Uroguanylin levels in intestine and plasma are regulated by nutritional status in a leptin-dependent manner.
OBJECTIVE
Uroguanylin (UGN) is a 16 amino acid peptide produced mainly by intestinal epithelial cells. Nutrients intake increases circulating levels of prouroguanylin that is processed and converted to UGN to activate the guanylyl cyclase 2C receptor (GUCY2C). Given that the UGN-GUCY2C system has been proposed as a novel gut-brain endocrine axis regulating energy balance, the aim of the present study was to investigate the regulation of UGN protein levels in duodenum and circulating levels in lean and obese mice under different nutritional conditions and its potential interaction with leptin.


METHODS
Swiss, C57BL/6 wild-type and ob/ob male adult mice under different nutritional conditions were used: fed ad libitum standard diet (control); 48 h fasting (fasted); 48 h fasting followed by 24 h of feeding (refed); and fed high-fat diet (45 %) during 10 weeks. In addition, peripheral leptin administration was performed. Intestinal uroguanylin expression was studied by Western blot analysis; plasma levels were measured by ELISA.


RESULTS
Food deprivation significantly reduced plasma UGN levels, which were correlated with the lower protein levels of UGN in duodenum. These effects were reverted after refeeding and leptin challenge. Consistently, in ob/ob mice UGN expression was decreased, whereas leptin treatment up-regulated UGN levels in duodenum in these genetically modified mice compared to WT. Diet-induced obese mice displayed increased UGN levels in intestine and plasma in comparison with lean mice.


CONCLUSIONS
Our findings suggest that UGN levels are correlated with energy balance status and that the regulation of UGN by nutritional status is leptin-dependent.
Grupo Fisiopatología Endocrina, Laboratorio 14, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Universidad de Santiago de Compostela (USC), Travesía da Choupana s/n, 15706, Santiago de Compostela, Spain.|CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, Universidad de Santiago de Compostela (USC), Santiago de Compostela, Spain.|Department of Physiology, Research Centre of Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Universidad de Santiago de Compostela (USC), Santiago de Compostela, Spain.
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Folgueira
CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, Universidad de Santiago de Compostela (USC), Santiago de Compostela, Spain.|Department of Physiology, Research Centre of Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Universidad de Santiago de Compostela (USC), Santiago de Compostela, Spain.
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Sanchez-Rebordelo
Grupo Fisiopatología Endocrina, Laboratorio 14, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Universidad de Santiago de Compostela (USC), Travesía da Choupana s/n, 15706, Santiago de Compostela, Spain.|CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, Universidad de Santiago de Compostela (USC), Santiago de Compostela, Spain.|Pediatric Department, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Universidad de Santiago de Compostela (USC), Santiago de Compostela, Spain.
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Barja-Fernandez
Pediatric Department, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Universidad de Santiago de Compostela (USC), Santiago de Compostela, Spain.
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Leis
CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, Universidad de Santiago de Compostela (USC), Santiago de Compostela, Spain.|Department of Physiology, Research Centre of Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Universidad de Santiago de Compostela (USC), Santiago de Compostela, Spain.
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Tovar
CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, Universidad de Santiago de Compostela (USC), Santiago de Compostela, Spain.|Laboratorio de Endocrinología Molecular y Celular, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Universidad de Santiago de Compostela (USC), Santiago de Compostela, Spain.
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Casanueva
CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, Universidad de Santiago de Compostela (USC), Santiago de Compostela, Spain.|Department of Physiology, Research Centre of Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Universidad de Santiago de Compostela (USC), Santiago de Compostela, Spain.
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Dieguez
CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, Universidad de Santiago de Compostela (USC), Santiago de Compostela, Spain. ruben.nogueiras@usc.es.|Department of Physiology, Research Centre of Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Universidad de Santiago de Compostela (USC), Santiago de Compostela, Spain. ruben.nogueiras@usc.es.
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Nogueiras
Grupo Fisiopatología Endocrina, Laboratorio 14, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Universidad de Santiago de Compostela (USC), Travesía da Choupana s/n, 15706, Santiago de Compostela, Spain. luisamaria.seoane@usc.es.|CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, Universidad de Santiago de Compostela (USC), Santiago de Compostela, Spain. luisamaria.seoane@usc.es.
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Seoane
D000818:Animals; D059305:Diet, High-Fat; D004734:Energy Metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D020738:Leptin / Q000097:blood / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D045265:Natriuretic Peptides / Q000097:blood* / Q000235:genetics; D009752:Nutritional Status; D015854:Up-Regulation
D020738:Leptin; D045265:Natriuretic Peptides; C084362:uroguanylin
Duodenum; Intestine; Leptin; Uroguanylin; ob/ob