title: A uroguanylin-GUCY2C endocrine axis regulates feeding in mice.
abstract: Intestinal enteroendocrine cells are critical to central regulation of caloric consumption, since they activate hypothalamic circuits that decrease appetite and thereby restrict meal size by secreting hormones in response to nutrients in the gut. Although guanylyl cyclase and downstream cGMP are essential regulators of centrally regulated feeding behavior in invertebrates, the role of this primordial signaling mechanism in mammalian appetite regulation has eluded definition. In intestinal epithelial cells, guanylyl cyclase 2C (GUCY2C) is a transmembrane receptor that makes cGMP in response to the paracrine hormones guanylin and uroguanylin, which regulate epithelial cell dynamics along the crypt-villus axis. Here, we show that silencing of GUCY2C in mice disrupts satiation, resulting in hyperphagia and subsequent obesity and metabolic syndrome. This defined an appetite-regulating uroguanylin-GUCY2C endocrine axis, which we confirmed by showing that nutrient intake induces intestinal prouroguanylin secretion into the circulation. The prohormone signal is selectively decoded in the hypothalamus by proteolytic liberation of uroguanylin, inducing GUCY2C signaling and consequent activation of downstream anorexigenic pathways. Thus, evolutionary diversification of primitive guanylyl cyclase signaling pathways allows GUCY2C to coordinate endocrine regulation of central food acquisition pathways with paracrine control of intestinal homeostasis. Moreover, the uroguanylin-GUCY2C endocrine axis may provide a therapeutic target to control appetite, obesity, and metabolic syndrome.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Division of Clinical Pharmacology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Valentino
authors.forename: Jieru E
authors.initials: JE
authors.lastname: Lin
authors.forename: Adam E
authors.initials: AE
authors.lastname: Snook
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Gilbert W
authors.initials: GW
authors.lastname: Kim
authors.forename: Glen
authors.initials: G
authors.lastname: Marszalowicz
authors.forename: Michael S
authors.initials: MS
authors.lastname: Magee
authors.forename: Terry
authors.initials: T
authors.lastname: Hyslop
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schulz
authors.forename: Scott A
authors.initials: SA
authors.lastname: Waldman
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001823:Body Composition; D001835:Body Weight; D006152:Cyclic GMP / Q000378:metabolism; D004435:Eating; D004703:Endocrine System / Q000166:cytology / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology; D005247:Feeding Behavior / Q000502:physiology*; D005260:Female; D007031:Hypothalamus / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D045265:Natriuretic Peptides / Q000235:genetics / Q000378:metabolism*; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled / Q000235:genetics / Q000378:metabolism*; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism*; D012527:Satiation; D015290:Second Messenger Systems / Q000502:physiology*
chemical_list: D007328:Insulin; D020738:Leptin; D045265:Natriuretic Peptides; D011498:Protein Precursors; D018000:Receptors, Peptide; C084362:uroguanylin; C000613655:Gucy2c protein, mouse; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled; D006152:Cyclic GMP