Uroguanylin Improves Leptin Responsiveness in Diet-Induced Obese Mice

Folgueira, Cintia; Beiroa, Daniel; Gonzalez-Rellan, María J.; Porteiro, Begoña; Milbank, Edward; Castelao, Cecilia; García-Palacios, María; Casanueva, Felipe F.; López, Miguel; Diéguez, Carlos; Seoane, Luísa M.; Nogueiras, Rubén

doi:10.3390/nu11040752

Cited by 8 publications

(7 citation statements)

References 41 publications

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“…To evaluate whether prolonged breastfeeding could improve leptin sensitivity in obesity, both SW-HFD and DW-HFD rats were given an intracerebroventricular (ICV) injection of either vehicle or leptin at a dose of 3 µg, known to induce a decrease in feeding and body weight in CD-fed rodents 20 .…”

Section: Resultsmentioning

confidence: 99%

“…In rats, anaesthesia was administered by i.p. injection (ketamine–xylazine mixture), and a cannula implanted by stereotaxic surgery in the hypothalamic lateral ventricle (coordinates: 1.3 mm posterior to bregma, 1.9 mm lateral to the midsagittal suture, and a depth of 3.5 mm; and in mice: 0.6 mm posterior to bregma, 1.2 mm lateral to the midsagittal suture and a depth of 2 mm) 20 . Animals were individually stabled 4 d before the experiment.…”

Section: Methodsmentioning

confidence: 99%

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Prolonged breastfeeding protects from obesity by hypothalamic action of hepatic FGF21

et al. 2022

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Early-life determinants are thought to be a major factor in the rapid increase of obesity. However, while maternal nutrition has been extensively studied, the effects of breastfeeding by the infant on the reprogramming of energy balance in childhood and throughout adulthood remain largely unknown. Here we show that delayed weaning in rat pups protects them against diet-induced obesity in adulthood, through enhanced brown adipose tissue thermogenesis and energy expenditure. In-depth metabolic phenotyping in this rat model as well as in transgenic mice reveals that the effects of prolonged suckling are mediated by increased hepatic fibroblast growth factor 21 (FGF21) production and tanycyte-controlled access to the hypothalamus in adulthood. Specifically, FGF21 activates GABA-containing neurons expressing dopamine receptor 2 in the lateral hypothalamic area and zona incerta. Prolonged breastfeeding thus constitutes a protective mechanism against obesity by affecting long-lasting physiological changes in liver-to-hypothalamus communication and hypothalamic metabolic regulation.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Prolonged breastfeeding protects from obesity by hypothalamic action of hepatic FGF21

et al. 2022

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“…Sixty hours after central intervention, mice were fasted for 12 h, then either vehicle (saline) or leptin (3 μg/mice) was i.c.v. injected [ 19 ]. Fifteen minutes later, the mice were anesthetized, and tissues were collected for further analysis.…”

Section: Methodsmentioning

confidence: 99%

C1q/TNF-related protein 4 restores leptin sensitivity by downregulating NF-κB signaling and microglial activation

Liu

Jia

et al. 2021

J Neuroinflammation

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Objective C1qTNF-related protein 4 (CTRP4) acts in the hypothalamus to modulate food intake in diet-induced obese mice and has been shown to exert an anti-inflammatory effect on macrophages. Since high-fat diet-induced microglial activation and hypothalamic inflammation impair leptin signaling and increase food intake, we aimed to explore the potential connection between the anorexigenic effect of CTRP4 and the suppression of hypothalamic inflammation in mice with DIO. Methods Using an adenovirus-mediated hypothalamic CTRP4 overexpression model, we investigated the impact of CTRP4 on food intake and the hypothalamic leptin signaling pathway in diet-induced obese mice. Furthermore, central and plasma proinflammatory cytokines, including TNF-α and IL-6, were measured by Western blotting and ELISA. Changes in the hypothalamic NF-κB signaling cascade and microglial activation were also examined in vivo. In addition, NF-κB signaling and proinflammatory factors were investigated in BV-2 cells after CTRP4 intervention. Results We found that food intake was decreased, while leptin signaling was significantly improved in mice with DIO after CTRP4 overexpression. Central and peripheral TNF-α and IL-6 levels were reduced by central Ad-CTRP4 administration. Hypothalamic NF-κB signaling and microglial activation were also significantly suppressed in vivo. In addition, NF-κB signaling was inhibited in BV-2 cells following CTRP4 intervention, which was consistent with the decreased production of TNF-α and IL-6. Conclusions Our data indicate that CTRP4 reverses leptin resistance by inhibiting NF-κB-dependent microglial activation and hypothalamic inflammation.

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“…Food intake raises circulating uroguanylin levels, but the stimulus for secretion is unknown (51). Although leptin, an adipocyte-derived hormone, has been linked to the nutritional status-based modulation of uroguanylin, direct supportive evidence is sparse (245). This link is particularly relevant to our understanding of the stimuli that inhibit postprandial secretion of uroguanylin into the circulation in obesity, which is evident in both human and animal models (123,(128)(129)(130).…”

Section: Regulation Of Endogenous Gc-c Ligandsmentioning

confidence: 99%

Receptor Guanylyl Cyclase C and Cyclic GMP in Health and Disease: Perspectives and Therapeutic Opportunities

2022

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Receptor Guanylyl Cyclase C (GC-C) was initially characterized as an important regulator of intestinal fluid and ion homeostasis. Recent findings demonstrate that GC-C is also causally linked to intestinal inflammation, dysbiosis, and tumorigenesis. These advances have been fueled in part by identifying mutations or changes in gene expression in GC-C or its ligands, that disrupt the delicate balance of intracellular cGMP levels and are associated with a wide range of clinical phenotypes. In this review, we highlight aspects of the current knowledge of the GC-C signaling pathway in homeostasis and disease, emphasizing recent advances in the field. The review summarizes extra gastrointestinal functions for GC-C signaling, such as appetite control, energy expenditure, visceral nociception, and behavioral processes. Recent research has expanded the homeostatic role of GC-C and implicated it in regulating the ion-microbiome-immune axis, which acts as a mechanistic driver in inflammatory bowel disease. The development of transgenic and knockout mouse models allowed for in-depth studies of GC-C and its relationship to whole-animal physiology. A deeper understanding of the various aspects of GC-C biology and their relationships with pathologies such as inflammatory bowel disease, colorectal cancer, and obesity can be leveraged to devise novel therapeutics.

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Uroguanylin Improves Leptin Responsiveness in Diet-Induced Obese Mice

Cited by 8 publications

References 41 publications

Prolonged breastfeeding protects from obesity by hypothalamic action of hepatic FGF21

Prolonged breastfeeding protects from obesity by hypothalamic action of hepatic FGF21

C1q/TNF-related protein 4 restores leptin sensitivity by downregulating NF-κB signaling and microglial activation

Receptor Guanylyl Cyclase C and Cyclic GMP in Health and Disease: Perspectives and Therapeutic Opportunities

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