Glucagon-like peptide-1 (GLP-1) pharmacotherapies have garnered much of the attention lavished on incretin mimetics in recent years, but glucose-dependent insulinotropic polypeptide (GIP) plays a similarly important role in regulating food intake, energy balance, and obesity.
“Consumption of energy-dense foods is a key driver of obesity. It directly affects pathological changes in the hypothalamus,” said Makoto Fukuda, PhD, Assistant Professor of Pediatrics and Nutrition, Baylor Medical College. “GIP drives inflammatory gene programs in the hypothalamus while GIP receptor activation also inhibits insulin signaling.”
Dr. Fukuda was the first of four researchers to discuss GIP signaling during Sunday’s ADA Diabetes Symposium—New Turf for the Other Incretin—GIP Signaling in the Brain and Effects on Food Intake and Energy Balance. The session can be viewed by registered meeting attendees at ADA2021.org through September 29, 2021. If you haven’t registered for the Virtual 81st Scientific Sessions, register today to access all of the valuable meeting content.
Researchers are in the early stages of characterizing the biomechanics of GIP in the brain, Dr. Fukuda explained. GIP research has lagged GLP-1 research because GIP has little to no clear impact on food intake or body weight while GLP-1 can produce dramatic impacts on both eating and obesity. But leptin has helped focus more attention on GIP.
“The GIP receptor is indispensable for induction of leptin resistance in the brain,” Dr. Fukuda said. “Endogenous GIP, signaling from the gut to the brain, can induce leptin resistance to increase obesity.”
The other incretin, GLP-1, also acts in the brain. The question is where?
“The central nervous system is an important target organ for GLP-1 and GIP pharmacotherapy to affect energy balance,” said Alice Adriaenssens, PhD, Research Associate, Cambridge University Institute of Metabolic Science, United Kingdom. “Dual GIP and GLP-1 receptor agonism can reduce adiposity. We have a critical need to understand the signaling involved.”
Both GIP and GLP-1 receptors are found in the hindbrain and hypothalamus, Dr. Adriaenssens continued. Both neuronal and non-neuronal cells express GIP receptors, but knocking out GIP receptors in the hypothalamus does not reduce the weight loss effect that results from combined GIP/GLP-1 receptor agonism. That leaves the hindbrain.
“The hindbrain is a known nexus for gut peptide action and associated pharmacology. Reducing GIP receptor activity in the hindbrain reduces food and water intake,” Dr. Adriaenssens said.
GIP receptors in the hindbrain engage the amygdala and the hypothalamus, as well as areas within the hindbrain, she continued. All of these areas have been implicated in regulating feeding behavior and energy balance.
Single-cell sequencing techniques have helped further localize GIP and GLP-1 receptors.
“The dorsal vagal complex (DVC) is optimally positioned to mediate the effects of incretins on food intake,” said Tune Pers, PhD, Associate Professor of Medicine, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Denmark. “GIP and GLP-1 receptors are expressed on just 1% of DVC cells. You need single-cell analysis to obtain useful information.”
GIP receptors are concentrated in oligodendrocytes and GABAergic neurons in the area postrema (AP). GLP-1 receptors are concentrated in GABAergic neurons and glutamatergic neurons in the AP, and in glutamatergic neurons in the nucleus tractus solitarii (NTS).
Integrating single-cell data with genome-wide association study data revealed the presence of gene enhancers that link specific genetic variants of these receptors to specific cell populations and effector genes. Early findings suggest that semaglutide increases chromatin accessibility in neurons expressing GLP-1 receptors to enhance their activity, including weight loss.
But nausea and vomiting are common patient complaints about GLP-1 therapy. About 25% of patients cannot use these agents appropriately due to physical discomfort.
“Hunger, satiety, nausea, and vomiting are all points on the same curve of ingestive behavior,” said Matthew R. Hayes, PhD, Associate Professor of Nutrition and Neuroscience, University of Pennsylvania Perelman School of Medicine. “If you push too far, you move from satiety and fullness to nausea, malaise, and vomiting. GIP receptor agonism blocks GLP-1 receptor-mediated emesis while maintaining the metabolic benefits of GLP-1 receptor agonism.”
GIP is active in multiple sites across the brain, Dr. Hayes noted, particularly the NTS—often called the vomiting complex. And while GIP and GLP-1 receptors are rarely expressed on the same cells, they occur on similar substrates in different neural circuits.
GIP receptors on GABA neurons seem to be the most active in blocking the nausea/emetic responses to GLP-1 receptor agonism.
“All first-generation GLP-1 based pharmacotherapies cause nausea and emesis,” Dr. Hayes said. “The sooner we adopt that concept, the sooner we will find a way around it.”