The Deubiquitinase OTUB1 Is a Key Regulator of Energy Metabolism.
Amalia Ruiz-SerranoChristina Neuner BoyleJosep Maria Monné RodríguezJulia GünterAgnieszka E JuchtSvende PfundsteinAndreas M BapstThomas A LutzRoland H WengerCarsten C ScholzPublished in: International journal of molecular sciences (2022)
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.
Keyphrases
- type diabetes
- glycemic control
- weight gain
- blood glucose
- signaling pathway
- high fat diet induced
- weight loss
- insulin resistance
- cell proliferation
- induced apoptosis
- body mass index
- transcription factor
- drug induced
- cardiovascular disease
- metabolic syndrome
- single cell
- birth weight
- protein kinase
- blood pressure
- physical activity
- intensive care unit
- cell cycle arrest
- cell death
- endoplasmic reticulum stress