by Simon Cork, Imperial College London, @simon_c_c
October 11th is officially “World Obesity Day”, a day observed internationally to promote practical solutions to end the obesity crisis. The term “obesity crisis” or “obesity epidemic” is often repeated by the media, but how big is the problem? Today, over 1.9 billion adults worldwide are overweight or obese. By 2025, this is projected to increase to 2.7 billion with an estimated annual cost of 1.2 trillion USD. Of particular concern is that 124 million children and adolescents worldwide are overweight or obese. In the UK, this equates to 1 in 10 children and adolescents and is projected to increase to 3.8 million by 2025. We know that obesity significantly raises the risk of developing 11 different types of cancer, stroke, type 2 diabetes, heart disease and non-alcoholic fatty liver disease, but worryingly, we now know that once someone becomes obese, physiological changes to the body’s metabolism make long-term weight loss challenging.
Our understanding of the physiology of food intake and metabolism and the pathophysiology of obesity has grown considerably over the past few decades. Obesity was seen, and often still is seen, as a social problem, rather than a medical issue: a lack of self-control and willpower. We now know that physiological changes occur in how our bodies respond to food intake. For example, hormones which are released from the gut following food intake and signal to the brain via the vagus nerve normally reduce food intake. However, in obesity, the secretion of these hormones is reduced, as is the sensitivity of the vagus nerve. The consequence of this is a reduced sensation of feeling full.
Imaging of the hypothalamus (a key region for keeping food intake at a balanced level) shows a reduction in activity following food intake in lean men, an effect which was absent in obesity. This effect may relate to a reduction in the body’s responses observed following food intake in obesity, such as balancing blood sugar and signalling that you are full. Furthermore, numerous studies have shown that obese individuals have a reduced availability of dopamine receptors, the structures on cells that respond to the pleasure chemical dopamine, in key brain regions associated with reward. Whether the reduction in dopamine receptor availability is a cause or consequence of obesity remains to be fully explored, but it is likely to be a combination of both of these factors. Individuals with a gene called the Taq1 A1, associated with a decreased availability of dopamine receptors, are more likely to become obese, suggesting that decreased responsiveness to high calorie foods leads to increased consumption in order to achieve the same level of reward. (Interestingly, this same gene is also associated with an increased risk of drug addiction). However, much like drug addiction, hyper-stimulation of the dopamine system (i.e. by consuming large quantities of dopamine-secreting, high calorie foods) can in turn lead to a reduction in dopamine receptor levels, thus creating a situation where more high calorie foods are required to stimulate the same level of reward.
It is therefore clear that obesity is not simply a manifestation of choice, but underpinned by complex changes in physiology which promote a surplus of food consumption, called positive energy balance. From an evolutionary standpoint, this makes sense, as maintaining a positive energy balance in times of abundant food would protect an individual in times of famine. However, evolution has failed to keep up with modern society, where 24-hour access to high calorie foods removes the threat of starvation. The good news is that we know that weight loss as small as 5% can yield significant improvements in health, and can often be managed without significant modification to lifestyle.
Presently, treatment options for obesity are limited. The first line treatment is still diet and exercise; but as the above examples of how our physiology changes show, maintaining long term weight loss through self-control alone is almost always impossible. However, the future does look bright, with new classes of drugs either recently licenced, or in production. Saxenda (a once-daily injectable drug which mimics the gut hormone GLP-1 made by Novo Nordisk) has recently been licenced for weight loss in patients with a BMI greater than 30. However, after 56 weeks treatment, average weight loss was a modest 8kg. Likewise Orlistat (which inhibits absorption of dietary fat, made by Roche) has been on the market for a number of years and shows average weight loss of around 10%. However, it is associated with unpleasant side effects, such as flatulence and oily stools. Presently, bariatric surgery is the only treatment that shows significant, long term weight loss (around 30%, depending on the surgical method used) and is also associated with long-term increases in gut hormone secretion and vagus nerve sensitivity. Research is currently underway to assess whether the profile of gut hormones observed post-surgery can be mimicked pharmacologically. Studies have shown that administering select gut hormones in combination results in a reduction in body weight and food intake greater than the sum of either hormone when administered in isolation. This observed synergy between gut hormones will undoubtedly form the basis for future pharmacotherapies with improved efficacy, with various combinations currently in both clinical and pre-clinical trials.
For healthcare policy makers, the future obesity landscape does not make for happy reading. A combination of better therapies and improved public health messages are undoubtedly needed to stem the rising tide. However, both policy makers and society as a whole should be mindful that changes in ones physiology mean maintaining long-term weight loss through diet and exercise alone are unlikely to be the whole answer.