A new study has discovered a previously unidentified mechanism explaining how obesity and high-fat diets can disrupt the appetite-suppressing signals from the brain and lead to overeating. The fascinating research revealed a hormone in the gut, triggered by high-fat meals, actually induces the body to keep eating.

Leptin is a hormone with a range of functions but it is probably best known for regulating appetite. Fat cells produce leptin, and the hormone communicates with the hypothalamus to let someone know when they should stop eating.

Obese people obviously have more fat cells, so they are known to have higher levels of leptin, however this counter-intuitively does not result in a suppressed appetite. This scenario is called leptin resistance, and scientists weren't sure exactly what causes the body to block these leptin signals in the brain and cause a person to overeat.

"We didn't know how a high-fat diet or overeating leads to leptin resistance," says corresponding author Makato Fukuda, explaining the origins of the research. "My colleagues and I started looking for what causes leptin resistance in the brain when we eat fatty foods. Using cultured brain slices in Petri dishes we screened blood circulating factors for their ability to stop leptin actions. After several years of efforts, we discovered a connection between the gut hormone GIP and leptin."

GIP, or gastric inhibitory polypeptide, is secreted by the gut in response to food. It is part of a family of molecules called incretins, known to help regulate insulin and energy expenditure. Prior research has found GIP levels are raised in obese subjects, and they directly increase in relation to fat and sugar consumption. Animal studies have also revealed inhibiting GIP can protect against weight gain from a high-fat diet.

The new research for the first time found an association between GIP and leptin, as well as discovering GIP receptors on the hypothalamus, suggesting the molecule can enter the brain and plausibly affect appetite signaling. When GIP activity in the brain was blocked in obese animal models, the rodents ate less and lost weight, however this same action did not occur in lean animals, suggesting GIP activity only plays a role in obesity or high-fat diet scenarios.

Homing in on the leptin connection, the researchers experimented with blocking GIP activity in mice engineered to be leptin deficient. In this instance, the obese animals did not respond at all to GIP inhibition, and continued overeating. This affirmed to the researchers that it seems to be GIP that modulates leptin resistance in obese subjects causing overeating and weight gain.

"… when eating a balanced diet, GIP levels do not increase and leptin works as expected, triggering in the brain the feeling of being full when the animal has eaten enough and the mice stop eating," says Fukuda. "But, when the animals eat a high-fat diet and become obese, the levels of blood GIP increase. GIP flows into the hypothalamus where it inhibits leptin's action. Consequently, the animals do not feel full, overeat and gain weight. Blocking the interaction of GIP with the hypothalamus of obese mice restores leptin's ability to inhibit appetite and reduces body weight."

Last year a study was published describing the results of GIP antagonists on several different animal models of obesity. The results were certainly promising, suggesting inhibiting this particular pathway can result in weight loss. The research is still several years away from any human clinical outcome but this new study offers a compelling insight into how obesity can perpetuate weight gain, and how high-fat meals disrupt the brain's ability to tell the body to stop eating.

The new study was published in The Journal of Clinical Investigation.