How a pill might one day reduce our cravings for sweet and fatty foods

Going under the knife to reduce the volume or absorptive area of the stomach - otherwise known as bariatric surgery - has been the most effective treatment for obesity, resulting in rapid sustained weight loss and often resolving type 2 diabetes.

But while for a long time it was thought that the surgery's beneficial effects came from the patient's post-operative inability to consume large meals or absorb as many calories, in recent years scientists have discovered that there is more to it than that.

Bariatric surgery has shown to also change the way the gut-brain axis signals information to the brain regions that regulate appetite and food intake. After the operation, for example, it's been found that patients have a decreased desire to consume fatty foods and prefer less-sweet foods - a reversal of the preferences seen in obesity.

These recent revelations of bariatric surgery have contributed to a rising interest in the gut-brain connection, says Dr John Menzies, a senior research fellow at the University of Edinburgh's Centre for Integrative Physiology.

"Understanding the gut-brain connection may allow us to eventually develop food or medication that mimic the effects of bariatric surgery, without surgery taking place," he says.

Menzies' particular focus is the role of gut hormones called neuropeptides, which are small protein-like molecules that are essential to proper appetite control and which have an unrecognised role in reward-driven eating.

"Little is known about which populations of reward-related neurones are peptide-sensitive, what neural circuits they form and how these networks evoke, inhibit or modify behaviour," he says.

Ghrelin is the only hunger-promoting gut hormone that's known so far, but there are many gut peptides that contribute to the termination of food intake by signalling satiety.

Glucagon-like peptide (GLP-1) and peptide YY3-36, for example, are co-released from the ileum and colon to act in the brain to reduce acute food intake. Obese people have lower circulating levels of these two peptides, and injection of either causes weight loss in both lean and obese humans.

"Some of the initial studies suggest that in mice on a high-fat diet, there's a disruption of the ability of the gut to release some hormones like GLP-1," adds co-researcher and physiology professor Mike Shipston, who recently visited Hong Kong with University of Edinburgh colleagues.

Using an optical technique called optogenetics, the researchers manipulate neuronal activity in rats to determine how specific neural populations influence food anticipation, the motivation to commence eating, food choice and meal termination.

In optogenetics, neurons are made to respond to light through the insertion of light-sensitive genes derived from particular microbial organisms. So, for example, scientists have been able to control how lab rats eat simply by manipulating light.

"When light is shined on the animals they eat voraciously," says Menzies. "When the light is switched off, they stop."

Menzies' and Shipston's research is part of Full4Health, a five-year, €9 million (HK$78.6 million) multidisciplinary research project funded by the EU that began in 2011. The project brings together 19 academic and industry partners to understand the mechanisms of hunger and satiety, which may lead to the development of solutions for appetite control.

The brain regions that regulate appetite and food intake operate via either the homeostatic or hedonic systems. Both are unconscious systems - meaning it's beyond our self-control - Menzies says.

The homeostatic systems, comprised of the hypothalamus and brainstem, appears to drive food intake based on caloric need or energy balance. This in part explains the difficulty experienced by most people trying to lose weight on calorie-restricted diets.

The hedonic, or reward, systems, appear to monitor many of the same hormonal signals from the gut and periphery that are being read by the hypothalamus. But these systems appear to have an override capability, leading to the consumption of palatable, rewarding food even after energy balance is achieved.

As bariatric surgery shows, changes in gut-brain signalling may alter hedonic eating, says Menzies. Understanding the mechanisms of how this works, therefore, could lead to the development of food or drugs to tackle the obesity epidemic.

Because the release pattern of certain gut peptides is dependent on the type of macronutrient consumed, foods in future may be designed to stimulate satiety either homeostatically or by enhancing the feeling of pleasure or reward, says Menzies.

Drugs that mimic the central effects of gut peptides are under development. Weekly injection of a modified GLP-1-like peptide reduces body weight and fat stores, while improving glucose tolerance in rats made obese by a high-fat diet.

"There are a lot of health and socio-economic costs that are associated with obesity, and at the moment it's a problem that doesn't have good solutions," says Menzies.

"The usual solutions are changing diets and increasing exercise levels, but they basically don't work very well and not in the long term."

Appetite control is another approach to battling obesity. The Full4Health research project is therefore focused on unravelling the gut-brain mechanisms that govern hunger and satiety.

Apart from the neuropsychology of food choice and reward, the project is also investigating the potential for dietary manipulation through macronutrient form and structure, and how the developmental process affects the food-gut-brain axis across lifespan. It also includes a major study comparing human volunteers during childhood, adolescence, adulthood and in later life.

Scientists at the University of Maastricht in the Netherlands, for example, have undertaken a study in which lean humans were fed meals varying in protein content over three 12-day periods. It was found that overall energy intake decreased as more protein was consumed, and subjects did not report feeling hungrier.

Based on this finding, the Dutch researchers helped British retail chain Marks & Spencer develop a brand of high-protein ready meals called Simply Fuller Longer. These meals contain an average of 10 grams of protein per 100 grams, about double that of typical ready meals.

Another Full4Health study, by the University of Aberdeen, looks at satiation and satiety and the energy density and structure of food. How are our diets influenced by whether the food is high in protein, fat or carbs, or if the food is solid or liquid, even if the total calorie content is the same?

Yet another Full4Health study in Gothenburg, Sweden, investigates how gut bacteria - which until recently were thought to only be involved in food digestion - may affect obesity by sending signals to parts of the brain regulating body fat and hunger.

Comparing gene expression of food-intake-regulating peptides in the hypothalamus and brainstem in germ-free and conventionally-raised (normal) mice, the researchers found that normal mice show reduced expression of the genes encoding two body fat-suppressing neuropeptides, implying a role for gut microbes in the regulation of body fat.

While processed foods that are high in sugar, fat and calories have been blamed as one of the major causes of the obesity epidemic, Full4Health hopes to make food part of the solution by harnessing its physiological interactions with the gut.

"Why do people get fat? You think it's an easy question: either you eat too much or don't exercise enough," Shipston says.

"But the realisation now is there's a complex interaction between the brain and the rest of the body."