STAT1 Dissociates Adipose Tissue Inflammation From Insulin Sensitivity in Obesity

Cox, Aaron R.; Chernis, Natasha; Bader, David A.; Saha, Pradip Kumar; Masschelin, Peter M.; Felix, Jessica B.; Sharp, Robert; Lian, Zeqin; Putluri, Vasanta; Rajapakshe, Kimal I.; Kim, Kang Ho; Villareal, Dennis T.; Armamento-Villareal, Reina; Wu, Huaizhu; Coarfa, Cristian; Putluri, Nagireddy; Hartig, Sean M.

doi:10.2337/db20-0384

Cited by 31 publications

(28 citation statements)

References 52 publications

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“…8 ). These observations add to the growing number of reports invoking a potentially dichotomous relationship presented by inflammation in obesity: (a) the potentially advantageous inflammatory contributors to obesity development 15 , 32 , 48 and (b) established obesity-driven inflammatory cytokines that can exacerbate downstream metabolic derangements 49 . Thus, a balance between these two functions of the immune system likely needs to be tightly controlled and regulated.…”

Section: Discussionmentioning

confidence: 69%

A BAFF/APRIL axis regulates obesogenic diet-driven weight gain

et al. 2021

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The impact of immune mediators on weight homeostasis remains underdefined. Interrogation of resistance to diet-induced obesity in mice lacking a negative regulator of Toll-like receptor signaling serendipitously uncovered a role for B cell activating factor (BAFF). Here we show that overexpression of BAFF in multiple mouse models associates with protection from weight gain, approximating a log-linear dose response relation to BAFF concentrations. Gene expression analysis of BAFF-stimulated subcutaneous white adipocytes unveils upregulation of lipid metabolism pathways, with BAFF inducing white adipose tissue (WAT) lipolysis. Brown adipose tissue (BAT) from BAFF-overexpressing mice exhibits increased Ucp1 expression and BAFF promotes brown adipocyte respiration and in vivo energy expenditure. A proliferation-inducing ligand (APRIL), a BAFF homolog, similarly modulates WAT and BAT lipid handling. Genetic deletion of both BAFF and APRIL augments diet-induced obesity. Lastly, BAFF/APRIL effects are conserved in human adipocytes and higher BAFF/APRIL levels correlate with greater BMI decrease after bariatric surgery. Together, the BAFF/APRIL axis is a multifaceted immune regulator of weight gain and adipose tissue function.

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Section: Discussionmentioning

confidence: 69%

A BAFF/APRIL axis regulates obesogenic diet-driven weight gain

et al. 2021

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“…STAT1 has been related to prognosis of early-stage colorectal cancer [ 450 ], as constitutively active STAT is a hallmark of many cancers, also correlating inversely with FBG levels in obese humans and mice [ 451 ]. Also other inflammatory diseases, especially IBD, have been related to STAT3 activation [ 452 ].…”

Section: Markers Of Inflammation Relation To Disease and Practicamentioning

confidence: 99%

Common and Novel Markers for Measuring Inflammation and Oxidative Stress Ex Vivo in Research and Clinical Practice—Which to Use Regarding Disease Outcomes?

Menzel¹,

Samouda

Dohet³

et al. 2021

Antioxidants

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Many chronic conditions such as cancer, chronic obstructive pulmonary disease, type-2 diabetes, obesity, peripheral/coronary artery disease and auto-immune diseases are associated with low-grade inflammation. Closely related to inflammation is oxidative stress (OS), which can be either causal or secondary to inflammation. While a low level of OS is physiological, chronically increased OS is deleterious. Therefore, valid biomarkers of these signalling pathways may enable detection and following progression of OS/inflammation as well as to evaluate treatment efficacy. Such biomarkers should be stable and obtainable through non-invasive methods and their determination should be affordable and easy. The most frequently used inflammatory markers include acute-phase proteins, essentially CRP, serum amyloid A, fibrinogen and procalcitonin, and cytokines, predominantly TNFα, interleukins 1β, 6, 8, 10 and 12 and their receptors and IFNγ. Some cytokines appear to be disease-specific. Conversely, OS—being ubiquitous—and its biomarkers appear less disease or tissue-specific. These include lipid peroxidation products, e.g., F2-isoprostanes and malondialdehyde, DNA breakdown products (e.g., 8-OH-dG), protein adducts (e.g., carbonylated proteins), or antioxidant status. More novel markers include also –omics related ones, as well as non-invasive, questionnaire-based measures, such as the dietary inflammatory-index (DII), but their link to biological responses may be variable. Nevertheless, many of these markers have been clearly related to a number of diseases. However, their use in clinical practice is often limited, due to lacking analytical or clinical validation, or technical challenges. In this review, we strive to highlight frequently employed and useful markers of inflammation-related OS, including novel promising markers.

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“…Recently, it was reported that miR-155-5p directly regulated Gsk3b and participated in the regulation of steroid metabolism (39), and that Nr1h3 was related to autophagy. STAT1 was reported to be related to inflammation and insulin sensitivity in adipose tissue and obesity (40). MAPK14 has a wide effect on regulating inflammation and metabolism, and was shown to be regulated by miRNA epigenetics in PCOS in our previous study (24).…”

Section: Discussionmentioning

confidence: 83%

Aberrant miRNA-mRNA regulatory network in polycystic ovary syndrome is associated with markers of insulin sensitivity and inflammation

et al. 2021

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Background: Polycystic ovary syndrome (PCOS) is a common multifactorial metabolic and endocrine disorder in women of reproductive age. Increasingly, evidence indicates that the microRNA (miRNA)-mRNA axis contributes to the development of PCOS. Methods:To investigate the molecular mechanisms through which miRNA-mRNA expression affects hyperandrogenism, ovarian tissue samples from prenatally androgenized (PNA) mice were subjected to miRNA-seq and RNA-seq analysis. Analyses were performed to identify differentially expressed microRNAs (DEmiRs) and differentially expressed genes (DEGs). In combination with our previous data obtained from clinical samples, we have performed an integrated miRNA-mRNA analysis of PNA mice and granulosa cells (GCs) from patients with PCOS. The changes in expression were validated by RT-qPCR in more mouse models and clinical samples.Results: In total, 3,432 genes and 16 miRNAs were differentially expressed in PNA mice compared with the control mice. We investigated the regulation pattern of miRNAs-mRNAs and observed a total of 12 miRNA-mRNA pairs involved in negative regulation. Functional analysis concentrated on insulin resistance, the T cell receptor signaling pathway, and other inflammation-related pathways. Verification of these results by RT-qPCR showed that the expression of miR-106-5p and miR-155-5p in clinical GCs was consistent with that in PNA mice. After predicting the target genes of miR-106-5p and miR-155-5p and performing negative regulation analysis, six target genes were obtained in GCs. The integration analysis showed that the network of miR-106-5p/miR-155-5p targets was mostly concentrated in pathway related to insulin resistance and inflammation. In addition, the upregulation of the inflammatory genes Il18/IL18 and Socs3/SOCS3 was validated in the PNA mice and GCs from patients compared with the appropriate control sample. The in vitro experiments showed that the regulatory relationship observed may be related to the direct stimulation of DHT.Conclusions: Our results showed that the miRNA-mRNA regulatory network in PCOS was associated with markers of insulin sensitivity and inflammation. Our study provides a new genetic basis and novel insight regarding the pathogenesis of PCOS.

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STAT1 Dissociates Adipose Tissue Inflammation From Insulin Sensitivity in Obesity

Cited by 31 publications

References 52 publications

A BAFF/APRIL axis regulates obesogenic diet-driven weight gain

A BAFF/APRIL axis regulates obesogenic diet-driven weight gain

Common and Novel Markers for Measuring Inflammation and Oxidative Stress Ex Vivo in Research and Clinical Practice—Which to Use Regarding Disease Outcomes?

Aberrant miRNA-mRNA regulatory network in polycystic ovary syndrome is associated with markers of insulin sensitivity and inflammation

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