scholarly journals FTO suppresses STAT3 activation and modulates proinflammatory interferon-stimulated gene expression

2021 ◽  
Author(s):  
Michael J McFadden ◽  
Matthew T. Sacco ◽  
Kristen A. Murphy ◽  
Moonhee Park ◽  
Nandan S. Gokhale ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Type I Interferon ◽  
Type I ◽  
Type I Ifn ◽  
Rna Modifications ◽  
Inflammatory Genes

Signaling initiated by type I interferon (IFN) results in the induction of hundreds of IFN-stimulated genes (ISGs). The type I IFN response is important for antiviral restriction, but aberrant activation of this response can lead to inflammation and autoimmunity. Regulation of this response is incompletely understood. We previously reported that the mRNA modification m6A and its deposition enzymes, METTL3 and METTL14 (METTL3/14), promote the type I IFN response by directly modifying the mRNA of a subset of ISGs to enhance their translation. Here, we determined the role of the RNA demethylase FTO in the type I IFN response. FTO, which can remove either m6A or the cap-adjacent m6Am RNA modifications, has previously been associated with obesity and body mass index, type 2 diabetes, cardiovascular disease, and inflammation. We found that FTO suppresses the transcription of a distinct set of ISGs, including many known pro-inflammatory genes, and that this regulation is not through the actions of FTO on m6Am. Further, we found that depletion of FTO led to activation of STAT3, a transcription factor that mediates responses to various cytokines, but whose role in the type I IFN response is not well understood. This activation of STAT3 increased the expression of a subset of ISGs. Importantly, this increased ISG induction resulting from FTO depletion was partially ablated by depletion of STAT3. Together, these results reveal that FTO negatively regulates STAT3-mediated signaling that induces proinflammatory ISGs during the IFN response, highlighting an important role for FTO in suppression of inflammatory genes.

The role of IGF-I and its binding proteins in the development of type 2 diabetes and cardiovascular disease

2008 ◽  
Vol 10 (3) ◽  
pp. 198-211 ◽  
Author(s):  
Vivienne A. Ezzat ◽  
Edward R. Duncan ◽  
Stephen B. Wheatcroft ◽  
Mark T. Kearney
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Binding Proteins ◽  
Igf I

scholarly journals Adipocyte PU.1 knockout promotes insulin sensitivity in HFD-fed obese mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Denise E. Lackey ◽  
Felipe C. G. Reis ◽  
Roi Isaac ◽  
Rizaldy C. Zapata ◽  
Dalila El Ouarrat ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Target Genes ◽  
Obese Mice ◽  
Tissue Macrophage

Abstract Insulin resistance is a key feature of obesity and type 2 diabetes. PU.1 is a master transcription factor predominantly expressed in macrophages but after HFD feeding PU.1 expression is also significantly increased in adipocytes. We generated adipocyte specific PU.1 knockout mice using adiponectin cre to investigate the role of PU.1 in adipocyte biology, insulin and glucose homeostasis. In HFD-fed obese mice systemic glucose tolerance and insulin sensitivity were improved in PU.1 AKO mice and clamp studies indicated improvements in both adipose and liver insulin sensitivity. At the level of adipose tissue, macrophage infiltration and inflammation was decreased and glucose uptake was increased in PU.1 AKO mice compared with controls. While PU.1 deletion in adipocytes did not affect the gene expression of PPARg itself, we observed increased expression of PPARg target genes in eWAT from HFD fed PU.1 AKO mice compared with controls. Furthermore, we observed decreased phosphorylation at serine 273 in PU.1 AKO mice compared with fl/fl controls, indicating that PPARg is more active when PU.1 expression is reduced in adipocytes. Therefore, in obesity the increased expression of PU.1 in adipocytes modifies the adipocyte PPARg cistrome resulting in impaired glucose tolerance and insulin sensitivity.

scholarly journals Vascular Disease in Diabetic Women: Why Do They Miss the Female Protection?

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Ana Paula Villela Dantas ◽  
Zuleica Bruno Fortes ◽  
Maria Helena Catelli de Carvalho
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Type 2 Diabetes Mellitus ◽  
Vascular Disease ◽  
Vascular Dysfunction ◽  
Protective Effects ◽  
Vascular Protection

Gender plays a pivotal role in the onset as well as in the progression of the cardiovascular disease with a higher morbidity and mortality being detected in men with respect to women. Type 2 Diabetes Mellitus (T2DM) may reduce gender-related differences in the prevalence of cardiovascular disease by fading the vascular protective effects afforded by estrogen in females. This article will discuss the role of sex and sex hormones on the incidence and mechanisms involved in vascular dysfunction associated to T2DM, which might explain why women with T2DM lack the vascular protection.

scholarly journals No Association Between Statin Use and the Prognosis of Endometrial Cancer in Women With Type 2 Diabetes

2021 ◽  
Vol 12 ◽  
Author(s):  
Elina Urpilainen ◽  
Anne Ahtikoski ◽  
Reetta Arima ◽  
Ulla Puistola ◽  
Peeter Karihtala
Keyword(s):  
Type 2 Diabetes ◽  
Endometrial Cancer ◽  
Cancer Diagnosis ◽  
Progression Free Survival ◽  
Epidemiological Studies ◽  
University Hospital ◽  
Type I ◽  
Statin Use

Preclinical studies have suggested statins have antiproliferative and anti-metastatic effects on endometrial cancer cells. Similarly, most previous epidemiological studies have reported a better prognosis of endometrial cancer in patients who used statins. In this study, we explored the role of statins in the prognosis of endometrial cancer in women with type 2 diabetes in a hospital-based cohort. This retrospective cohort consisted of 119 women with type 2 diabetes who were diagnosed and treated for endometrial cancer at Oulu University Hospital, Finland, between 2007 and 2014. The patients were classified as statin users (n = 58) and nonusers (n = 61) based on the type of medication they were using at the time of endometrial cancer diagnosis. Statin use showed no association with progression-free survival or overall survival in the whole cohort nor the subgroups with type I or type II histology, in lower or higher body mass index groups, or at an early or advanced stage. The results remained similar in the multivariate analysis after adjusting for the patient’s age, cancer stage, and histology. Furthermore, statin use seemed not to have any association with most of the prognostic factors at the time of endometrial cancer diagnosis.

scholarly journals mSphere of Influence: the Key Role of Neutrophils in Tuberculosis and Type 2 Diabetes Comorbidity

mSphere ◽  
2021 ◽  
Vol 6 (3) ◽  
Author(s):  
Anne E. Mayer Bridwell
Keyword(s):  
Type 2 Diabetes ◽  
Metabolic Regulation ◽  
Neutrophil Extracellular Trap ◽  
Type I ◽  
Pathological Feature ◽  
Link Type ◽  
Systems Immunology ◽  
Shed Light

ABSTRACT Annie Mayer Bridwell works in the field of tuberculosis pathogenesis from the host perspective. She is fascinated by comorbidities, and in this paper, she reflects on three publications that shaped her model of neutrophil-centric pathology in tuberculosis and type 2 diabetes comorbidity. She explains that “Systems immunology of diabetes-tuberculosis comorbidity reveals signatures of disease complications” (C. A. Prada-Medina, K. F. Fukutani, N. Pavan Kumar, L. Gil-Santana, et al., Sci Rep 7:1999, 2017, https://doi.org/10.1038/s41598-017-01767-4) led her to consider neutrophils as a central immunological player in comorbid patients. “Type I IFN exacerbates disease in tuberculosis-susceptible mice by inducing neutrophil-mediated lung inflammation and NETosis” (L. Moreira-Teixeira, P. J. Stimpson, E. Stavropoulos, S. Hadebe, et al., Nat Commun 11:5566, 2020, https://doi.org/10.1038/s41467-020-19412-6) and “Diabetes primes neutrophils to undergo NETosis, which impairs wound healing” (S. L. Wong, M. Demers, K. Martinod, M. Gallant, et al., Nat Med 21:815–819, 2015, https://doi.org/10.1038/nm.3887) then shed light on neutrophil extracellular trap (NET) formation as a common pathological feature of dysregulated neutrophils in tuberculosis and diabetes, respectively. Together, these works laid the foundation for Dr. Mayer Bridwell's interest in metabolic regulation of NETosis during TB infection and diabetes comorbidity.

scholarly journals Endothelial Dysfunction: Is There a Hyperglycemia-Induced Imbalance of NOX and NOS?

2019 ◽  
Vol 20 (15) ◽  
pp. 3775 ◽  
Author(s):  
Cesar A. Meza ◽  
Justin D. La Favor ◽  
Do-Houn Kim ◽  
Robert C. Hickner
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Blood Flow ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Vascular Dysfunction ◽  
Vascular Complications ◽  
Enzymatic Production

NADPH oxidases (NOX) are enzyme complexes that have received much attention as key molecules in the development of vascular dysfunction. NOX have the primary function of generating reactive oxygen species (ROS), and are considered the main source of ROS production in endothelial cells. The endothelium is a thin monolayer that lines the inner surface of blood vessels, acting as a secretory organ to maintain homeostasis of blood flow. The enzymatic production of nitric oxide (NO) by endothelial NO synthase (eNOS) is critical in mediating endothelial function, and oxidative stress can cause dysregulation of eNOS and endothelial dysfunction. Insulin is a stimulus for increases in blood flow and endothelium-dependent vasodilation. However, cardiovascular disease and type 2 diabetes are characterized by poor control of the endothelial cell redox environment, with a shift toward overproduction of ROS by NOX. Studies in models of type 2 diabetes demonstrate that aberrant NOX activation contributes to uncoupling of eNOS and endothelial dysfunction. It is well-established that endothelial dysfunction precedes the onset of cardiovascular disease, therefore NOX are important molecular links between type 2 diabetes and vascular complications. The aim of the current review is to describe the normal, healthy physiological mechanisms involved in endothelial function, and highlight the central role of NOX in mediating endothelial dysfunction when glucose homeostasis is impaired.

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