Richard L. Atkinson
Virginia Obesity Research Institute, USA
In 1998 the World Health Organization stated that there was a “global epidemic of obesity.” Starting around 1980 in most countries of the world, both developed and undeveloped, the prevalence of obesity began to rise. There are now more overweight and obese people than starving people in the world. Multiple hypotheses have been advanced to explain the etiologies of the obesities in general and this epidemic in particular. Unfortunately, attention by most governmental authorities and many scientists has focused on the “obvious” etiologies of the “obesogenic” environment. This has led to a governmental, clinical, and research emphasis on diet and physical activity for treatments. Many guidelines for the treatment of obesity state that “diet and exercise are the primary treatment of obesity.” If the search terms “human obesity and diet and activity and treatment” are used in PubMed, there are 7130 references. No long term studies have shown success of lifestyle treatment of obesity and the 5 year failure rate is >95%. For millennia, humans have thought they knew the etiology of obesity – too much diet and too little exercise. It seems logical, but just because a perturbation affects a disease, does not mean that it is the cause of the disease. Simple differences in diet and exercise likely account for only a small percentage of obesity. A new paradigm is needed in the thinking about the etiology of obesity and the treatment of obesity. There is insufficient knowledge about obesity to accept the current standard treatments and more basic research is needed. Some of the areas that may prove fruitful for future research and may lead to more successful treatments of obesity are:
1. Central nervous system regulation of food intake, physical activity, energy expenditure, body composition, and body weight – ie, the “body weight set point” mechanisms.
2. Role of the gut and gut hormones in regulating food intake and energy expenditure.
3. Role of the vagal and enteric nervous system.
4. Role of the gut microbiome.
5. Genes and combinations of genes contributing to obesity.
6. The epigenetic factors contributing to obesity, particularly intrauterine and intergenerational factors.
7. The contribution of adenovirus 36 (Adv36) and other lipogenic viruses to the epidemic of obesity.
All of these topics cannot be covered in one talk, so this talk will summarize the research on a few of the etiologies of obesity, and particularly those that may be major contributors to obesity. Genetic factors are very important. At least 60 genes have been shown to contribute to or prevent obesity. Calculating the factorial (60 x 59 x 58, etc), there are more combinations of genes for obesity than there are people on Earth. Understanding common combinations of genes that lead to obesity and developing drugs and individualized treatment plans based on those genetic patterns will be very important. Adv36 was first reported in the 1970s, just before the prevalence of obesity dramatically increased across the world. Migratory birds have been postulated as the source of the rapid spread since chickens were the first animal model showing that Adv36 can cause obesity. Adv36 unequivocally causes obesity in animals, including chickens, mice, rats, and monkeys. In multiple countries that have been studied, about 30% of obese humans have been infected compared to about 10%-20% of non-obese humans, and most studies show that infected humans are heavier and/or fatter than uninfected. An infectious cause of obesity holds great promise for treatment since vaccines can be produced for many infections. One animal study shows that vaccination can prevent Adv36-induced obesity. If 30% of obesity might be prevented by a vaccine, this has major public health implications. Antiviral drugs will need to be developed to treat patients already infected with Adv36. Epigenetic factors affecting women of child bearing age appear to be a major cause of the obesity epidemic. The following factors before and during pregnancy increase the risk of obesity in offspring by 2-20 fold, especially in combination: obese at conception, increased weight gain, smoking, eating a high fat or high carbohydrate diet, lack of exercise, older age, taking certain drugs, and perhaps one of the most important, developing gestational diabetes during pregnancy. Almost all of these factors may be avoided or removed, and some evidence suggests that this will prevent a great deal of obesity in offspring. Other factors that may play a role in causing obesity are certain drugs that are taken much more commonly in the last 30 years, certain industrial pollutants in the environment, and alteration of gut microbiota by changes in the diet. The etiology of obesity is so complex that a concerted effort must be made to identify basic biochemical and molecular factors leading to obesity. This information must be used to identify new drugs for treating obesity. Finally, in contrast to most “cookie cutter” treatment of obesity today, individualized treatment must be developed in the future. No two patients are alike and it seems likely that obesity treatment options will need to be very numerous in the future.