Gut-brain connection sheds light on how overeating causes obesity
“We have uncovered a new piece of the complex puzzle of how the body manages energy balance and affects weight,” said corresponding author Dr. Makoto Fukuda, assistant professor of pediatrics at Baylor and the USDA/ARS Children’s Nutrition Research Center at Baylor and Texas Children’s Hospital.
The study looked at mice consuming a high-fat diet, which increased their levels of gastric inhibitory polypeptide (GIP), a gut hormone involved in managing the body’s energy balance. The researchers found that excess GIP travels through the blood and into the brain, thus inhibiting the action of leptin, a satiety hormone that triggers the sensation of being full within the brain. Therefore, the mice continued to eat and gain weight.
Blocking the link between GIP and the brain restored the leptin’s ability to subdue appetite and led to eventual weight loss.
“We didn’t know how a high-fat diet or overeating leads to leptin resistance,” Fukuda said. “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.”
The first task the researchers had to complete was to figure out if GIP was involved in leptin malfunctioning. They did so by confirming that the GIP receptor, the binding molecule on cells that grabs hold of GIP and balances its effects, is expressed in the brain. They then experimented with blocking GIP receptors via a monoclonal antibody infusion within the brain. This experiment reduced body weight of obese mice.
“The animals ate less and also reduced their fat mass and blood glucose levels,” Fukuda said. “In contrast, normal chow-fed lean mice treated with the monoclonal antibody that blocks GIP-GIP receptor interaction neither reduced their food intake nor lost body weight or fat mass, indicating that the effects are specific to diet-induced obesity.”
“In summary, 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,” Fukuda continued. “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.”
These findings show that GIP and its receptor in the brain’s hypothalamus, the area that regulates appetite, are needed and sufficient to evoke leptin resistance. More research is needed, however, researchers believe that these findings could be used to develop weight-loss strategies in the near future.
The research is published in the Journal of Clinical Investigation.
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