Feature: Eat to live, or live to eat?
4 June 2007. By Caroline Cross
Like most people, at Christmas you might put on a bit of weight and in January try to compensate with a healthy diet and exercise. But the chances are that even if you give up worrying in February, your weight at the end of the year will be within a kilo of what it was at the beginning of the year.
Like a smoothly running engine, we need fuel (food) to keep us going (and for growth and repair). And the amount of fuel we need depends on how hard our body engine works. Thanks to a complex series of feedback circuits between the gut, body tissues and brain, our bodies maintain a close watch on the fuel gauge, monitoring whether the number of calories we take in is the same as the number we use. If there is a surplus and weight goes up, body metabolism speeds up to compensate (among other changes); if weight drops, we are prompted to eat more.
Over a year, we eat about a million calories, yet our weight usually changes by less than 1 per cent. Recent research has shown that the brain's main appetite control centre - the hypothalamus - is key to this astonishingly precise balancing act, integrating signals about energy and food from around the body.
Eating to live
The gut and fat cells produce hormones such as ghrelin, which signals hunger, and leptin and peptide YY, which signal fullness. They travel via the blood to the hypothalamus, where they bind to receptors on neurons that transmit signals to other parts of the brain. And, via a complex series of feedback circuits, they influence feeding behaviour and energy expenditure.
The hypothalamus has two major populations of neurons that both respond to leptin and but have opposing actions on appetite and metabolism. The first population, when fired, increases food intake by produce appetite-stimulating neurotransmitters such as neuropeptide Y and agouti-related peptide. The other group releases peptides, including proopiomelanocortin, that decrease food intake andincrease energy expenditure. Pro-opiomelanocortin peptides are cut by enzymes to generate active peptides called melanocortins, which bind to melanocortin receptors.
Orexin neurons, a newly characterised family of neurons in the hypothalamus, connect with almost the entire brain and can control food intake, metabolism and food-seeking behaviours such as alertness and reward. When energy levels fall, they become active and stimulate wakefulness and activity to ensure an animal seeks out food. Conversely, glucose and hormones such as leptin block them, which may be why we feel sleepy after a meal. Glucose appears to block the activity of orexin neurons by turning on unusual sugar-activated potassium channels. This newly described physiological pathway, through which sugar may affect sleep, appetite, stress and reward, may provide a target for pharmacological intervention for body weight disorders.
Living to eat
If we have all these mechanisms to regulate the amount we eat, why is obesity rising at such a rapid rate in developed countries? It appears that the feedback mechanisms that counter weight loss are more powerful than those that counter weight gain - an evolutionary mechanism to help survival in times of little food. But in developed societies, with easy access to low-cost food and desk-bound jobs, the calories are stored not burned, and the body automatically resists dieting.
In the future, a 'small-molecule' drug that interacts with a component of the appetite system might be developed to reduce the amount we eat, but at present there are no really effective therapeutics. One newly available appetite suppressant - Acomplia or rimonabant - works by blocking a cannabinoid receptor (CB1). But it does have side-effects such as a risk of depression, which in overweight people is already a common problem.
An alternative 'cure' for obesity is a surgical bypass of part of the stomach and part of the upper small intestine - a procedure known as a JI bypass, which can help people lose up to half their body weight and regain fitness and health. It turns out that rather than affecting food adsorption, JI bypass reduces appetite by fooling the gut into overproducing satiety hormones such as oxyntomodulin, which are normally only released at the end of a meal. These act on neurons in the hypothalamus, signalling fullness. In a trial run by Professor Steve Bloom from Imperial College, London, a group of obese people was given oxyntomodulin to inject before meals; after four weeks, their weight loss was almost as great as it would have been after a JI bypass. Professor Bloom now hopes to take oxyntomodulin treatment to phase II trials and has set up a company - Thiakis - with Wellcome Trust support.
Pancreatic polypeptide, which is released with oxyntomodulin after meals and works similarly, could also provide a solution to appetite suppression. With funding from the Trust's Seeding Drug Discovery initiative, Professor Bloom hopes to develop a synthetic form of hormone that can be administered to patients.
Others are targeting the hunger hormone ghrelin. Scientists at the Scripps Research Institute, La Jolla, California, have devised an antibody therapy against ghrelin that prevents hunger signals reaching the brain. When given to rats it reduces body weight and fat mass; the researchers are hopeful it can be adapted for human use.
Beyond appetite
But for most of us it is not only hunger that drives us to eat. Pleasure and our emotions affect our food intake, and manufacturers play on our desires with their vigorous marketing of energy-rich food. So to cap our intake and prevent obesity, we not only have to wrestle with our body's physiology and exercise self-control, we also have to deal with novel social circumstances. It is a complex network of interactions that science is only just beginning to untangle.
Appetite genes
The field of appetite genetics was relatively low-key until 1994, when Jeffrey Friedman and colleagues at the Howard Hughes Medical Institute in New York discovered why ob/ob mice had voracious appetites and were so fat they could hardly move: they had mutations in the leptin gene and never knew they were full. The press and pharmaceutical companies quickly realised the potential for slimming drugs based on leptin, but it turns out that humans with leptin mutations are exceedingly rare - although they do show a dramatic response to daily injections of leptin, which takes them from massive obesity to normal weight.
Professor Stephen O'Rahilly at the University of Cambridge, who is funded by the Wellcome Trust, originally described and treated human leptin deficiency and, with his colleague Dr Sadaf Farooqi (a Wellcome Trust clinician scientist) has found several other human gene defects that affect proteins in neuronal appetite pathways and lead to extreme obesity. Most of the mutations are extremely rare, although mutations in the melanocortin 4 receptor gene (MC4R) have been implicated in up to 6 per cent of severe childhood obesity and are found at a frequency of about 1 in 1000 in the UK population, making this disease one of the commonest single-gene disorders in the UK.
In an illuminating study of children with a MC4R mutation, Professor O'Rahilly's team has shown that if they test MCR4 protein activity, they can accurately predict how much food an individual will eat at a meal. The children who eat most are those with two copies of a completely dysfunctional MCR4 receptor; children with one copy of the mutation eat less than those with two; and those whose mutations only result in a partial defect eat less than those with a complete defect.
Caroline Cross is a freelance writer based in Reading.
Further reading
- Coll JA et al. Hormonal control of food intake. Cell (forthcoming).
- Farooqi IS, O'Rahilly S. Monogenic obesity in humans. Annu Rev Med 2005;56:443-58.
- Murphy KG, Bloom SR. Gut hormones and the regulation of energy homeostasis. Nature 2006;444(7121):854-9.
- Cooke D, Bloom S. The obesity pipeline: current strategies in the development of anti-obesity drugs. Nat Rev Drug Discov 2006;5(11):919-31.
- Saper CB et al. The need to feed: homeostatic and hedonic control of eating. Neuron 2002;36(2):199-211.
- Friedman JM. A war on obesity, not the obese. Science 2003;299(5608):856-8