A uroguanylin-GUCY2C endocrine axis regulates feeding in mice

Valentino, Michael; Lin, Jieru E.; Snook, Adam E.; Li, Peng; Kim, Gilbert W.; Marszalowicz, Glen P.; Magee, Michael S.; Hyslop, Terry; Schulz, Stephanie; Waldman, Scott A.

doi:10.1172/jci57925

Cited by 138 publications

(293 citation statements)

References 55 publications

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“…In mice, pro-UGN is released from the gut immediately after nutrient intake and is converted into active UGN within the hypothalamus, thereby activating GUCY2C and reducing food intake (11). In agreement with these results, pharmacological stimulation of GUCY2C inhibited feeding in obese mice, and mice lacking GUCY2C are hyperphagic and more prone to develop metabolic syndrome (11).…”

supporting

confidence: 52%

“…Whereas one report (11) showed a decreased food intake 2 h after the central injection of STs, a subsequent study (12) failed to detect changes in food intake after the administration of ST or UGN. Similar to the first report (11), we found that UGN (25 mg i.c.v.)…”

Section: Discussionmentioning

confidence: 94%

“…A previous study (11) proposed that the activation of GUCY2C is also relevant in the regulation of energy balance in mammals. In mice, pro-UGN is released from the gut immediately after nutrient intake and is converted into active UGN within the hypothalamus, thereby activating GUCY2C and reducing food intake (11).…”

mentioning

confidence: 99%

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Uroguanylin Action in the Brain Reduces Weight Gain in Obese Mice via Different Efferent Autonomic Pathways

et al. 2015

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The gut-brain axis is of great importance in the control of energy homeostasis. The identification of uroguanylin (UGN), a peptide released in the intestines that is regulated by nutritional status and anorectic actions, as the endogenous ligand for the guanylyl cyclase 2C receptor has revealed a new system in the regulation of energy balance. We show that chronic central infusion of UGN reduces weight gain and adiposity in diet-induced obese mice. These effects were independent of food intake and involved specific efferent autonomic pathways. On one hand, brain UGN induces brown adipose tissue thermogenesis, as well as browning and lipid mobilization in white adipose tissue through stimulation of the sympathetic nervous system. On the other hand, brain UGN augments fecal output through the vagus nerve. These findings are of relevance as they suggest that the beneficial metabolic actions of UGN through the sympathetic nervous system do not involve nondesirable gastrointestinal adverse effects, such as diarrhea. The present work provides mechanistic insights into how UGN influences energy homeostasis and suggests that UGN action in the brain represents a feasible pharmacological target in the treatment of obesity.After the ingestion of a meal, the presence of nutrients in the gastrointestinal (GI) tract initiates complex neural and hormonal responses that send signals to the brain about the ongoing changes in nutritional status. Among the different strategies used to communicate to the brain, the gut secretes peptides that reach the central nervous system (CNS) via afferent nerve fibers or the circulation (1,2). New gut hormones are continuously discovered, and, with the exception of ghrelin, which is the only peptidic hormone favoring weight gain and adiposity, all of them are associated with a negative energy balance and are thus potential targets for the treatment of obesity (3,4).One of the most recently discovered gut hormones is uroguanylin (UGN), a 16-amino acid peptide secreted mainly from duodenal epithelial cells. UGN is synthesized as a prohormone (pro-UGN), which, after cleavage by a still unknown enzyme, is converted to the active UGN (3,5). Both pro-UGN and UGN activate the guanilate cyclase 2C receptor (GUCY2C), which is also targeted by diarrheagenic bacterial heat-stable enterotoxins (STs) (6). The activation of GUCY2C leads to elevated intracellular levels of cyclic guanosine monophosphate (7), which in invertebrate species has been demonstrated to lead to alterations in food behavior and energy-balance regulation (8,9). Circulating UGN levels were decreased in fasted and leptin-deficient mice but recovered after refeeding or exogenous leptin

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supporting

confidence: 52%

Section: Discussionmentioning

confidence: 94%

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Uroguanylin Action in the Brain Reduces Weight Gain in Obese Mice via Different Efferent Autonomic Pathways

et al. 2015

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“…An endocrine axis regulating feeding in mice was recently described for UGN that could have clinical implications for the control of appetite, obesity and metabolic syndrome (Valentino et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, uroguanylin participates in an endocrine axis regulating feeding in mice (Valentino et al, 2011). In this system, prouroguanylin is converted to uroguanylin in the central nervous system , activates guanylyl cyclase 2C (GUCY2C) receptors in the brain to reduce food intake in mice.…”

Section: Introductionmentioning

confidence: 99%

Uroguanylin induces electroencephalographic spikes in rats

et al. 2013

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Uroguanylin (UGN) is an endogenous peptide that acts on membrane-bound guanylate cyclase receptors of intestinal and renal cells increasing cGMP production and regulating electrolyte and water epithelial transport. Recent research works demonstrate the expression of this peptide and its receptor in the central nervous system. The current work was undertaken in order to evaluate modifications of electroencephalographic spectra (EEG) in anesthetized Wistar rats, submitted to intracisternal infusion of uroguanylin (0.0125 nmoles/min or 0.04 nmoles/min). The current observations demonstrate that 0.0125 nmoles/min and 0.04 nmoles/min intracisternal infusion of UGN significantly enhances amplitude and frequency of sharp waves and evoked spikes (p = 0.03). No statistical significance was observed on absolute alpha and theta spectra amplitude. The present data suggest that UGN acts on bioelectrogenesis of cortical cells by inducing hypersynchronic firing of neurons. This effect is blocked by nedocromil, suggesting that UGN acts by increasing the activity of chloride channels.Keywords: neuroexcitatory response, brain spikes, neuronal depolarization. Uroguanilina induz potenciais em espiga no eletroencefalograma de ratos ResumoA uroguanilina (UGN) é um peptídeo endógeno que age em receptores do tipo guanilato ciclase de membrana de células intestinais e renais aumentando a produção de GMPc e regulando o transporte epitelial de eletrólitos e água. Pesquisas recentes demonstraram a expressão deste peptídeo e de seus receptores no sistema nervosa central. O presente trabalho foi realizado com objetivo de avaliar possíveis mudanças no espectro do eletroencefalograma (EEG) de ratos Wistar anestesiados, submetidos à infusão intracisternal de uroguanilina (0.0125 nmoles/min or 0.04 nmoles/min). Os resultados apresentados no corrente trabalho demonstram que a infusão intracisternal de ambas as doses de UGN aumenta significativamente a amplitude e frequência das espículas (p = 0.03). Não foram encontradas diferenças estatísticas na amplitude absoluta dos espectros alfa ou teta. Os dados apresentados neste trabalho mostram que a UGN age na bioeletrogênese de células corticais induzindo disparo hipersincrônico de neurônios. Este efeito é bloqueado por nedocromil, sugerindo que UGN atua pelo aumento de atividade de canais de cloreto.Palavras-chave: neuroexcitação, cerebral spikes, despolarização neuronal.

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