The Deubiquitinase OTUB1 Is a Key Regulator of Energy Metabolism

• Published in: International journal of molecular sciences Vol. 23; no. 3; p. 1536
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 28-01-2022; MDPI
• Subjects: Adenosine Triphosphate - metabolism; Adenylate Kinase - metabolism; AKT protein; Amino acids; Animals; Blood Glucose; Body fat; Body Weight; Body weight gain; Cell Size; Cells, Cultured; Clonal deletion; Cysteine Endopeptidases - genetics; Cysteine Endopeptidases - metabolism; deubiquitinating enzyme; Diabetes mellitus; Energy; Energy expenditure; Energy Metabolism; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; FIH; Gene Deletion; Genotype & phenotype; Glucose; Homeostasis; Hypersensitivity; Hyperthyroidism; Insulin; Insulin - administration & dosage; Insulin - adverse effects; Insulin Resistance - genetics; Kinases; liver; Metabolism; Mice; Mixed Function Oxygenases - metabolism; Oxidation; Oxygen probes; Phosphorylation; Physiological effects; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Therapeutic targets; Thyroid gland; ubiquitin system; hypoxia; FIH; insulin; deubiquitinating enzyme; liver; Hif1an; energy expenditure; ubiquitin system
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23031536

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 (
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,
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
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.