Obesity-associated inflammation is recognized as a critical factor in the development of insulin resistance leading to Type 2 diabetes and other metabolic disorders. However, the critical question of whether inhibiting inflammation is a good approach in the attempt to treat insulin resistance remains open. Our long-term goal is to investigate the endogenous regulatory mechanisms geared toward prevention of hyper-activation of inflammatory responses in the adipose tissue and to understand whether blunting inflammation may be partially counterproductive in maintaining insulin sensitivity. The rationale being that while the detrimental effects of pro-inflammatory cytokines are well known, there may be beneficial effects of inflammation that have been generally overlooked. G-protein Pathway Suppressor 2 (GPS2) is a transcriptional cofactor and an inhibitor of ubiquitin signaling playing an important anti-inflammatory role in the adipose tissue. This proposal is designed to: i) take advantage of the aP2-GPS2 mouse model to dissect the opposing effects of inhibiting inflammation in the context of obesity-induced insulin resistance;ii) uncover the molecular mechanism of GPS2 transcriptional actions as a novel coactivator of PPAR?. To address these questions, we propose three Aims:
Specific Aim 1 will characterize the metabolic and inflammatory phenotype of the aP2-GPS2 transgenic mice and investigate the hypothesis that GPS2- mediated inhibition of inflammatory responses in adipocytes and macrophages impairs the storage capacity of the adipose tissue and induce ectopic fat deposition.
Specific Aim 2 will dissect the molecular mechanism of GPS2-mediated transcriptional regulation of the adipokine gene resistin and broadly assess the relevance of GPS2 as a transcriptional coactivator in adipocytes.
Specific Aim 3 will elucidate the structural basis of GPS2-mediated regulation of inflammatory responses via inhibition of specific ubiquitin machineries. Overall, the proposed studies will contribute significantly to the general understanding of the effects of inhibiting inflammatory responses on the regulation of the adipose tissue homeostasis and ectopic fat accumulation, and will define the molecular and structural basis of GPS2 transcriptional actions as a novel coactivator for the nuclear receptor PPAR?.

Public Health Relevance

United States has the highest obesity rates in the developed world and obesity is one of the leading health issues, with more than 75 percent of Americans being considered either overweight or obese. The constant increase in obesity rates in the past 10-15 years has been steadily associated with a worrisome increase in obesity-related disorders, including insulin resistance, Type-2 Diabetes and cardiovascular diseases in adults and children alike. As most existing anti-diabetic drugs have harmful side effects, there is an immediate need to find novel approaches towards modulating insulin resistance in obese patients and it is critical to understand how to best target inflammation.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
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Abraham, Kristin M
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Boston University
Schools of Medicine
United States
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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
Mahdaviani, Kiana; Benador, Ilan Y; Su, Shi et al. (2017) Mfn2 deletion in brown adipose tissue protects from insulin resistance and impairs thermogenesis. EMBO Rep 18:1123-1138
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
Huang, Jiawen; Cardamone, M Dafne; Johnson, Holly E et al. (2015) Exchange Factor TBL1 and Arginine Methyltransferase PRMT6 Cooperate in Protecting G Protein Pathway Suppressor 2 (GPS2) from Proteasomal Degradation. J Biol Chem 290:19044-54
Cardamone, M Dafne; Tanasa, Bogdan; Chan, Michelle et al. (2014) GPS2/KDM4A pioneering activity regulates promoter-specific recruitment of PPAR?. Cell Rep 8:163-76