Host: The Japanese Pharmacological Society, The Japanese Society of Clinical Pharmacology
Name : WCP2018 (18th World Congress of Basic and Clinical Pharmacology)
Location : Kyoto
Date : July 01, 2018 - July 06, 2018
The hypothalamus has a critical role in the regulation of energy and glucose homeostasis. Over-nutrition triggers profound cellular and physiological changes of the hypothalamus diminishing hypothalamic responses to insulin and leptin, critical hormones maintaining normal blood glucose and body weight. This decline in hypothalamic responses has been proposed as crucial processes that underlie the pathophysiology of metabolic disease, and its mechanism is of particular interest in understanding the neural basis of overnutrition-associated diseases. Through a combination of ex vivo brain explant assays, electrophysiology, genetic, and pharmacologic studies in mice, we recently identified EPAC (the GTP/GDP exchange factor directly activated by cAMP), and its effector, the small GTPase Rap1, as a molecular pathway that responds to nutrient excess, promotes hypothalamic pathological changes and mediates obesity. Because the Epac-Rap1 pathway can be activated by G protein-coupled receptors (GPCRs) via G protein Gs-cAMP signaling, we searched for a GPCR ligand that activates EPAC-RAP1 signaling and might also cause hypothalamic hormone resistance. Of the candidate GPCR ligands, we identified the gut hormone gastric inhibitory polypeptide (GIP), whose levels are elevated during diet-induced obesity, as a factor that caused hypothalamic resistance to leptin and insulin in ex vivo brain explants. Moreover, centrally administered GIP in vivo caused obesity-associated hypothalamic pathogenic events via its receptor GIPR. Global gene expression profiling analysis revealed that brain signaling pathways most affected by GIP are inflammatory-related; inflammation is known to induce leptin and insulin resistance. Our data suggest that GIP administration is sufficient to recapitulate key aspects of hypothalamic pathophysiology of obesity. More importantly, blocking brain GIPR action with a monoclonal antibody reversed body weight and adiposity effects and normalized the impaired hypothalamic metabolic regulatory pathways of dietary obese mice. Collectively, our studies reveal GIP acts as a signal that arises from excess caloric intake and drives hypothalamic pathophysiological changes, and also unveil a previously unrecognized neural pathway connecting GIP/GIPR signaling to hypothalamic pathology in obesity, via neuronal EPAC-RAP1 signaling.
