by TNF alpha, which is released by a number of activated immune cells and by the adipocytes.  TNF alpha inhibits IRS-1, the insulin receptor, while TNF alpha and IL-6, working by different pathways, suppress the availability of Glut4, required to deliver glucose; similarly TNF alpha and IL-6 suppress the production of LPL interrupting fat metabolism.  ROS, generated by activated by PMN, decrease the oxygen carrying capacity of the erythrocytes and prevent the erythrocytes from entering the capillaries a function required to deliver oxygen to the muscle cells and for the clearance of Co2.

The obese are at a considerable biochemical disadvantage when compared to the normal weighted individuals

Orthodox thinking on the subject of obesity has been dominated for nearly eighty years by the ‘energy imbalance’ theory; energy, it maintains, consumed in the form of food but not expended through activity will be converted to fat and stored, resulting in excess weight.  Equally, it is generally believed that if activity uses more energy than is consumed as food, excess fat will be released as an alternative fuel and weight loss will occur.

Despite the logical simplicity of the theory, in practice there is a global epidemic of obesity and the supposed related illnesses of CHD, hypertension, atherosclerosis and diabetes (Type II) perpetuated, at least in part, by a predilection to doubt the veracity of the sufferer rather than the theory following unsuccessful intervention.  Recent developments in immunology,[1] however, demonstrate that it is not an energy imbalance but inefficient energy conversion that underlies excess weight and its successful treatment and, furthermore, that the inflammatory conditions responsible for the inefficiency are capable of creating an environment that favors the development of ‘obesity-related’ diseases.

Irrespective of conflicting theories, it is a fact that the muscle cell is responsible for realizing the majority of the potential energy contained in food.  Digestion converts foods into a form that can be used by the muscle cells, primarily glucose and free fatty acids.  Following the consumption of a meal, blood sugar rises triggering the pancreas to release insulin.  Insulin inhibits lipolysis[2] (the process by which fat, in the form of triacylglycerols, is converted into free fatty acids) and presents glucose to the muscle – in order to cross the muscle cell membrane there must be an abundance of Glut4 available[3] and a sufficient number of insulin receptors (IRS-1 inhibited by TNF alpha)  on the muscle cell membrane to stimulate the movement of the Glut4 to the surface – without Glut4, glucose cannot enter the muscle cell.  As the glucose, which has successfully crossed into the muscle cell, is consumed, glucose levels in the blood fall and insulin production stops allowing lipolysis to occur, providing the muscle cell with energy until the next meal; if glucose is not able to enter the muscle cell insulin will send it to the fat cells for storage.

Lipolysis is, by comparison, a highly complex process.  Fat is stored in the fat cells (adipocytes) in the form of triacylglycerols (comprised of three free fatty acids and glycerol).  More than 10% of normal body weight is made up of this form of stored fat.  More triacylglycerols circulate in the blood and some are stored in the muscles.  Fat is released and made available as a fuel, when glucose levels are low, through the action of two main enzymes, hormone sensitive lipase (HSL) and lipoprotein lipase (LPL).  Following stimulation by epinephrine, HSL breaks apart the triacylglycerols stored in the adipocytes, releasing the free fatty acids (a process that is significantly reduced by obesity where HSL is less responsive to epinephrine[4]).  Once in the bloodstream the free fatty acids bind to albumin to be carried to the muscle cells.  As with glucose, the free fatty acids require a means of crossing the cell membrane; this task is performed by three tranporters, fatty acid binding protein (FABP), fatty acid translocase (FAT) and fatty acid transport protein (FATP).

LPL, the second hormone involved in lipolysis, is found on blood cell walls throughout the body and in the fat cells (adipose tissue).  LPL controls the flow of fat to the fat cells for storage and the flow of free fatty acids to the muscle cells as an alternative fuel.[5]  In addition, LPL converts serum triacylglycerols in the form of chylomicrons from intestinal absorption and lipoproteins from the liver into free fatty acids, LPL being activated by C-11 apoproteins from the triacylglycerols.

The efficiency of energy conversion is also determined by the amount of oxygen available to the muscle.  The Krebs cycle shows that a molecule of glucose burned aerobically (in the presence of oxygen) will release 36 molecules of ATP but that the same molecule burned anaerobically (without oxygen) will produce only 2 molecules of ATP.  Oxygen is delivered from the lungs to the muscle cells by the erythrocytes (red cells).

Thus it can be seen that the muscle cell, which is responsible for energy conversion, is fuelled by glucose and fat burned, for maximum efficiency, in the presence of oxygen.  However, this finely balanced system is susceptible to and can be completely subverted by the action of inflammation – in particular, low-level background inflammation.

Although there are complex sequences governing each aspect of energy conversion in the muscle cell, a number of key components – IRS-1, Glut4, LPL and oxygen, etc - can be upset by inflammation leading to a dramatic increase in appetite, a reduction in available physical energy and a subsequent increase in weight.

Inflammation is the key defender of the body against a hostile immediate environment.  The immune system, which creates inflammation after detection of a potential threat from ‘non-self’ material, is highly complex and extremely robust – any illness that threatens the immune system, e.g. AIDS, is normally fatal.  The system can be triggered very quickly and by a variety of routes that will be discussed in the next section. 

Elements of ‘non-self’ entering via the epithelium almost certainly stimulate the release of the cytokine TNF alpha, initially from mucosal mast cells but also from other immune cells and, ironically, adipocytes, too.  TNF alpha results in insulin resistance both directly by the induction of SOCS-3, which reduces IRS-1 and indirectly by stimulating the production of stress hormones.[6]  The trans-cell membrane carrier, Glut4 is also adversely affected by TNF alpha effectively cutting off the muscle cell from glucose fuelling; levels of Glut4 have been found to be 37% lower in obese individuals in comparison to lean individuals,[7] whereas TNF alpha is elevated in obese individuals.[8]  Unable to enter the muscle cells due to the effects of insulin resistance, glucose is re-directed to the adipocytes where it can further effect the development of obesity – fatty acids will be re-esterified (stored) if glycerol 3-phosphate is plentiful, as opposed to being released into the plasma when glycerol 3-phosphate is scare as is the case when glucose supplies in the adipocytes are scarce.

TNF alpha also has a major direct effect on the prevention of fat (in the form of free fatty acids) being used as an alternative fuel.  LPL plays a triple role in the use of fat as a muscle cell fuel.  LPL transports fat to the adipocytes, transports free fatty acids from the adipocytes back to the muscle cells and converts serum triglycerides into free fatty acids.  Disruption of these key events has a catastrophic effect on muscle cell fuelling and on the arterial health of the individual.

Despite its key role, LPL is sensitive to disruption by a number of aspects of the inflammatory response.  TNF alpha, largely responsible for insulin resistance also has an inhibitory effect on LPL [9 and 10] which increases (i.e. deteriorates) the more insulin resistant the individual.[11]   In addition to TNF alpha, which is expressed by a number of different immune cells and adipocytes, LPL activity is decreased by IL-6 which is also expressed by a similar range of cells and adipocytes.  Furthermore, IL-6 stimulates the hypothalamic-pituitary-adrenal axis, which is also involved in the development of insulin resistance.[12]  While the obese are disadvantaged by the fact that adipocytes express both TNF alpha and IL-6, increasing exercise, in line with orthodox advice, also has an adverse effect on LPL production,[13] which is not apparent when exercise is undertaken by the non-obese.[14]  Exercise can also increase the rate of adaptation to a high fat diet by increasing the rate of fat oxidation.[15]  Calorie restriction, too, can have a dramatic effect on LPL activity, falling by as much as 50% after calorie restriction for as little as seven days.[16] 

The PMN, operating either directly or via the mast cells, is capable of disturbing the muscle cell microenvironment to the extent that glucose and free fatty acid availability is serious impeded.  The effect on energy conversion is further enhanced by the PMN’s ability to generated ROS.  ROS can severely damage the erthyrocytes, reducing their ability to carry oxygen from the lungs (and to remove carbon dioxide).  In addition to effecting the ability of the cell to carry oxygen, obesity and associated low grade inflammation has been shown to have the effect of promoting erythrocyte adhesiveness.[17]  As the single erythrocyte has to reduce its surface area in order to enter the capillary to deliver its oxygen load to the muscle cell, aggregation would ensure that the available oxygen would decrease significantly.  Reducing oxygen to the muscle cell ensures that the cell operates anaerobically reducing the ATP generation from a molecule of glucose falls from 36 molecules to 2 molecules.

 

 Biochemical disadvantage of obese/overweight over normal weighted persons

• HSL less responsive to epinephrine thus less triacylglycerols converted to free fatty acids

• less LPL to deliver free fatty acids from adipose tissue to muscle cells and to convert triacylglycerols, in the form of chylomicrons and lipoproteins in the bloodstream to free fatty acid (fuel) form

• less LPL to deliver fats to fat cells thus increasing triacylglycerols in the bloodstream with increased risk of oxidation by free oxidising radicals increasing risk of atherosclerosis

• poor muscle to fat ratio thus less muscle cells to metabolise fats

• increased TNF alpha production from fat cells up-grading subversion of muscle cell microenvironment

• higher HL-LPL ratio resulting from peripheral insulin resistance

• increased insulin resistance leading to lower LPL activity and higher triacylglycerols in the bloodstream

• decrease in LPL activity following endurance training (non obese individuals experience higher LPL activity after similar training)

• higher body mass index (BMI) is associated with higher C-reactive protein (CRP) which is itself a risk factor in CHD

• adipose tissue (fat) releases IL-6 which decreases LPL and monomeric LPL levels in plasma, this increases macrophage uptake of lipids creating foam cells – the major part of an atheroma. Foam cells express further IL-6. Circulating IL-6 stimulates hypothalamic-pituitary hypertension and insulin resistance

• increased erythrocyte aggregation reducing oxygen delivery to the muscle cells and carbon dioxide removal
 

 

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