1. The Deubiquitinase OTUB1 Is a Key Regulator of Energy Metabolism
- Author
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Ruiz-Serrano, Amalia, Boyle, Christina N, Monné Rodríguez, Josep M, Günter, Julia, Jucht, Agnieszka E, Pfundstein, Svende, Bapst, Andreas M, Lutz, Thomas A, Wenger, Roland H, Scholz, Carsten C, University of Zurich, Wenger, Roland H, and Scholz, Carsten C
- Subjects
Blood Glucose ,insulin ,1503 Catalysis ,QH301-705.5 ,10184 Institute of Veterinary Pathology ,1607 Spectroscopy ,610 Medicine & health ,liver ,Catalysis ,10052 Institute of Physiology ,Mixed Function Oxygenases ,Inorganic Chemistry ,Mice ,Adenosine Triphosphate ,energy expenditure ,1312 Molecular Biology ,1706 Computer Science Applications ,Animals ,FIH ,Phosphorylation ,Biology (General) ,Physical and Theoretical Chemistry ,deubiquitinating enzyme ,QD1-999 ,Molecular Biology ,Cells, Cultured ,Spectroscopy ,Cell Size ,ubiquitin system ,1604 Inorganic Chemistry ,Adenylate Kinase ,Body Weight ,Organic Chemistry ,General Medicine ,Fibroblasts ,10081 Institute of Veterinary Physiology ,Computer Science Applications ,Cysteine Endopeptidases ,Chemistry ,Hif1an ,hypoxia ,570 Life sciences ,biology ,Insulin Resistance ,1606 Physical and Theoretical Chemistry ,Energy Metabolism ,Proto-Oncogene Proteins c-akt ,Gene Deletion ,1605 Organic Chemistry - Abstract
Dysregulated energy metabolism is a major contributor to a multitude of pathologies, including obesity and diabetes. Understanding the regulation of metabolic homeostasis is of utmost importance for the identification of therapeutic targets for the treatment of metabolically driven diseases. We previously identified the deubiquitinase OTUB1 as substrate for the cellular oxygen sensor factor-inhibiting HIF (FIH) with regulatory effects on cellular energy metabolism, but the physiological relevance of OTUB1 is unclear. Here, we report that the induced global deletion of OTUB1 in adult mice (Otub1 iKO) elevated energy expenditure, reduced age-dependent body weight gain, facilitated blood glucose clearance and lowered basal plasma insulin levels. The respiratory exchange ratio was maintained, indicating an unaltered nutrient oxidation. In addition, Otub1 deletion in cells enhanced AKT activity, leading to a larger cell size, higher ATP levels and reduced AMPK phosphorylation. AKT is an integral part of insulin-mediated signaling and Otub1 iKO mice presented with increased AKT phosphorylation following acute insulin administration combined with insulin hypersensitivity. We conclude that OTUB1 is an important regulator of metabolic homeostasis.
- Published
- 2022