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.
Highlights
Metabolic perturbations are associated with many common human diseases, including obesity, heart failure, diabetes and cancer [1,2]
Assessing possible gross phenotypes in adult mice with induced whole-body Otub1 deletion (Otub1 iKO), Otub1 was ablated by tamoxifen gavage over five consecutive days and body weight (BW) progression was monitored for 122 days
Analyzing various excised adipose tissues, we found that subcutaneous white adipose tissue weight was significantly lower in Otub1 iKO mice and perigonadal WAT showed a strong tendency towards being decreased (Figure 1C)
Summary
Metabolic perturbations are associated with many common human diseases, including obesity, heart failure, diabetes and cancer [1,2]. Pharmaceutical targeting of the bioenergetic metabolism is a current focus in the development of novel treatment option for many of these diseases [2]. For the identification of possible unknown therapeutic targets, it is of key importance to improve our understanding of metabolic homeostasis as well as of the underlying signaling pathways and proteins. Proteins of virtually all known signaling pathways are regulated by the ubiquitin system, which is an important contributor to cell and tissue homeostasis [3]. K48-linked polyubiquitination is the most abundant Ub modification in cells, targeting modified proteins for proteasomal degradation [5]. K63-Ub poly-ubiquitination is the second most abundant Ub modification [5], serving as inducible scaffold in multiple signaling pathways [6]
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