Fat Flies

Scientists can systematically knock-out genes across the entire mouse genome. Any dramatic effects on mouse body weight help them identify genes involved in fat store regulation. But it’s expensive. Using fruit fly (Drosophila melanogaster) is easier and cheaper, making it an attractive model system for obesity research. “Flies can be obese,” reveals Bader, “and there is a surprising amount of overlap between insect and mammalian biology. For example, both humans and flies use insulin to regulate fat.”

In mammals, hypothalamic brain centres are informed about the status of body fat storage by the leptin and insulin pathways. These centres respond by prompting change in food intake and metabolism to regulate body weight. Electrical stimulation of some of these suppresses food intake, while bilateral lesions of others cause an increase in food intake and obesity. Bader's first goal was to look for a parallel in fly brain using transgenic technology (see Wikipedia page for Gal4/UAS). He identified specific groups of brain cells in flies (Fru-Gal4 and c673a-Gal4 neurons), which when suppressed caused obesity, while overactivating the neurons generated lean flies.

However, his team wanted to know why. Are the modified neurons causing the flies to overeat? Do they become sluggish? Is their metabolism affected? Do they store more fat than normal flies, or do they fail to use those stores when they need to? Flies with silenced c673a-Gal4 neurons overeat, and they tend to make more fat than normal. They’re also slightly less able to use stored fat when they need to. In contrast, flies with silenced Fru-Gal4 neurons don’t overeat, though they also make more fat than normal and struggle to use fat stores when starved. Hyperactivation of either neuronal group reduced fat stores by ramping up metabolism (Neuron, 2009).

In another experiment Bader and colleagues developed a food behaviour assay (see Fly Dye Expt), which revealed that mutations in neuropeptide hormone leucokinin (leuc) and its receptor lkr caused flies to engorge and their guts to bloat. Although in the short term these flies tend to overeat, in the long run they consume a similar amount of food as normal flies. “So they compensate for the large increase in meal size by reducing the number of times they eat,” he explains.

The leucokinin receptor is found in the brain and foregut – which contains stretch receptors known to be responsible for monitoring meal size in other insects. So in normal flies, the stretch receptors signal to the brain that it is time to stop eating when the gut becomes full. In leuc or lkr mutants the ‘time to stop’ signal isn't properly relayed, and the flies—unaware that their bellies are full—continue to eat (Curr Biol, 2010). Leucokinin and its receptor are similar to the vertebrate tachykinin pathway, components of which are expressed in mammalian brain centres that regulate food intake.

Fly Dye Experiment Normal flies exposed to food mixed with red dye after 24-hour starvation (left, Figure 2); leucokinin mutant flies tested under the same conditions (right). Assay involves exposing starved flies to food mixed with red dye. After 20 min, those flies are given new food mixed with blue dye for another 15 min. Normal flies became satiated during their first exposure to red food and don’t eat blue food, so they have a small red abdomen. Flies with an abnormal feeding behavior either ate excessive amounts of red food, making them visibly bloated, and/or continued feeding during second exposure to the blue food, making their abdomen appear purple.]

Whether our body size really is more down to nature than nurture, there is clearly a strong genetic component. And it seems that since Stunkard’s observations two decades ago, ‘fat’ genes have spread in human populations. Initiatives to pinpoint the offending human genes and elucidate underlying molecular pathways are of global importance. And research in flies seems to be paving the way.

BM