Could SCGF-Beta Levels Be Associated with Inflammation Markers and Insulin Resistance in Male Patients Suffering from Obesity-Related NAFLD?

One of the pathologic hallmarks of obesity is macrophage infiltration of adipose tissue that has been confirmed as source of multipotent adult stem cells. Stem cell growth factor-beta (SCGF-β) shows activity on granulocyte/macrophage progenitor cells in combination with granulocyte macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF). Obesity-associated inflammation induces insulin resistance (IR), which is central to nonalcoholic fatty liver disease (NAFLD) or hepatic steatosis (HS). We searched for relationship between levels of SCGF-β and those of C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-β (TNF-β), interleukin-12p40 (IL-12p40), interleukin-10 (IL-10), ferritin, GM-CSF and M-CSF and between SCGF-β concentrations and IR in obese patients with HS. Eighty obese patients were retrospectively studied. Serum cytokines levels were appreciated by magnetic bead-based multiplex immunoassays. IR was evaluated by homeostatic model assessment (HOMA), HOMA-derived β-cell function (HOMA-B%), quantitative insulin sensitivity check Index (QUICKI) and single point insulin sensitivity estimator (SPISE). HS and spleen volume were assessed by ultrasonography (US). SCGF-β and IL-6 levels predicted HOMA values (p = 0.032 and 0.041, respectively) only in males. In male patients, CRP and IL-6 levels (p = 0.007) predicted SCGF-β concentrations (p = 0.03 and 0.007, respectively), which in turn predicted HS at US, p = 0.037. SCGF-β levels were linked to IR and HS severity with the mediation role of CRP. IL-10 levels negatively predicted SCGF-β concentrations (p = 0.033). M-CSF levels predicted serum concentration of both TNF-β and IL-12p40 (p = 0.00), but did not predict serum IL-10 (p = 0.30). Prediction of HOMA values by SCGF-β levels, likely mediated by markers of inflammation, characterizes this study, shedding some light on mechanisms inducing/worsening IR of male patients with obesity-related NAFLD.


Introduction
Indeed, there is a reduced group of studies appearing in literature concerning different settings and what is more, they are characterised by a surprising variability of the serum concentrations of this growth factor. For example, serum levels of SCGF-β ranged in patients undergoing bone marrow transplantation from 9760 ± 6810 to 25,010 ± 15,140 pg/mL [1]. Still, different levels of this cytokine were found in unstable asymptomatic carotid plaques compared to stable plaques, varying from undetectability to levels of 600 pg/mL [2]. Furthermore, SCGF-β was significantly increased in patients suffering from Chagas' disease with advanced heart failure compared to those without heart failure, exceeding 22,940 ± 2638 pg/mL, [3]. Recently, authors demonstrate that levels > 21,000 pg/mL) of serum SCGF-β are associated with non responsiveness to therapy of HCC [4]. SCGF-β is elevated in the circulation of patients with chronic spinal cord injury confronted with uninjured subjects, i.e., 47,037 pg/mL vs. 35,521 pg/mL [5]. Finally, Schirmer et al. found in plasma samples from human collateral circulation a median (interquartile) value of SCGF-β equal to 2624.00 (1646.38) pg/mL [6].

Aim
Considering that AT participates in inflammatory pathways [7] and recruitment of macrophages into AT involves interactions of innate and adaptive immunity in multiple organs, although the crosstalk between adipocytes and macrophages lays at its core [8,9], we asked ourselves whether SCGF-β could have a direct or indirect role in a new AT environment characterised by an inflammatory status, leading to IR. Table S1. Predictions of SCGF-β levels by indices of inflammatory responses. It is noteworthy that CRP is the stronger predictor, while IL-10 negatively predicted SCGF-β; d.v., dependent variable; i.v., independent variable. In bold are highlighted the significant ones. The low R-squared in presence of significance shows that even noisy, high-variability data can have a significant trend. The trend indicates that the predictor variable still provides information about the response even though data points fall further from the regression line in graph.  Table S4. Prediction of HOMA by SCGF-β, M-CSF, TNF-β, IL-12p40, IL-6 and IL-10. Apart the prediction of HOMA by IL-6, SCGF-β predicted sufficiently insulin resistance, evaluated as HOMA. On the basis of the prediction of HOMA by IL-6 the evaluation of a confounding variable, i.e., CRP was carried out, see Supplementary Table S9. The low R-squared shows that even noisy, highvariability data can have a significant trend. The trend indicates that the predictor variable still provides information about the response even though data points fall further from the regression line in graph; d.v., dependent variable; i.v., independent variable. In bold are highlighted the significant ones.

Conclusion
In other words, this is a possible example of an immunometabolic regulation. Anyway, it is still the case for expecting more confirmation from other studies, mainly on the side of gender difference, beyond a more compelling one from a purely mechanistic standpoint to give our hypotheses a greater construct.

Future directions
Being chronic inflammation a major factor in obesity and related co-morbidities, the hope is that some of the specific mechanisms could translate to optimising immune function in the obese during ageing in order to improve their health.

Methods
Measuring statistical associations, we chose a very powerful technique, i.e., regression, https://s3-eu-west-1.amazonaws.com/.../chapter_summary_ch13, which is used to identify the strength of the effect that independent variables have on a dependent variable. By the way, the predicted values do not depend on the order of predictors in the equation, in the sense that we are always solving the same equation. The statistical associations were performed separately on males and females, but presented as unique group or separate groups according to their significance.