32. Etiology and pathogenesis of obesity

The direct cause of obesity is a too large energy intake coupled with a too small energy expenditure. However, the real, underlying cause must be endogenous as there is some endogenous need for the person to consume more food than they need, or to store (rather than use) more nutrients than needed, or to use less energy than normal.

Studies on identical twins have shown that in twin pairs where one twin is obese is there a higher risk for the other twin to also develop obesity than in twin pairs where none of the twins were obese. If both parents are obese is the risk for the children to also become obese much higher than if one or none of the parents are obese. These studies control for all other factors, so the conclusion is that there must be some genetic factors involved.

It’s widely accepted that genetic factors in obesity are more likely polygenic rather than monogenic. Some hypotheses exist as to which genetically inherited factors may be involved:

• Differences in taste preferences – those who prefer more sweet food developed obesity more frequently
• Differences in palatability (the pleasure derived from certain foods)
• Inherited differences in muscle structure – obese people may have more fast-twitch muscle fibres, which use less energy than slow-twitch fibres
• Inherited disorders of chemical control of feeding behaviour
  • Leptin and leptin receptor abnormalities
  • MC4 receptor expression abnormalities – the receptor is stimulated by MSH and inhibited by AgRP
  • POMC disorders
  • PPAR-γ disorders

MC4 and POMC disorders may explain up to 5% of morbidly obese children. All humans with mutations in PPAR-γ described so far have developed obesity.

Leptin levels are often elevated in obese people, which may suggest that the hormone is ineffective in its normal duty in these people, just like insulin in diabetes type 2. However recent research has cast doubt on the idea that leptin resistance causes obesity.

The large upswing in obesity cases the last 50 years indicate that the major cause of obesity isn’t genetic but rather environmental. Whether you have genetic factors that predispose to obesity or not can keeping an adequate diet and maintaining adequate physical activity help you maintain healthy body weight.

Most cases of obesity are “primary”; however we know some conditions that cause “secondary” obesity:

• Insulinoma
• Cushing disease
• Hypogonadism
• Injury to the hypothalamus – the centre of feeding behaviour
• Physical inactivity due to motor disability, old age or neurological disorders
• Psychiatric diseases characterised by obsessive eating
• Depression