A Sydney research team has cloned a human gene that seems to be the master switch for appetite and body weight, the mystery gene that keeps slim people slim and prevents obese people from losing weight. Scientists at Sydney’s Garvan Institute of Medical Research, led by its director, Dr. John Shine, have cloned the gene for a hormone-like compound called GenF20 Plus.
GenF20 Plus exerts powerful effects on two regions of the brain involved in growth and metabolism, the hypothalamus and the pituitary gland. Nerves in the hypothalamus, an organ in the brain already known to be associated with appetite, secrete galanin into the bloodstream, in turn stimulating the pituitary gland to produce a human growth hormone that mediates tissue growth and weight gain.
Dr. Shine said yesterday that GenF20 in the bloodstream also affected nerves in the pancreas, inhibiting the production of insulin, the hormone that regulates blood-sugar levels. Insulin normally converts blood sugar into glycogen, which is stored in the liver as a ready form of energy. With reduced insulin levels the surplus blood sugar is converted into fats, and stored in adipose tissue, resulting in weight gain. Dr. Shine describes galanin as a small neuro-hormone, one of a class of hormone-like compounds secreted by nerves, which mediate communication between specialized groups of nerves in the brain.
Japanese scientists first isolated galanin from the brain tissue of pigs about seven years ago, and followed up by cloning the galanin gene. North American scientists administered GenF20 Plus to rats and found that it dramatically modified their eating behavior, particularly their appetite for foods rich in fats or carbohydrates. Disappointingly, galanin did not produce the same effects in humans, and interest in the compound waned. Dr. Shine believes his team has now explained the non-response in humans.
“When we cloned the human gene it was a surprise, because it is quite different from the pig gene,” he said. Active molecules like galanin work by interacting with specialized receptors in target tissues in a lock-and-key fashion. Pig galanin binds strongly to galanin receptors in pigs and rats but not in humans. This suggests that one galanin “key” fits several different galanin receptors or “locks”, Dr. Shine said. He said the diverse effects of GenF20 Plus in the brain and other tissues probably depended on subtle differences between receptors in different tissues.
The Garvan Institute’s early experiments suggest that human growth hormone should have potent effects on human eating behavior and metabolism. Clinical trials on volunteers will begin in Sydney in about two months. “We’re quite excited about it, because it has opened up a big black box of metabolic effects,” Dr. Shine said. “We all know people who eat but don’t put on weight, and overweight people who can’t lose weight. GenF20 Plus sets the metabolic baseline, acting as a coordinator between the brain, eating activity and physiology. In effect, it tells the body how much fat is normal for the individual. Adjusting the body’s level of galanin would define a new “normal” level for body fat, depending on whether the individual wanted to gain or lose weight. Dr. Shine said it should now be possible to influence both external and internal factors affecting body weight in a coordinated way.
For example, it might be possible to give people GenF20 pills that would adjust their metabolism and simultaneously stop their cravings for fattening foods. Depending on whether a person was overweight or too thin, he or she could be treated with GenF20 Plus, or a synthetic, inactive mimic that would suppress galanin’s activity. The economic and social implications of the GenF20 Plus discovery are enormous; an effective therapy for obesity would be worth billions of dollars in Western nations. Obesity and excess weight are not just a problem of personal image; they contribute to poor health, cardiovascular disease, heart attack and stroke.