Scientists headed by a team at Baylor College of Medicine have identified a previously unknown gut-brain connection that helps to explain why eating a high-fat diet (HFD) leads to overeating, weight gain, and obesity. The researchers’ studies showed that mice fed a HFD produce increased amounts of a hormone known as GIP, which is involved in energy balance. These elevated levels of GIP produced in the gut inhibit signaling by the hormone leptin in the brain, effectively switching of satiety signals, so the animals continue to eat and gain weight. Blocking GIP receptors in the brain then reinstates leptin responses in HFD-fed obese mice, and the animals start to eat less and lost weight.

“We have uncovered a new piece of the complex puzzle of how the body manages energy balance and affects weight,” said Makoto Fukuda, PhD, assistant professor of pediatrics at Baylor and the USDA/ARS Children’s Nutrition Research Center at Baylor and Texas Children’s Hospital. “After several years of efforts, we discovered a connection between the gut hormone GIP and leptin.”

Dr. Makoto Fukuda
Makoto Fukuda, PhD [Baylor College of Medicine]

Fukuda is corresponding author of the researchers’ published paper in the Journal of Clinical Investigation, which is titled, “Gut sensitive GIP activates central Rap1 to impair leptin sensitivity during overnutrition.”

The body’s energy balance is controlled by the hypothalamus in the brain, but overeating—effectively taking in too many calories—triggers activation of inflammatory and stress response pathways that affect the neural activities of leptin, a hormone that is produced by fat cells, and which plays a key role in bodyweight control. Leptin signaling in the brain normally triggers the sensation of feeling full when an individual has eaten enough, and this tells them to stop eating. However, in the case of overeating or consuming a high-fat diet the body effectively stops responding to leptin signals. This switches off feelings of satiety, and the individual continues to overeat, leading to weight gain. “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.”

The researchers reasoned that one potential link to leptin resistance is glucose-dependent insulinotropic polypeptide, also known as gastric inhibitory polypeptide (GIP). This incretin hormone is produced in the gut and directly acts on cells to stimulate insulin secretion. Studies have also found that GIP is involved in controlling energy balance under conditions of overeating, or nutrient excess. “Circulating levels of GIP are elevated during obesity and after consumption of fat or sugar,” the researchers noted. “Genetic and pharmacological inhibition of GIP and its receptor protects against high-fat diet–induced (HFD-induced) body weight gain.”

To investigate whether GIP may be involved in leptin resistance, Fukuda and colleagues first confirmed that GIP receptors (GIPRs) are present in the brain. They next assessed the direct impact on obesity of blocking brain GIPRs, by infusing an anti-GIPR monoclonal antibody (known as Gipg013) directly into the brains of experimental mice. They found that administration of the anti-GIPR antibody led to significant reductions in bodyweight in HFD-induced obese mice. “Food intake and fat mass were also significantly reduced in Gipg013-treated obese mice,” the investigators wrote. “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.”

The investigators reasoned that the bodyweight-lowering effect of Gipg013 was due to reduced food intake because energy expenditure was no different between mice treated using the GIPR-blocking antibody, and animals given a control antibody. In contrast to its effects in HFD-fed animals, Gipg013 administration had no effect on animals fed a normal, chow diet. “… 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,” Fukuda stated. “These data collectively indicate a key role of central GIPR signaling in diet-induced obesity,” the authors wrote.

Interestingly, administering the Gipg013 antibody to a mouse model of obesity that is genetically engineered to lack leptin also had no effect on energy balance, reaffirming the notion that Gipg013 in the brain acts through leptin signaling, the researchers pointed out.

They next investigated the effects of GIPR on leptin action in genetically engineered mice that had no GIPR receptors (Gipr-KO mice). These experiments showed that leptin administration resulted in significantly lower body weight and reduced food intake when both the control, wild-type animals and the Gipr-KO mice were fed a normal amount of calories. However, while wild-type animals fed a HFD exhibited the expected reduced responses to leptin, Gipr-KO mice fed a HFD retained their sensitivity to leptin. “… our data suggest that Gipr is necessary for diminished responses to exogenous leptin in diet-induced obese mice,” the authors stated.

Subsequent tests in brain slices and in engineered mice indicated that activation of a small GTPase protein called Rap1 was necessary for eliciting GIP-induced leptin resistance, and may represent the intracellular mediator of GIP activity in the brain. “The results suggest that elevated circulating GIP levels in obesity drive both activation of brain Rap1 and neural leptin resistance,” the team concluded. “Altogether, our results identify GIPR/Rap1 signaling in the brain as a molecular pathway linking overnutrition to the control of neural leptin actions.”

“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 said. “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.”

While more research will be needed to validate and build on the findings, the scientists speculate that their findings may ultimately lead to the development of weight-loss strategies that restore the brain’s ability to respond to leptin by inhibiting the inhibitory effects of GIP on leptin in the brain.

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