Written by Joyce Smith, BS. Researchers identified a molecular pathway in the brain called GIPR/Rap1 signaling that links overeating and obesity to leptin resistance.
A gastro-inhibitory polypeptide (GIP) is an incretin hormone 1-4 produced in the gut and acts directly upon pancreatic cells to stimulate insulin secretion. Studies have shown that GIP levels are elevated during obesity and after consumption of fats or sugars 1-4.
Kaneko and team, in a series of studies 5 done at the Baylor College of Medicine, identified a previously unknown gut-brain connection that helps clarify why a high fat-diet (HFD) leads to obesity. They showed that mice fed a high-fat diet produced increased amounts of GIP, which is involved in energy balance. These elevated levels of GIP produced in the gut inhibit signaling by the hormone leptin in the hypothalamus of the brain, and effectively switch off satiety signals so the mice do not feel full, overeat and become obese. Blocking GIP receptors in the brain restores leptin’s ability to inhibit appetite; thus, the mice eat less and lose weight.
To investigate a potential role of GIP in leptin resistance, 5 Kaneko and team first confirmed that GIP receptors (GIPRs) are present in the brain. They then investigated how blocking the brain GIPRs would affect obesity by infusing an anti-GIPR monoclonal antibody (Gipg013) directly into the brains of experimental mice: HFD-induced obese mice, normal chow-fed lean mice, and control IgG-treated mice. The result was a significant reduction in bodyweight in the HFD-induced obese group of mice. The animals ate less and significantly reduced their fat mass and blood glucose levels in contrast to the normal chow-fed lean mice or the HFD-induced mice who received a control antibody (p<0.001). The lean mice neither reduced their food intake nor lost body weight or fat mass, while the control group continued to eat more and gain weight, thus indicating that the effects are specific to diet-induced obesity.
When the Kaneko team administered the neutralizing (anti-GIPR) monoclonal antibody Gipg013 to a mouse model of obesity that is genetically engineered to lack leptin, there was also no effect on energy balance, thus reaffirming the belief that Gipg013 in the brain acts through leptin signaling. Next, when genetically engineered mice that had no GIPR receptors (Grip-KO mice) were fed a normal amount of calories, both control [wild-type animals (WT)], and Grip-KO mice significantly lost weight and reduced food intake. However, while the WT animals fed a HFD reduced their leptin sensitivity, Grip-KO mice retained their leptin sensitivity. Subsequent tests identified GIPR/Rap1 signaling in the brain as a molecular pathway linking overeating and obesity to the control of leptin. The results suggest that elevated circulating GIP levels in obesity drive both activation of brain Rap1 and neural leptin resistance, revealing a previously unidentified molecular pathway that links GIPR to obesity via EPAC/Rap1 signaling in the brain.
The authors conclude that “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. 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.”
Although more research is needed, researchers hope these results might someday translate into weight loss strategies that restore the brain’s ability to respond to leptin by inhibiting GIP’s anti-leptin effect.
Source: Kaneko, Kentaro, Yukiko Fu, Hsiao-Yun Lin, Elizabeth L. Cordonier, Qianxing Mo, Yong GAO, Ting Yao et al. “Gut-derived GIP activates central Rap1 to impair neural leptin sensitivity during overnutrition.” The Journal of clinical investigation 129, no. 9 (2019).
© 2019 Kaneko et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
Click here to read the full text study.
Posted September 9, 2019.
Joyce Smith, BS, is a degreed laboratory technologist. She received her bachelor of arts with a major in Chemistry and a minor in Biology from the University of Saskatchewan and her internship through the University of Saskatchewan College of Medicine and the Royal University Hospital in Saskatoon, Saskatchewan. She currently resides in Bloomingdale, IL.
References:
- Holst JJ, Deacon CF. Is there a place for incretin therapies in obesity and prediabetes? Trends in Endocrinology & Metabolism. 2013;24(3):145-152.
- Cho YM, Kieffer TJ. K-cells and glucose-dependent insulinotropic polypeptide in health and disease. Vitamins & Hormones. Vol 84: Elsevier; 2010:111-150.
- Parker HE, Reimann F, Gribble FM. Molecular mechanisms underlying nutrient-stimulated incretin secretion. Expert reviews in molecular medicine. 2010;12.
- Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell metabolism. 2013;17(6):819-837.
- Kaneko K, Fu Y, Lin H-Y, et al. Gut-derived GIP activates central Rap1 to impair neural leptin sensitivity during overnutrition. The Journal of clinical investigation. 2019;129(9).
