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A uroguanylin-GUCY2C endocrine axis regulates feeding in mice
- Source :
- Journal of Clinical Investigation. 121:3578-3588
- Publication Year :
- 2011
- Publisher :
- American Society for Clinical Investigation, 2011.
-
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.
- Subjects :
- Leptin
Male
medicine.medical_specialty
Receptors, Peptide
Guanylin
media_common.quotation_subject
Hypothalamus
Receptors, Enterotoxin
Endocrine System
Enteroendocrine cell
Satiation
Biology
Second Messenger Systems
Mice
Eating
chemistry.chemical_compound
Paracrine signalling
Intestinal mucosa
Internal medicine
medicine
Insulin
Animals
Intestinal Mucosa
Protein Precursors
Natriuretic Peptides
Cyclic GMP
media_common
Mice, Knockout
Behavior, Animal
digestive, oral, and skin physiology
Body Weight
Epithelial Cells
Appetite
Feeding Behavior
General Medicine
Mice, Inbred C57BL
Endocrinology
Receptors, Guanylate Cyclase-Coupled
chemistry
Body Composition
Commentary
Female
Signal transduction
Research Article
Uroguanylin
Hormone
Subjects
Details
- ISSN :
- 00219738
- Volume :
- 121
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Investigation
- Accession number :
- edsair.doi.dedup.....559d4644a0131048e879e0a9843f507f