We have shown that long term WL CR modulates adipocyte

We have shown that long-term WL/CR modulates adipocyte differentiation of ASCs in human sWAT by inducing both positive and negative regulators of the IGF-1 system at early stages of adipogenesis. Importantly, we identified DIRAS3 as novel negative regulator of adipogenesis, which slows down this process by inactivating Akt–mTOR signaling. Congruent with our data, it was shown in other cell systems that mTOR-induced adipogenesis is mediated partly by 4E-BP1 via regulation of the translation of PPARγ2 and by S6K1, which regulates the expression of early adipogenic transcription factors including C/EBPβ (Laplante and Sabatini, 2012). Moreover, in line with data showing that activated ERK can phosphorylate and thereby activate C/EBP-β (Park et al., 2004), we showed that DIRAS3 inhibits ERK phosphorylation in ASCs and this correlates with reduced C/EBPβ activation. Pro-adipogenic effects of IGF-1 have been shown in previous studies (Bäck and Arnqvist, 2009; Boucher et al., 2010). We extended this knowledge showing that IGF-1 can act as positive regulator of adipogenesis in primary human ASCs and simultaneously induces IGF-1R and DIRAS3, indicating an interplay between IGF-1 and DIRAS3 in modulating adipogenesis. The following are the supplementary data related to this article.
Author contributions
Acknowledgments This work was supported by intramural funding from the University of Innsbruck. The authors declare no conflict of interests.
Introduction With a rapid rise in number of type 2 diabetes (T2D) patients, diabetic nephropathy has become the leading cause of chronic kidney disease (CKD). In recent decades, CKD has been an important public health problem in both developed and developing countries (Levey and Coresh, 2012; Zhang et al., 2012). The evaluation of diabetic nephropathy depends on assessment of two markers, albumin colorimetric rate and glomerular filtration rate (GFR) (Jerums et al., 2009). It is generally believed that microalbuminuria is an early clinical manifestation of diabetic nephropathy, and that decreased GFR occurs secondarily, mainly in individuals with longstanding diabetes (Reutens, 2013). Randomized controlled trials (RCTs) have also shown that intensive diabetes treatment was associated with better renal outcomes, including lowering risk of albuminuria and increasing estimated GFR (eGFR) (de Boer et al., 2011; DCCT/EDIC research group, 2014; de Boer, 2014), suggesting a possible causal link between diabetes and renal outcomes. However, because conventional epidemiological studies are subject to a variety of bias such as confounding or reverse causation, and the RCTs are largely limited by short-term intervention, other novel approaches are needed to investigate the causal relation between T2D and renal dysfunction. Recently, the Mendelian Randomization (MR) approach has been widely used for assessing causality in population studies (Jansen et al., 2014; Ding et al., 2009). Because the genetic alleles are allocated randomly during gamete formation and are inherited independent of potential confounding factors and represented as a life-long exposure, using the genetic variants as the instrumental variable (IV) have become a widely-used approach for causal inference (Lawlor et al., 2008). In the present study, we performed a MR analysis to explore the causal relation between T2D and decreased eGFR and increased uACR, in a large community-based sample of Chinese participants. In order to reduce the statistical errors with multi-testing, we created a T2D genetic risk score (GRS) by using 34 T2D associated common variants that were identified in East Asians and represented the comprehensive genetic susceptibility of T2D, to be used as the IV (Palmer et al., 2012; Liu and Song, 2010). In addition, we also explored the genetic variations according to their roles in insulin secretion and insulin resistance.