Obesity is a complex condition that involves the interaction of multiple genetic and environmental factors. Despite this complexity, the cause of obesity is often oversimplified to a condition of a positive energy balance. A small but consistent overconsumption of energy, coupled with a small but consistent decrease in energy expenditure in the form of physical activity, over time results in weight gain. While the laws of thermodynamics suggests that a positive energy balance is associated with obesity, to suggest that it is the cause of unhealthy weight gain could be erroneous. For example, while it could be argued that fat is stored in adipose tissue because it is not oxidised, it could equally be argued that the fat is stored in adipose tissue because it cannot be oxidised. Both of these situations satisfy the law of thermodynamics, but in each case the cause and effect is not the same.
A healthy normal weight individual in free-living conditions is able to regulate appetite, energy expenditure and thermogenesis to a degree that prevents unhealthy weight gain and provides stability to bodyweight. During eating, peptide hormones from the gastrointestinal tract (e.g. peptide YY) feedback to the hypothalamus causing the release of anorexic hormones to limit further food intake. If body fat accumulates, plasma levels of leptin rise to cause longer term decreases in food intake via the same system. In addition, increases in plasma fatty acid concentrations stimulate the expression of uncoupling protein-3 and this dissociates the oxidation of energy from ATP production to heat generation. Physical activity increases the oxidation of fuels in muscle tissue which then sensitises muscle cells to further uptake of glucose facilitating subsequent bouts of physical activity. The healthy individual can therefore regulates body weight despite fluctuations in energy intake.
However, in obese individuals some or all these regulatory mechanisms may be dysfunctional, resulting in preferential storage of energy as adipose tissue. There is some evidence that during a meal, the short-term regulatory mechanisms show minor differences to those seen in normal-weight counterparts. However, this evidence is controversial and the physiology of satiety is not fully understood. There is good evidence that long-term appetite regulation under the control of the leptin system is dysfunctional in obesity, possibly due to insensitivity in the leptin receptors. But the evidence that is the cause of obesity is not convincing. More likely plasma leptin concentrations, that rise in proportion to total fat reserves, causes a gradual down-regulation of the leptin receptor as body fat accumulates and leptin levels rise. Dysfunction of appetite regulation is therefore probably not the overriding cause of obesity, although it may play a secondary role.
Once food is digested and absorbed into the blood, it must be correctly allocated to the desired location to fulfil the bodies energy requirements. This is achieved by a complex regulatory mechanism that involves both hormones and nervous system activity. Evidence is accumulating that it is this regulatory step that is dysfunctional in obese individuals. In particular, the metabolism and storage of carbohydrates has been identified as faulty. Recent research has focussed on the insulin receptor, that appears to become insensitive in a number of individuals. This results in the development of metabolic syndrome, a condition associated with a number of physiological changes such as abdominal weight gain, oxidative stress, detrimental blood lipid changes and systemic inflammation. If left untreated, these physiological changes may increase the risk of the individual developing cardiovascular disease, type 2 diabetes, non-alcoholic fatty liver disease and obesity.
The mechanism by which this insulin resistance may cause obesity is well documented and researched. Both animal and human studies suggest that fructose overconsumption is one of the primary drivers of insulin insensitivity, but in general an overconsumption of poor quality refined carbohydrates, with low intakes of the mineral chromium are likely implicated. Fructose can cause insulin insensitivity if eaten in high concentrations because once hepatic glycogen stores are full, the only metabolic fate is conversion to triglycerides by the liver. These triglycerides enter the plasma in very low density lipoproteins and are the direct cause of high triglyceride levels associated with metabolic syndrome. The triglycerides are transported to muscle tissue, where they are stored as intra-muscular fat droplets. The fatty acids can then be converted to signal molecules such as sphingolipids, phospholipids and eicosanoids, that desensitise the insulin receptor in skeletal muscle resulting in insulin resistance.
As insulin sensitivity deteriorates in skeletal muscle partitioning of blood glucose away from storage as glycogen in myocytes and towards storage as triglycerides in adipocytes, intensifies. High insulin levels associated with insulin resistance exacerbates the problem because insulin stimulate the conversion of glucose to fatty acids in adipocytes and inhibits oxidation. Excessive conversion of glucose to triglycerides in the liver can result in non-alcoholic fatty liver disease. Accumulation of white adipose tissue causes the influx of macrophages which stimulate the release of cytokines that leads to systemic inflammation. This inflammation is thought to damage endothelial cells of arteries leading to the eventual development of cardiovascular disease. The diversion of plasma glucose to storage as triglycerides results in a reduction in glycogen levels in muscle which stimulates the hypothalamus to increase energy intake to compensate. This cycle of compensatory overeating because of incorrect energy partitioning leads to weight gain.
If we return to the laws of thermodynamics and the question of energy balance, it can be seen that overeating in obesity could quite easily be explained by the incorrect distribution of energy due to a metabolic defect. Analogous to this situation would be an engine with two fuel tanks. Adding fuel to the filler increases energy in both tanks but only one is connected to the engine. The lower energy availability causes reduced work from the engine, that can only be compensated for by adding extra fuel to the tank. However, each time fuel is added the quantity diverted to the isolated tank increases, but is unavailable for work and so results in weight gain for the machine. To state that the isolated fuel tank has accumulated fuel due to the lack of work by the engine or an over filling of the tank is as misleading as it would be to consider obesity as result of overeating or a lack of physical exercise.
RdB
