Uroguanylin: a new actor in the energy balance movie
- C Folgueira1,2,3,
- S Barja-Fernandez1,2,
- P Gonzalez-Saenz1,2,
- V Pena-Leon1,2,
- C Castelao1,2,
- M Ruiz-Piñon1,4,
- F F Casanueva2,5,
- R Nogueiras2,3 and
- L M Seoane1,2⇑
- 1Fisiopatología Endocrina, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago de Compostela (CHUS/SERGAS), Santiago de Compostela, Spain
- 2CIBER Fisiopatología Obesidad y Nutrición (CiberOBN), Instituto Salud Carlos III, Madrid, Spain
- 3Department of Physiology, CIMUS, USC, IDIS Santiago de Compostela, Santiago de Compostela, Spain
- 4Operative Dentistry and Endodontics, USC, Santiago de Compostela, Spain
- 5Laboratorio de Endocrinología Molecular y Celular, USC, Santiago de Compostela, Spain
- Correspondence should be addressed to L M Seoane: luisamaria.seoane{at}usc.es or Luisa.Maria.Seoane.Camino{at}sergas.es
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Figure 1
Mechanism of action of the GUCY2C-mediated signaling pathway. (1) Agonists of GUCY2C (guanylin (GN), uroguanylin (UGN), Staphylococcal enterotoxins (STs), linaclotide, plecanatide, and dolcanatide) activate the GUCY2C expressed on the apical surface of the cells, hydrolyze guanosine triphosphate (GTP), and increase the production of intracellular cyclic guanosine monophosphate (cGMP). (2) Elevated cGMP concentrations activate cGMP-dependent protein kinase, type 2 (PKG-II) and inhibit the activity of the cAMP‐phosphodiesterase PDE3, thereby cross‐activating cAMP‐dependent protein kinase (PKA), leading to the phosphorylation and activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, which stimulates the secretion of chloride (Cl−) and bicarbonate (HCO3−) ions in the lumen. (3) The CFTR-mediated secretion of Cl− and HCO3− ions is accompanied by the efflux of positive ions (Na+ and H+), which follow the electronegative osmotic gradient.
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Figure 2
Regulation of intestinal uroguanylin (UGN) production by nutritional status is dependent of leptin levels. Food deprivation reduces UGN production in the duodenum, an effect that is reversed by the resumption of feeding or leptin treatment. Consistently, in an ob/ob mouse model of leptin deficiency, UGN expression is reduced in the duodenum and the levels revert after leptin treatment. Diet-induced obese mice with elevated levels of leptin exhibit increased UGN levels in the intestine compared with lean mice.
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Figure 3
Mechanism of central uroguanylin (UGN) action to reduce body weight and adiposity. The chronic central infusion of UGN reduces weight gain and adiposity in diet-induced obese mice, independently of food intake, and acts at different levels: centrally administered UGN induces brown adipose tissue thermogenesis, as well as browning and lipid mobilization in white adipose tissue through stimulation of the sympathetic nervous system. In contrast, brain UGN augments fecal output through the vagus nerve.
- © 2018 Society for Endocrinology
