Guanylin and uroguanylin mRNA expression is increased following Roux-en-Y gastric bypass, but guanylins do not play a significant role in body weight regulation and glycemic control

Fernández-Cachón, María L.; Pedersen, Sven; Rigbolt, Kristoffer; Zhang, Chen; Fabricius, Katrine; Hansen, Henrik H.; Elster, Lisbeth; Fink, Lisbeth Nielsen; Schäfer, Matthias; Rhee, Nicolai; Langholz, Ebbe; Wandall, Erik; Friis, Stine; Vilmann, Peter; Kristiansen, Viggo B.; Schmidt, Christina; Schreiter, Kay; Breitschopf, Kristin; Hübschle, Thomas; Jorsal, Tina; Vilsbøll, Tina; Schmidt, Thorsten; Theis, Stefan; Knop, Filip K.; Larsen, Philip J.; Jelsing, Jacob

doi:10.1016/j.peptides.2017.12.024

Cited by 16 publications

(18 citation statements)

References 59 publications

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“…The key role of UGN in the regulation of energy homeostasis through the gut-brain axis has lately acquired great relevance [4,5,32]. In humans, UGN stimulates lipolysis in adipocytes [32] and the UGN mRNA expression is increased in obese patients following bariatric surgery [9]. Moreover, the circulating levels of pro-UGN are decreased in obese adults [33] and obese female adolescents [34] compared to lean subjects.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, it has been shown that UGN could bind GUCY2C at a hypothalamic level inducing the activation of anorexigenic pathways [6]. Although, subsequent studies failed to confirm UGN effects on food intake [8,9], we have recently reported that UGN centrally administered induced a body weight decrease on diet-induced obese (DIO) mice by increasing the energy expenditure in a food intake-independent manner [10].…”

Section: Introductionmentioning

confidence: 99%

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Uroguanylin Improves Leptin Responsiveness in Diet-Induced Obese Mice

et al. 2019

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The gastrointestinal-brain axis is a key mediator of the body weight and energy homeostasis regulation. Uroguanylin (UGN) has been recently proposed to be a part of this gut-brain axis regulating food intake, body weight and energy expenditure. Expression of UGN is regulated by the nutritional status and dependent on leptin levels. However, the exact molecular mechanisms underlying this UGN-leptin metabolic regulation at a hypothalamic level still remains unclear. Using leptin resistant diet-induced obese (DIO) mice, we aimed to determine whether UGN could improve hypothalamic leptin sensitivity. The present work demonstrates that the central co-administration of UGN and leptin potentiates leptin’s ability to decrease the food intake and body weight in DIO mice, and that UGN activates the hypothalamic signal transducer and activator of transcription 3 (STAT3) and phosphatidylinositide 3-kinases (PI3K) pathways. At a functional level, the blockade of PI3K, but not STAT3, blunted UGN-mediated leptin responsiveness in DIO mice. Overall, these findings indicate that UGN improves leptin sensitivity in DIO mice.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Uroguanylin Improves Leptin Responsiveness in Diet-Induced Obese Mice

et al. 2019

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“…Activation of hypothalamic guanylyl cyclase 2C through the intestinal hormone uroguanylin has been shown to regulate feeding and to induce BAT thermogenesis as well as WAT browning in mice, in part possibly through hypothalamic POMC signaling (Valentino et al 2011, Folgueira et al 2016. However, some studies question the metabolic relevance of this new proposed gut-brain axis (Begg et al 2014, Fernandez-Cachon et al 2018.…”

Section: Neuronal Control Of Wat Beigingmentioning

confidence: 99%

Adipose tissue browning in mice and humans

Herz

Kiefer

2019

Journal of Endocrinology

107

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In the midst of an obesity epidemic, the promotion of brown adipose tissue (BAT) function and the browning of white adipose tissue (WAT) have emerged as promising therapeutic targets to increase energy expenditure and counteract weight gain. Despite the fact that the thermogenic potential of bone fide BAT in rodents is several orders of magnitudes higher than white fat containing brite/beige adipocytes, WAT browning represents a particularly intriguing concept in humans given the extreme amount of excess WAT in obese individuals. In addition, the clear distinction between classic brown and beige fat that has been proposed in mice does not exist in humans. In fact, studies of human BAT biopsies found controversial results suggesting both classic brown and beige characteristics. Irrespective of the true ‘color’, accumulating evidence suggests the induction of thermogenic adipocytes in human WAT depots in response to specific stimuli, highlighting that WAT browning may occur in both, mice and humans. These observations also emphasize the great plasticity of human fat depots and raise important questions about the metabolic properties of thermogenically active adipose tissue in humans and the potential therapeutic implications. We will first review the cellular and molecular aspects of selected adipose tissue browning concepts that have been identified in mouse models with emphasis on neuronal factors, the microbiome, immune cells and several hormones. We will also summarize the evidence for adipose tissue browning in humans including some experimental pharmacologic approaches.

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“…Circulating proguanylin levels were lower in people with obesity and raised following Roux-en-Y gastric bypass surgery 28 , suggesting potential links to metabolism or food intake. Corresponding with these findings, mice fed a high fat diet had lower expression and peptide levels of guanylin and forced re-expression of guanylin reduced the rate of obesity associated colorectal cancer 29 .…”

Section: Introductionmentioning

confidence: 99%

“…In wild-type mice, food intake was reduced following intravenous administration of pro uro guanylin, but not proguanylin, and increased following treatment with a prouroguanylin antiserum and it was speculated local processing in the hypothalamus releases active uroguanylin 30,31 , suggesting a central role for GC-C signalling. However, another group found that neither systemic nor central administration of proguanylin-derived peptides modulated food ingestion or glucose homeostasis in mice 28 , despite targeting the same GC-C receptor. GC-C activation has, however, been shown to stimulate secretion of the anorectic peptide glucagon-like peptide-1 (GLP-1) from enteroendocrine cells in the GI tract 32 .…”

Section: Introductionmentioning

confidence: 99%

Characterisation of proguanylin expressing cells in the intestine – evidence for constitutive luminal secretion

Dye

Larraufie

Kay

et al. 2019

Sci Rep

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Guanylin, a peptide implicated in regulation of intestinal fluid secretion, is expressed in the mucosa, but the exact cellular origin remains controversial. In a new transgenic mouse model fluorescent reporter protein expression driven by the proguanylin promoter was observed throughout the small intestine and colon in goblet and Paneth(-like) cells and, except in duodenum, in mature enterocytes. In Ussing chamber experiments employing both human and mouse intestinal tissue, proguanylin was released predominantly in the luminal direction. Measurements of proguanylin expression and secretion in cell lines and organoids indicated that secretion is largely constitutive and requires ER to Golgi transport but was not acutely regulated by salt or other stimuli. Using a newly-developed proguanylin assay, we found plasma levels to be raised in humans after total gastrectomy or intestinal transplantation, but largely unresponsive to nutrient ingestion. By LC-MS/MS we identified processed forms in tissue and luminal extracts, but in plasma we only detected full-length proguanylin. Our transgenic approach provides information about the cellular origins of proguanylin, complementing previous immunohistochemical and in-situ hybridisation results. The identification of processed forms of proguanylin in the intestinal lumen but not in plasma supports the notion that the primary site of action is the gut itself.

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Guanylin and uroguanylin mRNA expression is increased following Roux-en-Y gastric bypass, but guanylins do not play a significant role in body weight regulation and glycemic control

Cited by 16 publications

References 59 publications

Uroguanylin Improves Leptin Responsiveness in Diet-Induced Obese Mice

Uroguanylin Improves Leptin Responsiveness in Diet-Induced Obese Mice

Adipose tissue browning in mice and humans

Characterisation of proguanylin expressing cells in the intestine – evidence for constitutive luminal secretion

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