Obesity- associated inflammation is widely recognized as a critical factor in the development of insulin resistance leading to type 2 diabetes (T2D) and other metabolic disorders. However, surprisingly, treatment with anti-inflammatory drugs have not proven successful in treating these metabolic syndromes and the critical question of whether inhibiting inflammation is a good approach in the attempt to treat insulin resistance remains unanswered. G-protein pathway suppressor 2 (GPS2) has recently emerged as an important, novel regulator of homeostasis and inflammatory responses in various metabolic organs, most importantly adipose tissue. Previous work from our lab and others describes GPS2 as a multifunctional protein. GPS2 is found to function in the cytosol, where it inhibits the stress kinase, JNK, activation by modulating ubiquitin signaling events downstream of the TNF? receptor, and in the nucleus, where it acts as a cofactor regulating gene expression by inhibiting transcription of pro-inflammatory targets and activating key mediators of the lipolysis pathway. Here, we present the characterization of the adipo-specific GPS2 knockout (AKO) mouse model confirming the critical role of GPS2 in regulating obesity-induced inflammation and lipid metabolism in vivo. We observe that the GPS2 AKO mice become more obese and inflamed than WT mice during high fat diet feeding yet are protected from developing insulin resistance. We hypothesize that GPS2 AKO mice are metabolically healthier than their wild type littermates because of increased adipose tissue lipid storage capacity resulting from increased lipogenesis and decreased lipolysis in the adipocytes. We also hypothesize that the increased stimulation of inflammatory responses in the adipose tissue has a positive and protective role against the development of insulin resistance. Thus, we propose to understand how GPS2 regulates lipid flux in adipose tissue by modulating key regulators of lipid metabolism and to elucidate the role of GPS2 in controlling macrophage infiltration with potential consequences for tissue remodeling and expansion. The GPS2 AKO mice represents a unique model to improve our comprehension of the interplays between inflammation and adipose tissue functionality in the development of insulin resistance and contribute to understand whether inhibiting inflammation in the context of obesity is a viable strategy to ameliorate metabolic functionality.
There is an immediate need to discover successful therapies for the treatment of metabolic diseases, such as type 2 diabetes (T2D). The current central dogma suggests inflammation plays a major causal role in the development of this disease, however, more recent studies suggest there is more complexity than has been previously described. Therefore, we wish to use our novel mouse model to get a better understand of the development of this disease and to change the way people think about treating T2D in order to develop successful and specific drug therapeutics.
| Cardamone, Maria Dafne; Tanasa, Bogdan; Cederquist, Carly T et al. (2018) Mitochondrial Retrograde Signaling in Mammals Is Mediated by the Transcriptional Cofactor GPS2 via Direct Mitochondria-to-Nucleus Translocation. Mol Cell 69:757-772.e7 |
| Cederquist, Carly T; Lentucci, Claudia; Martinez-Calejman, Camila et al. (2017) Systemic insulin sensitivity is regulated by GPS2 inhibition of AKT ubiquitination and activation in adipose tissue. Mol Metab 6:125-137 |
| Lentucci, Claudia; Belkina, Anna C; Cederquist, Carly T et al. (2017) Inhibition of Ubc13-mediated Ubiquitination by GPS2 Regulates Multiple Stages of B Cell Development. J Biol Chem 292:2754-2772 |
