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Your search keyword '"Wenger, Roland H."' showing total 2 results
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2 results on '"Wenger, Roland H."'

1. PAS Kinase Is a Nutrient and Energy Sensor in Hypothalamic Areas Required for the Normal Function of AMPK and mTOR/S6K1

Author

Bazán, Nicolas G., Hurtado Carneiro, Verónica, Roncero Rincón, Isabel, Egger, Sascha S., Wenger, Roland H., Blázquez Fernández, Enrique, Sanz Miguel, María Del Carmen, Álvarez García, Elvira, Bazán, Nicolas G., Hurtado Carneiro, Verónica, Roncero Rincón, Isabel, Egger, Sascha S., Wenger, Roland H., Blázquez Fernández, Enrique, Sanz Miguel, María Del Carmen, and Álvarez García, Elvira

Abstract

The complications caused by overweight, obesity and type 2 diabetes are one of the main problems that increase morbidity and mortality in developed countries. Hypothalamic metabolic sensors play an important role in the control of feeding and energy homeostasis. PAS kinase (PASK) is a nutrient sensor proposed as a regulator of glucose metabolism and cellular energy. The role of PASK might be similar to other known metabolic sensors, such as AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR). PASK-deficient mice resist diet-induced obesity. We have recently reported that AMPK and mTOR/S6K1 pathways are regulated in the ventromedial and lateral hypothalamus in response to nutritional states, being modulated by anorexigenic glucagon-like peptide-1 (GLP-1)/exendin-4 in lean and obese rats. We identified PASK in hypothalamic areas, and its expression was regulated under fasting/re-feeding conditions and modulated by exendin-4. Furthermore, PASK-deficient mice have an impaired activation response of AMPK and mTOR/S6K1 pathways. Thus, hypothalamic AMPK and S6K1 were highly activated under fasted/re-fed conditions. Additionally, in this study, we have observed that the exendin-4 regulatory effect in the activity of metabolic sensors was lost in PASK-deficient mice, and the anorexigenic properties of exendin-4 were significantly reduced, suggesting that PASK could be a mediator in the GLP-1 signalling pathway. Our data indicated that the PASK function could be critical for preserving the nutrient effect on AMPK and mTOR/S6K1 pathways and maintain the regulatory role of exendin-4 in food intake. Some of the antidiabetogenic effects of exendin-4 might be modulated through these processes., Ministerio de Ciencia e Innovación, Universidad Complutense de Madrid, Instituto de Salud Carlos III, Banco Santander, Mutua Madrileña, CIBERDEM :: Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Depto. de Fisiología, Depto. de Bioquímica y Biología Molecular, Depto. de Biología Celular, Fac. de Medicina, TRUE, pub

Published
2024

2. Selective Hypoxia-Sensitive Oxomer Formation by FIH Prevents Binding of the NF-κB Inhibitor IκBβ to NF-κB Subunits.

Author

Volkova, Yulia L., Jucht, Agnieszka E., Oechsler, Nina, Krishnankutty, Roopesh, von Kriegsheim, Alex, Wenger, Roland H., and Scholz, Carsten C.

Subjects
OXYGEN detectors, AMINO acid sequence
Abstract

Pharmacologic inhibitors of cellular hydroxylase oxygen sensors are protective in multiple preclinical in vivo models of inflammation. However, the molecular mechanisms underlying this regulation are only partly understood, preventing clinical translation. We previously proposed a new mechanism for cellular oxygen sensing: oxygen-dependent, (likely) covalent protein oligomer (oxomer) formation. Here, we report that the oxygen sensor factor inhibiting HIF (FIH) forms an oxomer with the NF-κB inhibitor β (IκBβ). The formation of this protein complex required FIH enzymatic activity and was prevented by pharmacologic inhibitors. Oxomer formation was highly hypoxia-sensitive and very stable. No other member of the IκB protein family formed an oxomer with FIH, demonstrating that FIH-IκBβ oxomer formation was highly selective. In contrast to the known FIH-dependent oxomer formation with the deubiquitinase OTUB1, FIH-IκBβ oxomer formation did not occur via an IκBβ asparagine residue, but depended on the amino acid sequence VAERR contained within a loop between IκBβ ankyrin repeat domains 2 and 3. Oxomer formation prevented IκBβ from binding to its primary interaction partners p65 and c-Rel, subunits of NF-κB, the master regulator of the cellular transcriptional response to pro-inflammatory stimuli. We therefore propose that FIH-mediated oxomer formation with IκBβ contributes to the hypoxia-dependent regulation of inflammation. [ABSTRACT FROM AUTHOR]

Published
2024
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