455 and miR-1192 was up-regulated in PPARc DN animals whereas miR-592 was down-regulated in these mice compared to wt. After heterodimerization with the retinoic acid-like receptor (RXR), PPARc recognizes the peroxisome proliferator response element (PPRE), that is located in the promoters of many adipocyte-specific target genes and thereby acts as transcription activator recruiting other transactivators like PGC-1 [31]. Therefore the diet-independent downregulation of miR-592 in PPARc DN animals indicates that miR-592 expression is directly or indirectly (if e.g. co-expressed as an intronic miRNA within the transcript of a PPARc-responsive host gene) driven by PPARc. As miR-199a, miR-455 and miR-1192 were up-regulated in PPARc DN animals this may indicate that PPARc normally inhibits their expression directly (e.g. by recruiting transcriptional inhibitors to those promoters) or indirectly (by the PPARc specific transctiva- tion of a transcriptional inhibitor). Eleven of the 21 miRNAs were found to be up-regulated in these animals upon feeding a high fat diet, irrespective of the PPARc activity. Among those, let-7i, miR-146b, miR-152, miR-155, miR- 214*, miR-299 and miR-411 are similarly regulated in differentiating MSCs, whereas miR-421, miR-702 and miR-703 were oppositely regulated in MSCs. According to our statistical analysis, the regulation of miR-7b, miR27a and miR-34a is influenced by diet and genotype of the animals together. In PPARc-wt animals, administration of a high fat diet leads to significantly higher expression levels compared to lean control animals, whereas PPARc-dominant negative animals do not show increased expression levels of these microRNAs when receiving the same high fat diet. This indicated that PPARc activity is indispensable for the HFD induced expression of these three miRNAs. In a recent study investigating the influence of the body mass index (BMI) of obese and lean human donors on miRNA expression in the subcutaneous fat depot, miR- 34a was found to positively correlate with BMI .30.0 Kg/m2 [32]. On the other hand the expression levels of miR-34a remains constant in our leptin-deficient ob/ob mice as well as PPARc-dominant negative HFD animals in comparison to the respective control group even though the degree of obesity in these animals is at least comparable to or in the case of ob/ob mice much higher than in the group of PPARc-wt HFD mice. These findings suggest that miR-34a is only up-regulated in obese individuals having a normal genetic background and with normal levels of PPARc activity. Overall there were relatively few miRNAs that were similarly regulated in the ob/ob model and by HFD. This may be because References 1. Caballero B (2007) The global epidemic of obesity: an overview. Epidemiol Rev 29: 1–5. 2. 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Kumar P, Johnston BH, Kazakov SA (2011) miR-ID: a novel, circularization- based platform for detection of microRNAs. Rna 17: 365–380. PLoS ONE | www.plosone.org 11 June 2011 | Volume 6 | Issue 6 | e21305